PB93154680

GREAT LAKES WATER QUALITY INITIATIVE
CRITERIA DOCUMENTS FOR
THE PROTECTION OF HUMAN HEALTH
(February 1993 Draft)

REPRODUCED BY:
È lV fe
U.S, Department o l Commerce
National Teehnieel Information Service
Springfield, Virginia 22161

2/26/93

GREAT LAKES W A T E R QUALITY INITIATIVE
W A T E R QUALITY CRITERIA FOR P ROTECTION OF HUMAN HEAL T H
CRI T E R I A DOCUMENTS
Benzene ................................................

. . . .

1

. . . .

17

. ...

43

C h l o r d a n e .................................... ..
Chlorobenzene .........................................
Cyanides

..............................................

Dieldrin

..............................................

2 , 4-Dimethylphenol

.................................

. ...

51

2 , 4-Dinitrophenol

....................................

. .. .

57

. . . .

79

. . .

101

.................................

. . .

143

T o l u e n e ............................... .. ..............

. . .

157

Heptac h l o r

...........................................

H e x a c h l o r o b en z e n e ...................
H e x a c h l o r o e th a n e

. ............

....................................

Lindane ................................................
Mercury

................................................

M e t h y l e n e chloride
PCBs

(class)

.........................................

P e n t a c h l orophenol
2 , 3 , 7 , 8 —T C D D

.................................

. . .

....................................

T o x a p h e n e .............................................
T r i c h l o r o e t hy l e n e ....................................

October 23, 1991

GREAT LAKES INITIATIVE
T I E R I HUMAN HEALTH C RITERIA FOR
BENZENE
CAS NO. 71-43-2

T i e r 1 Human Noncancer Criterion

A c u t e exposure to benzene vapors by humans is often
associated w i t h neurot o x i c i ty ch a r a c t e r i z ed by loss of
sensation, vertigo, hea d a c h e and depres s i o n of the central
nervous system.

Hemat o p o i e t ic t oxicity

involving changes

in the bone marrow, spleen, and thymus has be e n a ssociated
with benzene exposure.

Benzene has al s o been found to cause

embryo/fe t o to x i c i t y in experimental animals

(EPA, 1980).

There are few chronic or oral studies a v a i lable w hich
examine the noncarcino g en i c effects of benzene.
subchronic oral study by Wolf et al.

The

(1956) was consi d e r e d

a ppropriate for Tier 1 HNC derivation.

In this study,

female W i star rats in groups of 10 were adm i n i s t e r e d benzene
in olive oil by gavage for 5 days/week for six months.
g r o u p of 20 rats served as controls.
10, 50, and 100 m g / k g / b w / d a y .

Dose levels we r e 0, 1,

During this p e riod

1

A

hemato l o g i c examinations were pe r f o r m e d on s elected animals.
Growth, body weight,

organ weights,

behavior,

urea nit r o g e n

in blood, histopat h o l og i c a l changes and bone m a r r o w counts
w e r e also evaluated.

Rats exposed to 50 and 100 m g / k g /d a y

exhib i t e d leukopenia and e r y t h r o c y t o p e n i a , whe r e a s these
e f fects were marginal in the 10 m g / k g / d a y group.

The l

m g / k g / d a y dose/level wa s considered the N O A E L for this
study.

This dose is equivalent to 0.71 m g / k g / d a y after

being adjusted for e xposure for only 5 days/week.

The findings of the Wolf et al.

(1956) study are s u p p orted

by the results of a chronic study by NTP
study, C 5 7 B L 1 6 N mice and F344 rats

(1986).

In this

(50 animals/sex/group)

were a d m i n i s t e r e d benzene orally at doses of 0, 50, 100 or
200 mg/kg,

5 days/week,

for 103 weeks.

A n additi o n a l group

c o n s i s t i n g of female rats an d mice of both sexes we r e
a d m i n i s t e r e d 25 mg/kg.

Blood was taken for ana l y s i s from 10

a n i m a l s / s e x /g r o u p at various times d u ring the study.

The

results of the study show e d dose - r e l a t e d leukopenia in rats
and mice of each sex for the first 18 m o n t h s of the study.
However,

at 24 months, the numbers of white b l o o d cells in

h i g h dose male rats, high dose female rats, a nd mid - d o s e
m a l e mice were higher than controls.

Numbers of w h i t e blood

cells in dosed female mice were not signi f i c a n t ly d i f f e r e n t
from controls.

2

H e m a t opoietic toxicity of benzene following exposure via
inhalation was reported by Deichmann et al.

(1963).

In this

study, groups of male and female S p r a g ue-Dawley rats were
exposed for 5 hours/day,

4 days/week for periods ranging

from 5 weeks to 7 months to benzene concentrations of 0, 15,
29, 31, 44, 47, 61, 65, or 831 ppm. Several hemat o l o g i c
parameters,

and other parameters including

body weight,

food intake and blood benzene levels were d e t e r m i n e d
perio d i c a l l y during the study.

Following 2-4 w e e k s of

exposure, groups exposed to benzene c o n c e ntrations of 61 to
831 p p m demonstrated a s i g nificantly increased level of
leukopenia.

Hematopoi e t ic effects w e r e mo d e r a t e in groups

exposed to 44 to 47 ppm for 5-8 weeks.

E xposure to 31 ppm

benzene for over 4 months did not induce changes in the
h e m a topoietic system and was considered a N O A E L for this
study.

Based on the conditions of exposure and an assumed

absorption factor of 50% (EPA, 1987), a N O A E L of 2.35
m g / k g / d a y was calculated.

This value is comparable to the

value calculated in the Wolf et al.

(1956) study.

EPA (1985) suggested that the Wolf et al.

(1956) a nd Chang

(1972) studies could be used to establish a range of
acceptable d a i l y intake

(ADI) values.

In the C h a n g (1972)

study 119 w o rkers occu p ationally exposed to benz e n e were
examined.

Hematologic al abnormalities we r e rep o r t e d in 28

of the workers exposed to benzene.
3

These abnor m a l i t i es

included 21 workers wi t h anemia,
w i t h anemia and leukopenia.

2 wi t h leukopenia, and 5

Based on an e stimate of

e x p osure d u r ation and benzene c o n c e n t r a t i on t he resear c h e r
d e r i v e d an exponential function which suggested a t h r eshold
level of 10 p p m for h e m a t o l o g i c effects.

This study was not

used for c r i t erion de v e l o p m e n t due to the route of exposure
and the absence of rel i a b l e data on the actual exposure
c o n c e n trations for the individual employees.

R o z e n et al.

(1984) e x amined the effect of inhalation

exposure to 0, 10, 31, 100 and 301 pp m benzene on B- and Tlymphocyte mito g e n - i n d u c e d b l a s t o g e n e s is in C57B1 mice.
Exposure to benzene at all doses for 6 h o u r s / d a y for 6 days
resulted in a signifi c a n t d e p r e s s i o n in femoral
lipopoly s a c ch a r i d e

(LPS)-induced B - colony forming ability

w h i l e total numbers of B - l ymphocytes we r e signi f i c a n t ly
d e p r e s s e d at 100 and 300 ppm.

Splenic p h y t o h e m a g g l u t i n i n

(PHA)-induced blastog e n e s is w a s signi f i c a n t ly d e p r e s s e d at
31,

100 and 300 p p m w h i l e total numbers of T - l y m p h o c y t es

w e r e signi f i c a n t ly de p r essed at 100 and 300 ppm.

Th i s study

was not used for risk asses s m e n t because it u s e d the
inhalation route of exposure and it is q u e s t i o n a b l e w h e t h e r
the e f fects p r o d u c e d in this study are b i o l o g i c a l l y
s i g n i f i c a n t and adverse.

4

Few studies using the oral route of exposure have e x amined
the reproductive/deve l o p m e n t a l effects of benzene.
and Staples
(790,

(1979)

administered 0.3,

Nawrot

0.5 or 1.0 m l / k g / d a y

1320 and 2640 mg/kg/day, respectively)

benz e n e to

p r e gnant CD-I mice during days 6-15 or 12-15 of gestation.
Despite some maternal lethality and e m b ryonic resorptions at
the two h i g h e r doses, no evidence of t e r a t o l o g y was seen.

ADE = 0.71 mq/kg/d = 0.00071 mg/kg/d
1000

Where:

U ncertainty Factor = 1000, c omposed of:
10 x for interspecies variability
10 x for intraspecies v a r i a b i l i t y
10 x for subchronic to chronic e x t r a p o l a t i on

Drinking W a t e r Sources:

HNV = ADE x Wh x RSC

= 0.00071 ma/kcr/d x 70 ka_________

w c + (FC X BAF)

2 1/d + (0.015 kg/d x 13 1/kg*)

= 0.0226 mg/1

(rounded off to 0.02 mg/1

5

(Tier 1))

N o n d r i n k i n g Water Sources:

HNV = A P E x Wh x RSC = 0.00071 ma/kcr/d x 70 ka________
W C + (FC x BAF)

= 0.242 mg/1

Where:

0.01 1/d + (0.015 kg/d x 13 1/kg*)

(rounded off to 0.2 mg/1

(Tier 1))

*BAF = 13 1/kg, p r ovided by EPA-Duluth and

M i n n e s o t a PCA.

Note:

A relative source contribution (RSC)

factor has not

been u t i l i z e d in these draft calculations.

REFERENCES:
Chang, I.W.
1972.
Study on the t h r eshold limit v alue of
b e n zene and early diagnosis of benzene poisoning.
J.
Cath. Med. Coll.
23:429.
Deichmann, W.B., W.E. MacDonald, and E. Bernal.
1963.
hemat o p o i e t ic tissue t oxicity of benzene vapors.
Toxicol. Appl. Pharmacol.
5:201-224.

The

International A g e n c y for R e s e a r c h on Cancer (IAR C ) . 1982.
IARC Monograph: E valuation of the C a r c i nogenic R i s k of
Chemicals to Humans, V o lume 29,
WH O Pub l i c a t i o n s
Center, USA, Albany, NY, pp 1-416.
National T o x i c o l o g y Program (NTP). 1986.
T o x i c o l o g y and
C arcinogenesis Studies of Benzene in F344/N Rats and
B6C3F1 Mice (Gavage S t u d i e s ) . NTP Technical Repo r t
Series. 289., National T oxicology Program, Re s e a r c h
T r i a n g l e Park, NC.
Nawrot, P.S. and R.F. Staples.
1979.
Embryo-fetal t o xicity
and t eratogenicit y of benzene and tol u e n e in the mouse.
Teratology.
1 9 :41a.

6

Rozen, M.G., C .A. Snyder, and R.E. Albert.
1984.
Depressions in B- and T-lymphocyte m i t o g e n - i n d u c e d
blastogenesis in mice exposed to low conce n t r a t i on s of
benzene. Toxicol. Letters.
20:343-349.
U.S. Environmental Protection Agen c y (EPA). 1987.
Integrated Risk Information System (IRIS d a t a b a s e ) .
Chemical file for benzene (CAS No. 71-43-2).
V e r i f i c a t i o n Date 10/9/87.
Last R e v i e w e d 10/9/87.
U.S. Environmental Protection A g e n c y (EPA).
1985.
Drinking
Water Criteria Document for Benzene (Final D r a f t ) .
U.S. Environmental Protection Agency, PB86-118122.
Washington, D.C.
U.S. Environmental Protection A g ency (EPA).
1980.
W a t e r Q u ality criteria Document for Benzene.
Washington, DC.
EPA 440/5-80-018.

Ambient

Wolf, M.A., V.K. Rowe, D.D. McCollister, R.L. H o l l i n g s w o r th
and F. Oyen.
1956.
Toxicological studies of certain
alkylated benzenes and benzene.
A.M.A. Arch. Indust.
Health.
14:357-398.
Tier l Human Cancer Criterion

A c c o rding to the weight - o f - e vi d e n c e m e t h o d for the
classification of carcinogens, benzene is a Class A
carcinogen
1989).

(known human carcinogen)

(IARC,

1982; EPA, 1987;

This is based on sufficient evidence from

epidemiologic studies on the incidence of non- l y m p h o c yt i c
leukemia from occupational exposure, and increased incidence
of neoplasms in rats and mi c e exposed to benz e n e by
inhalation and gavage

(EPA,

1987).

In addition, numerous

studies have found a significant increase in chromosomal
aberrations of bone m a r r o w cells and p eripheral lymphocytes
from w o rkers exposed to benzene

(IARC,

1982).

sufficient to d erive a Tier 1 HCC for benzene.
7

The data are

Numerous epidemiologic and case studies have shown a
relati o n s h i p between leukemia and exposure to ben z e n e (IARC,
1982).

The oral slope factor for benzene based on human

data is estimated to be 2.9E-2

(mg/kg/day)-1 (EPA, 1987).

The unit risk estimate is based on t h e g e o m etric mean of
four m a x i m u m likelihood p oint estimates using p o o l e d data
from the studies of Rinsky et al.

(1981) and Ott et al.

(1978)/ which was then a d justed for the results from the
Wong et al.

(1983) study as d e s c ribed by EPA (1987).

The slope factor of the dose- r e s p o n se curve for the
c a r cinogenic effects of benzene by the oral route,

2.9E-2

(mg/kg/day)-1 is used in the calculation of the HCC for
benzene.

RAD = l x 10 5______________
2.9E-2

(mg/kg/d)-1

= 0.0003448 m g / k g / d - 0.00034 m g / k g/day

D r i n k i n g W a t e r Sources:

HCV = RAD

X

Wh________ = 0.00034 mq/ k q / d x 70 kg_________

W C + (FC

X

= 0.0108 mg/1

BAF)

2 1/d + (0.015 kg / d x 13 1/kg*)

(rounded off to 0.01 mg/1

8

(Tier 1))

Nondrinking Water Sources:

H C V = RAD x Wh________ = 0.00034 ma/ka/d x 70 ka______________
WC + (FC x BAF)

= 0.116 mg/1

Where:

0.01 1/d + (0.015 kg/d x 13 1/kg*)

(rounded off to 0.1 mg/1

(Tier 1))

*BAF = 13 1/kg provided by E PA-Duluth and M i n n esota

PCA.

REFERENCES:
International A gency for Research on Cancer (IAR C ) . 1982.
IARC Monograph: Evaluation of the C a r c i n o g e n i c R i s k of
Chemicals to Humans; Volume 29, W HO Publications
Center, USA, Albany, NY, pp 1-416.
Ott, M.G., J.C. Townsend, W.A. F i shbeck and R.A. Langner.
1978.
M o r t a l i t y among individuals o c c u p a t i o n a ll y
exposed to benzene.
Arch. Environ. Health., 33: 3-10.
Rinsky. R . A . , R.J. Young and A.B. Smith.
1981.
Leukemia in
benzene workers. Am. J. Ind. Med.
2: 217-245.
U.S. Environmental Protection Agency
Effects Asses s m e n t for Benzene.
Cincinnati, OH.

(EPA). 1987.
H e alth
EPA/600/8-89/086.

U.S. Environmental Prote c t i o n A g e n c y (EPA).
1987.
Integrated Risk Information System (IRIS d a t a b a s e ) .
Chemical file for benzene (CAS No. 71-43-2).
Verifi c a t i o n Date 10/9/87. Last Rev i e w e d 10/9/87.
U.S. Environmental Prote c t i o n A g e n c y (EPA).
1980.
Water Q u ality Criteria Document for Benzene.
Washington, DC.
EPA 440/5-80-018.

Ambient

Wong, O . , R.W. Morgan and M.D. Wharton.
1983.
Comments on
the N IOSH study of leukemia in benzene workers.
Technical report submitted to Gulf Canada, Ltd., by
Environmental Health Associates.
9

10

S e p tember 6, 1991
GREAT LAKES I NITIATIVE
HUMAN HEALTH CRITERIA FOR
CHLORDANE
CAS NO. 57-74-9
Tier l Human Noncance r Criterion
A r eview of the available literature indicates that the most
appropriate study for H NC d erivation for c h l ordane is a
study conducted by Velsicol Chemical Corp o r a t i o n (198 3 a ) .
In this study,

80 Fischer 344 rats of each sex were

admini s t e r e d 0, 1, 5 or 25 p p m chlordane for 130 weeks.
Hematological,

biochemical, urinary and pathological

measur e m e n t s were made on eight a n i m a l s / s e x /g r o u p at w e e k s
26 and 52.

The same mea s u r e m e n t s were m a d e on animals which

survived to w e e k 130.
at 5 p p m

Liver hype r t r o p h y o c curred in females

(0.273 mg/kg/d) and a NO E L of 1 pp m (0.055 mg/kg/d)

was determined.

No liver lesions we r e found in ma l e rats

and a N O E L of 25 ppm (0.1175 mg/kg/d) was determined.

The N O E L for female rats is s l ightly lower t h a n the NOELs
determ i n e d for mice and dogs.

A 2 4 -month chronic study in

ICR mice found NOELs of 0.123 m g / k g and 0.138 m g / k g for male
and female mice, r e s p e c t i v e l y (Velsicol,

1983b).

A study

using Beagle dogs found NOELs of 0.06 m g / k g and 0.09 m g / k g
for m a l e and female dogs, respectively

ll

Preceding Page Blank

'\1

(Wazeter,

1967).

Data on the reproductive and developmental effects of
chlordane are limited.
et al.

A T S D R (1989)

cited a s tudy by Usami

(1986) which showed no malfor m a t i o ns in pups whose

dams were administered 20, 40 or 80 mg/kg/d ch l o r d a n e from
d a y 7 to 17 of gestation.

The finding of this study

suggests that exposure levels w h i c h m a y cause adverse
effects on develo p m e n t are h i gher than the N O E L c i t e d above
for the V e l sicol study (1983a).
C h e rnoff and K a vlock

Other studies r e p o r t e d by

(1982) and Ingle

(1952 as cited by EPA,

1990) also indicate that c riteria derived from the chronic
N O A E L of 0.055 m g / k g / d

(Velsicol,

1983a)

should be

protec t i v e of potential d e v elopmental effects.

The q u a l i t y of the V e lsicol

(1983a) rat study was deemed

sufficient to derive a Tier 1 HNC.
by EPA

This study was also used

(1989; 1990) to derive the oral RfD for chlordane.

The H N C was d e rived from the female rat N O E L u sing an
u n c e r t a i n t y factor of 100 to account for intraspecies
v a r i a b i l i t y and interspecies extrapolation.

ADE

=

0.055 m q /kq/ d

=

0.00055 m g / k g / d

=

100

Where:

U n c e r t a i n t y factor = 100, c o mposed of:
lOx for intraspecies variability
lOx for interspecies extrapolation
12

550 ng/kg/d

D r i n k i n g Water Sources:

HNV

=

ACE x l/i x RSC

=

UC + (FC x BAF)

=

550 ng/kg/d x 70 kg x 0.8__________
2 L/d + <0.015 kg/d x 219,375 l/kg*>

9.35 ng/l (rounded off to 9 ng/l (Tier 1))

N o n d r i n k i n g Water Sources:

HNV

=

APE x Uh x RSC

= 550 noAo/d x 70 kg x 0.8_____________

UC + (FC x BAF)

=

0.01 l/d + (0.015 kg/d x 219,375 l/kg*)

9.36 ng/l (rounded off to 9 ng/l (Tier 1))

Where:

RSC = 0.8; the substance is p e r s i s t e n t and

bioaccumulative.

*BAF = 219,375, provi d e d by EPA-Duluth and M i n n e s o t a PCA.

REFER E N C E S
A g e n c y for T o x i c Substances and Dis e a s e R e g i s t r y ( A T S D R ) .
1989. T o x i c ological Pro f i l e for Chlordane.
D e p a r t m e n t of
H e alth and H u m a n Services.
U.S. Public H e a l t h Service.
Chernoff, N. and R. J. Kavlock.
1982.
An in v i v o
teratology screenu t i l i zi n g pr e g n a n t mice.
J. Toxicol.
Environ. Hlth.
10:541-550.
Ingle, L.
1952.
Chr o n i c oral t o xicity of c h l o rdane to
rats.
Arch.Ind. Hyg. Occup. Med.
6:357-367.
U.S. Environmental Prote c t i o n A g e n c y ( EPA). 1989.
Integrated R i sklnf o r m a ti o n Syst e m (IRIS d a t a b a s e ) .
Chemical file for chlordane (57-74-9).
V e r i f i c a t i o n Date
3/22/89.
Last Revised 7/1/89.

13

U.S. Environmental Protec t i o n Agency (EPA). 1990.
Drinking
Water Criteria Document for Heptachlor, Heptac h l o r
Epoxide and Chlordane.
Revised November, 1990.
ECAOCIN-406.
Usami, M . , K. K a w a s h i m a , S. Nakaura, et al.
1986.
Effects
of chlordane on prenatal d e v elopment of rats.
(Abstract).
Eisei Shikenso Hokoku.
104:68-73.
Velsicol Chemical Corporation.
1983a.
Yonemura, T . , F.
T a k amura and Y. Takahashi.
Thi r t y - m o n t h chronic
t o x icity and tumor i g e n i c it y test in rats by chlordane
technical.
(Unpublished study by Res e a r c h Institute
for Animal Science in B i o c h emistry and Toxicology,
Japan).
V e l sicol Chemical Corporation.
1983b.
Inui, S., K.
Yamazaki, T. Yonemura, et al.
T w e n t y - f o u r month
chronic toxicity and tumor i g e n i c it y test in mice by
chlordane technical.
(Unpublished study by Research
Institute for A ni m a l Science in Biochemistry and
Toxicology, J a p a n ) .
Wazeter, F.X,
1967.
T wo-Year Chronic Feeding Study in the
Beagle Dog. Sponsored by V e lsicol Chemical C o r poration
(Unpu b l i s h e d) .
T i e r 1 H u m a n Cancer Criterion
There are inadequate data available to d e t e r m i n e w h e t h e r
chlordane is a human c arcinogen (EPA, 1987; 1990).
studies using four strains of mi c e

Chronic

(CD-I, B6C3F1, C5781/6N,

ICR) of both sexes ha v e shown an increase in th e occurrence
of liver tumors.

Addit i o n a l w e i g h t - o f - e vi d e n c e for

c hlordane's c arcinoge n i ci t y is p r ovided by its structural
s i m i l a r i t y t o other compounds
heptachlor)

(i.e., d i e l d r i n and

w h i c h have been found to induce h e p a t o c e l l u la r

carcinomas in mice.

The results of various m u t a g e n i c i t y

studies are inconclusive as to this chemical's abi l i t y to
cause m u t a g e n i c effects.

The w e i g h t - o f - e vi d e n c e for

14

chlordane carcinogenici t y is sufficient for B2
human carcinogen)

(probable

clas s ification (EPA, 1986; 1987; 1990).

The data are sufficient to derive a Tier 1 HCC.

Two key studies
1986)

(NCI,

1977; Velsicol,

1973 as cited in EPA,

found a significant increase in hepat o c e l l u la r

carcinomas in treatment groups w h e n co m p a r e d to controls.
Both studies also showed a d o s e - r e s p o n se r e l a t ionship
b e t w e e n exposure of mice to chlordane and the occur r e n c e of
liver tumors.

EPA (1986; 1987; 1990) c a l c u l a t e d four

separate slope factors from t hese k ey studies, and deri v ed a
recomm e n d e d slope factor of 1.3

(mg/kg/d)

geome t r i c m e a n of these slope factors.

^ from the

This m e t h o d of

computing a slope factor is used "in situations w h e r e no
single study is judged most appropriate, y et several studies
colle c t i v e l y support the estimate ..."

(EPA, 1989).

A c c o r d i n g to EPA (1989), the advantage of this m e t h o d of
d e termining the slope factor is th a t all rel e v a n t data are
used in the computations.

RAD

-5
= 1 x 10— ______

=

7.7 x 10

-6

mg/kg/d

=

7.7 ng/kg/d

1.3 (mg/kg/d) 1

Drinking W a t e r Sources:

HCV

s

RAD x Uh______
WC + (FC x BAF)

=

7.7 na/ka/d x 70 kg_________________
2 l/d + (0.015 kg/d * 219,375 l/fcg*)

15

0.16 ng/l (rotnded off to 0.2 ng/l (Tier 1))

Nondr i n k i n g W ater Sources:

HCV

■

RAD x Wh______
WC + <FC x BAF)

■

=

7.7 no/ka/d x 70 kg_____________________
0.01 l/d + <0.015 kg/d x 219,375 l/kg*>

0.16 ng/l (rotxided off to 0.2 ng/l (Tier 1))

*BAF = 219,375, provid e d by EPA-Duluth and M i n n e s o t a PCA.

REFERENCES:
N a t ional Cancer Institute (NCI).
1977.
B i oassay of
Chlordane forpossible carcinogenicity.
NCI
Carcinogenesis
Tech. Rep. Ser. No. 8.
U.S. DHEW
Publ. No. (NIH) 77-808. Bethesda, MD.
U.S. Environmental Protec t i o n A g e n c y (EPA). 1986.
C a rcinogenicityAs s e s s m e n t of Chlordane and
Heptachl o r / He p t a c h l o r Epoxide.
Carcinogen A s s e s s m e n t
Group.
O ffice of Heal t h and Environmental Assessment,
Washington, DC.
U.S. Environmental P ro t e c t i o n A g e n c y (EPA).
1987.
Integrated R i s k Information System (IRIS d a t a b a s e ) .
Chemical file for chlordane (57-74-9).
Verification
Date 4/1/87.
Last R e v i s e d 1/1/91.
U.S. Environmental Protection A g e n c y (EPA).
1989.
Risk
A s s e s s m e n t Guidan c e for Superfund.
V o l u m e 1. Human
H e a l t h Evaluation Manual (Part A).
Int e r i m Final.
OERR.
E P A / 540/1-89/002.
U.S.

Environmental Prote c t i o n A g e n c y (EPA).
1990.
Drinking W ater Criteria Document for Heptachlor,
Heptac h l o r Epoxide and Chlordane.
R e v i s e d November,
1990.
ECAO-CIN-4 06.

16

N o v e m b e r 1, 1991
GREAT LAKES INITIATIVE
TIER 1 HUMAN HEALTH C R I T E R I A FOR
CHLOROBENZENE
CAS NO.

108-90-7

Tier l Human Noncance r criterion

A r e v i e w of the available literature indicates inadequate
h u m a n data for quantitative risk asses s m e n t of
chlorobenzene.

Humans exposed o c c u p a t i o n a ll y to

chlo r o b e n z e ne intermittently for up to 2 years d i s p layed
signs of neur o t o x i c i t y including numbness,

c y anosis

(from

d e p r e s s i o n of the resp i r a t o r y c e n t e r ) , h y p e r e s t h e s ia and
m uscle spasms

(Rozenbaum,

1947, as cited in ATSDR,

1990).

While these findings provide quali t a t i v e e v idence that
c h l o robenzene is pote n t i a l l y neurotoxic,

specific exposure

levels are not available to support quan t i t a t i v e risk
assessment.

Several animal studies were identified d u r i n g a r e v i e w of
the available literature.

The mo s t appro p r i a t e basis for

HNV derivation for chlorobenzene is the N O A E L from a
subchronic dog study by M o n s a n t o Comp a n y
adult pure-bred beagle dogs

(1967).

Young

(4/sex/group) were a d m i n istered

c h l o robenzene in gelatin capsules,
17

5 d a y s / w e e k at doses of

0, 0.025,

0.050 and 0.250 ml / k g / d a y (converted per EPA

(1989a) to 0, 27.25,
for 13 weeks.

54.5 and 272.5 mg/kg/day,

respectively)

Four high-level dogs died or were sacrificed

in m o r i b u n d condition between the third and fourth weeks of
the study.

These deaths were preceded by anorexia,

d e c r e a s e d activity, body w e i g h t loss, cachexia and coma.
The four surviving high-level dogs exhibited te m p o r a r y lack
of appetite and body w e ight loss.

Changes in hematology,

clinical chemistry and urine analyses were observed at the
high dose.

Pathologi c changes in the liver, kidney,

g a s t r o i ntestinal mucosa,

and hemat o p o i e t ic tissue we r e also

observed in high-dose animals.

At 54.5 mg/kg/day,

slight

h e patic alterations we r e observed, and severe cellular
variations in the epithelium of the terminal p roximal tubule
in the k i d n e y were also observed.

The N O A E L a nd L O A E L for

this study w e r e 27.25 and 54.5 mg/kg/day, respectively.

The d a t abase is judged to be sufficient for Ti e r 1 HNC
derivation.

The key study

(Monsanto,

1967) p r ovides a

subchronic NOAEL w h i c h is supported by additional data.

In a r a t study p e r f o r m e d by Mon s a n t o Company and abstra c t e d
by K n a p p et al.

(1971), significant elevations we r e n o t e d in

liver and k idney weights of rats administered Diet a r y levels
of 100 and 250 mg/kg/ d a y for 93 to 99 consecutive days.
r emarkable histopatho l og i c findings were reported.

18

No

No

effects were noted among rats r e c e iving 12.5 or 50
mg/kg/day.

The NOAEL and L OAEL for this study w e r e 50 and

100 mg/kg/day, respectively

(EPA,

1989a).

The authors

concluded that in compa r i s o n to rats, dogs di s p l a y e d a
higher sensitivity to chlorobenzene toxicity.

In a chronic study by the National T o x i c o l o g y Pro g r a m
1985), groups of F344/N rats and B6C3F1 mi c e

(NTP,

(50/sex/dose)

w e r e administered chlorobenzene by gavage in corn oil 5
days/week for 103 weeks.

The male and female rats received

0, 60 or 120 mg/kg/day; the female mi c e r e c e i v e d 0, 60 or
120 m g / k g / d a y and the male mice rec e i v e d 0, 30 or 60
mg/kg/day.

A statisti c a l ly sign i f i c a n t d ecrease in the

survival of high-dose ma l e rats was observed.

Histological

exami n a t i o n of the liver showed h e p a t o c e l l u la r necrosis,
g raded as m i nimal to mild, in all groups.

In m a l e mice,

m o r t a l i t y at both dose levels w as increased to a
statistically significant level.

N o other chlor o b e n z e ne -

r e lated clinical toxicity w as observed in mice.

Several reproductive and d e v elopmental studies ha v e been
p e r f o r m e d with chlorobenzene.

John et al.

(1984) exposed

Fischer 344 rats and N ew Zealand White rabbits by inhalation
to chlorobenzene for 6 h o u rs/day at doses of 0, 75, 210 or
590 ppm during periods of major organogenesis.

E xposure to

590 p p m caused elevated liver weights in bo t h species and

19

decreased body weight gain and feed cons u m p t i o n in rats.
The developmental N O A E L was 590 p p m for both species
(equivalent to 216 m g / k g / d a y for rats and 125 m g / k g / d a y for
rabbits, as per EPA, 1 9 6 9 a ) .

T he maternal N O AELs were 210

ppm

(equivalent to 77 mg/kg/day,

EPA,

1989a)

as per EPA,

as per

for rats and 75 p p m (equivalent to 16 mg/kg/day,
1989a)

for rabbits.

In a t w o - g eneration r e p r o d u c t i o n inhalation s tudy in rats
(Nair et al.,

1987) groups of 30 male and 30 female sprague-

D a w l e y CD rats

(FQ generation) we r e exposed to chlor o b e n z e ne

at target c o n c e ntrati on s of 0, 50, 150 or 450 p pm for 10
w eeks p r i o r to m a t i n g and d u r i n g mating, gestation,
lactation.

Groups of 30 m a l e and 30 female

.

and

animals were

e x posed to the same c o n c e ntrations of c h l o r o b e n z e ne as the
F 0 parents,

initiated 1 w e e k p o s t w e a n i n g and lasting through

mating, g e s t a t i o n and lactation.

H e p a t o c e l l u la r h y p e r t r o p h y

and renal changes w e r e observed among F q and F^ m a l e rats
e x p osed to 150 and 450 p pm but exposure of rats to
c h l o r o b e n z e ne at levels of 50, 150 or 450 p p m did not have
any a d verse effects on rep r o d u c t i v e p e r f o r m a n c e or fertility
of male and female rats.

A rep r o d u c t i v e N O A E L of 165

m g / k g / d a y and a systemic N O A E L of 18 m g / k g / d a y (conversions
w e r e from EPA,

1989a) were d e t e r m i n e d from this study.

20

The H N V is derived from the NOAEL dose of 27.25 m g / k g / d a y
(converted to 19.46 m g / k g / d a y for 5 d a y s /week
administration)
Company

from the 13-week dog study by M o n s a n t o

(1967) with an uncertainty factor of 1000.

from other studies

(John et al.,

Data

1984; Nair et al., 1987)

suggest that this value will be protective of
r e p r o d u c t i v e/developm e n t a l effects.

This approach is

consis t e n t w i t h the risk assessment of ch l o r o b e n z e ne for the
d e r i v a t i o n of the oral RfD, d r i n k i n g water equiva l e n t level
( DWEL), and m a x i m u m contaminant level goal
(EPA,1989a; EPA,

1989b; EPA,

(MCLG)

by EPA

1989c).

ADE = 19.46 m a / kq/d = 0.019 mg / k g / d a y
1,000

Where:

Uncer t a i n t y Factor = 1,000, composed of:
lOx for intraspecies v a r i a b i l i t y
lOx for interspecies e x t rapolation
lOx for subchronic to chronic e x t r a p o l a t i on

Drinking W a t e r Sources:

H N V = ADE x W h x RSC
W C + (FC x BAF)

= 0.49 mg/1

= 0,019 m a / k a / d x 70 ka________
2 1/d + (0.015 kg/d x 49 1/kg*)

(rounded off to 0.5 mg/1
21

(Tier 1))

N o n d r i n k i n g W a t e r Sources:
H N V = A P E x Wh x RSC
W C + (FC x BAF)

= 1.79 mg/1

Where:

= 0.019 mq/k o / d x 70 kg_________
0.01 1/d + (0.015 kg/d x 49 1/kg*)

(rounded off to 1.8 mg/1

(Tier 1))

*BAF = 49, pro v i d e d by EPA-Duluth and Mi n n e s o t a PCA.

NOTE:
A Relative Source Contribution (RSC) factor has not
been utilized in these draft calculations.

REFERENCES:
A gency for Toxic Substances and Disease R e g i s t r y (ATS D R) .
1990.
Toxicological Profile for Chlorobenzene.
U.S.
Public Health Service.
ATSDR/TP-90/06.
John, J . A . , W.C. Hayes, T.R. Hanley, Jr., K.A. Johnson, T.S.
G ushow and K.S. Rao.
1984.
Inhalation t e r a t o l o g y
study on monoch l o r o b en z e n e in rats and rabbits.
Toxicol. Appl. Pharmacol.
76(2):365-373.
Knapp, Jr., W.K., W.M. Busey, and W. Kundzins. 1971.
Subacute oral tox i c i t y of mo n o c h l o r o b en z e n e in dogs and
rats. Toxicol. Appl. Pharmacol. 19:393.
Nair, R.S., J.A. Barter, R.E. Schroeder, A. Knezevich, and
C.R. Stack. 1987. A two-g e n e r a t io n r e p r o d u c t i o n study
w i t h monochlo r o b en z e n e vapor in rats. Fundam. Appl.
Toxicol. 9(4):678-686.
National Toxicology Program ( NTP). 1985.
To x i c o l o g i c al and
C a r c i nogenesis Studies of Chlorobenzene in F 3 4 4 / N Rats
and B6C3F1 M i c e (Gavage Studies).
N T P - T R No. 261, NIH
P ublication No. 86-2517.
Rozenbaum, N.D., R.S. Blekh, S.N. Kremneva, et al.
1947.
[Use of chlorobenzene as a solvent from the standpoint
of industrial hygiene.]
Gig. Sanit.
12:21-24.
(Russian)
As cited in ATSDR (1990).

22

U.S. Environmental Protection A g e n c y ( E P A ) . 1989a.
Integrated Risk Information System (IRIS d a t a b a s e ) .
Chemical file for chlorobenzene (108-90-7).
Verification Date 1/19/89.
Last R eviewed 1/19/89.
U.S. Environmental Protection A g ency (EPA).
1989b.
Monochlorobenzene.
54 FR No. 97. pp. 22087-22088.
22, 1989.

May

U.S. Environmental Protection A g ency ( E P A ) . 1989c.
Heal t h
Effects Assess m e n t for Chlorobenzene.
PB90-142514/XAD.
E P A / 60/8-89/099

23

24

October 23, 1991
G R E A T LAKES INITIATIVE
TIER 1 H U M A N H E ALTH C R ITERIA FOR
CYANIDES
CAS NO. 57-12-5
Tier 1 yum»« Noncancer Criterion
A r e v i e w of the available literature indicates inadequate
human data for quanti t a t i v e risk a ssessment of cyanides.
Q u a l i t a t i v e data suggest that chr o n i c d i e t a r y exp o s u r e to
n a t u rally occurring cyanogens in cassava results in thyroid
a b n o rmalities in A f r i c a n countries where cassava is a staple
crop.

Effects seen,

including endemic goiter,

c r e t i n i s m and

con genital hypothyroidism, were p o t e n t i a t e d b y low iodine
intake and other dietary deficiencies.

Tropical ataxic

n e u r o p a t h y has also been linked to chronic cyan i d e ingestion
from cassava derivatives

(Njoh, 1990).

However, these data

do not provide a dose- r e s p o n se rela t i o n s h i p
1985b; ATSDR,

1988; Njoh,

(EPA, 1985a;

1990).

Fro m animal studies on the chronic oral tox i c i t y of
inorganic salts of cyanide, the mo s t appr o p r i a t e basis for
H N V deriv a t i o n for cyanides is the H N O A E L from the chronic
rat feeding study of Howard and H a nzal
rats

(10/sex/group)

(1955).

Weanling

were offered food fumigated w i t h

hydrogen cyanide at dietary concentrations of 100 and 300
p p m HCN, averaging 73 and 183 mg C N “ /kg diet)

for tw o years.

Dose levels were approximately 4.6 or 10.8 m g C N ~ / k g bw/d a y
25

Preceding Page Blank

to females, and 3.6 or 7.5 mg C N “ /kg bw/day to males
1985b, 1990).

(EPA,

At termination, h e m atological values were

w ithin normal limits and neither gross nor micro s c o p i c
e x amination of tissues

(including thyroid)

revealed evidence

of patho l o g y due to e x posure in any of the exposure groups.
Therefore, the H N OAEL from this study is 10.8 m g CN~/kg
bw/day.

The database is judged to be sufficient for Tier 1 HNC
derivation.

The key study (Howard and Hanzal,

1955)

p r o vides a chronic HNOA E L w h i c h is supported and
s u p plemented by other data.

In a chronic study (Philbrick et al.,

1979), t en male

w e a n l i n g rats were given 1500 p p m p o t a s s i u m cyan i d e in the
diet for 11.5 months.

The administered dose was

a p p r oximately 75 mg K C N/kg bw/day,

or 30 m g C N “ /kg bw/day

(ATSDR,

The cyanide exp o s u r e in

1988; EPA, 1985a; 1 9 8 5 b ) .

rats r e c e iving either normal or restr i c t e d diet r esulted in
reduced body w e i g h t gain, d e c r e a s e d thyr o i d g l a n d activity
and increased thyroid weights.

In a study by Tewe and Maner
pigs

(1981b), p regnant Yorkshire

(6/dose group) were fed fresh cassava diets c ontaining

0, 276 or

521 mg cyanide

(added as KCN) per kg of fresh

cassava o f f ered during gestation and parturition,
26

on the

110th day of gestation,

two gilts per dose g r o u p were

sacrificed and the fetuses were evaluated.

The r e m a i n i n g

gilts in each dose gro u p were allo w e d to n a t urally deliver
and were then mainta i n e d on a diet w i t h no cyanide
throug h o u t the 56-day lactation period.

No serious

interference was observed with the p r o d u c t i o n of the first
litter of o f f s pring by gilts r e c e iving cassava diets
contai n i n g up to 521 p p m added cyanide duri n g gestation.
Gilts in the high dose group, e x h i bited p o ssible adverse
effects on the thyroid (increased weight)
(proliferation of glome r u l a r c e l l s ) .

a nd k i d n e y

The h i g h exposure

level also suggests a L OAEL for devel o p m e n t al effects, as
the 110-day-old fetuses had decreased relative spleen,
thyroid and heart weights.

The evi d e n c e that the thyroid

m a y be a sensitive target organ in pigs lends support to the
thyroid effects reported by J a c k s o n (1988; see later
discussion).

However, data i nterpretation is d i f f i c u l t due

to the small number of gilts ev a l u a t e d (2/dose g r o u p ) .

The

a d ministered levels of 276 and 521 p p m C N ” in the diet
convert to 7.7 and 17 mg C N ” /kg b w / d a y for the gilts, using
the r e p orted animal bo d y weights a nd food intake from the
study.
diet,

The N O A E L for this study was 276 pp m C N ” in the
or approximately 7.7 m g C N “ /kg bw/day.

A n o t h e r developmental study

(Tewe and Maner,

1981a)

reports

that 500 p p m K C N administered in the diet to rats resulted
27

in a d e c r e a s e d protein e fficiency ratio among offspring
d u r i n g the p ostweanin g growth phase.

The dose level has

been c o n v erted to appro x i m a t e ly 50 mg C N “ /kg/day ass u m i n g a
10% food c onversion factor

(ATSDR,

1988), or ap p r o x i m a t e ly

10.6 mg C N~/kg/day per EPA (1985b).

Other a v a i lable oral studies are mo r e limited in design,
including the only relevant study w i t h d r inking water
exposure.

Palmer and Olson

(1979) gave 7 male Sprague-

D awley rats 200 mg/1 KCN in w a t e r
/kg/day per EPA,

1985a)

(or 80 mg/1 C N “ ; 10 mg C N ”

or 200 p p m KCN in diet

food; 8 mg C N “ /kg/day per EPA,

1985a)

(80 m g C N “ /kg

for 21 days.

A t the

end of the study, the only p arameters e v a l uated were body
w eight and liver weight.

Liver weights we r e increased over

controls following drinking w a t e r exposure only.

Alt h o u g h

inadequate for criteria derivation, this study suggests that
cyanide via drinking w a t e r is more potent for inducing
eff ects than feeding studies,

but is less p o t e n t th a n gavage

exposures.

In another notewo r t h y but limited study, the effects of oral
cya nide on g l ucose metabolism, thy r o i d function and an array
of b ehavioral indices were evaluated in m i n i a t u r e pigs
(Jackson,

1988).

Three swine/dose g r o u p (mixed sexes)

received 0, 0.4, 0.7 or 1.2 mg C N ” /kg/day by intraoral bolus
as K C N in aqueous solution, daily for 24 weeks.

28

The author

reports that treatment resulted in a d o s e - r e l a t e d increase
in the fasting blood glucose level, dose - r e l a t e d decreases
in T 3 and T 4 thyroid hormones,
behaviors.

and numerous altered

By Chi-square analyses these chan g e s were

determ i n e d to be significant, even in the low e x p o s u r e group
w i t h r egard to some parameters.

The alte r a t i o n s noted were

more p ronounced in the high-dose group, p a r t i c u l a r l y for
thyroid hormone levels, the pa r a m e t e r mo s t clearly
indicative of adverse effects.

Suppression of T 3 and T 4 was

dose-r e l a t e d w i t h a mu c h stronger response in the hi g h - d o s e
group

(roughly double the effect seen in the mid - d o s e g roup

at 24 w e e k s ) .

However, the limitations of the s tudy design

and r e p o r t i n g are substantial
communication).

(Papa, 1990, personal

Some of the m o s t critical defi c i e n c i e s in

d esign or r e p o rting include: small animal numbers per group;
lack of body weight and organ w e ight data; e x posure pattern
as a single daily bolus dose; uncl e a r biological
significance of the re ported biochemical effects; no report
of the variance about the m e a n for T 3 , T 4 , and blood glucose
values; and the distr i b u t i o n of sexes among t he four groups
was not reported.

The latter point appears critical because

from the 12 animals d i s tributed evenly among t he four
groups, five were females, and seven we r e c a s t r a t e d males.
The castrated m ales were, therefore, une v e n l y r e p resented
among the groups and the castration effect on t h y r o i d levels

29

and behavior is likely to be significant

(Papa,

1990,

personal c o m m u n i c a t i o n ) .

The 2-year dietary exposure study by Howa r d and Hanzal
(1955) has been selected as the key study for the derivation
of the risk assessmen t of cyanide in drinking water by EPA
(1985a,

1985b,

1990).

Those assessments have applied an

additional uncertaint y factor of 5 due to the d i e t a r y meth o d
of exposure.

This is intended to account for the relative

tolerance to cyanide when it is ingested wi t h food rather
than w h e n it is ingested in d r inking water.

T he v alue of 5

was based on an evalu a t i o n of c y a nide-binding affinity of
food and the GI absor p t i o n of cyanide in food versus
drink i n g water by Dr. Ernest Foulkes of the U n i v e r s i t y of
Cincinnati who served as an external reviewer for EPA
(1985a)

(Papa,

1990, personal communication).

This 5-fold

(or 20%) a djustment factor for differential b i o a v a i lability
b e t w e e n cyanide in feed a nd in drinking water is c o n c luded
to be a p propriate and s cientifically supportable in a more
r ecent analysis

(Pearsall and Chrostowski,

1990).

The HNC is therefore derived from the H N OAEL dose of 10.8 mg

CN"/kg/day in rats via feed (Howard and Hanzal,
an u ncertainty factor of 500.

1955), and

This consists of the 5-fold

30

adjustment discussed above, and inter- and intraspecies
extrapolation.

A D E = 10.8 m a CN~/kq/d = 0.0216 mg/k g / d
500

Where:

Uncert a i n t y Factor = 500, composed of :
lOx for intraspecies v a riability
lOx for interspecies extrapolation
5x adjustment for bioavailability,

feed vs. drinking

water

Drinking Water Sources:

HNV = ADE x Wh x RSC

= 0.022 m a / k a / d x 70 kg__________

w c + (FC x BAF)

2 1/d + (0.015 k g / d x 1 1/kg*)

= 0.75 mg/1

(rounded off to 0.8 mg/1

(Tier 1))

Nondri n k i n g Water Sources:

HNV = A D E x W h x RSC
W C + (FC x BAF)

= 60.5 mg/1

= 0.022 ma/ k a / d x 70 kg______________
0.01 1/d + (0.015 kg / d x 1 1/kg*)

(rounded off to 60 mg / 1

31

(Tier 1))

Where:

*BAF = 1.0 by default.

Per EPA-Duluth and M i n n esota

PCA, there are insufficient data to derive a BAF.

NOTE:

A Relative Source Contribution (RSC) factor has not

been utilized in these draft calculations.

REFERENCES:
A g e n c y for Toxic Substances and Disease Re g i s t r y (ATSDR).
1988.
Toxicological Profile for Cyanide.
U.S. Public
Health Service.
ATSDR/TP-88/12.
Howard, J. and R. Hanzal.
1955.
Chronic to x i c i t y to rats
of food treated w i t h hyd r o g e n cyanide.
J. Agric. Food
Chem. 13:325-329.
Jackson, L.
1988.
Behavioral effects of chronic sublethal
d i etary cyanide in an animal model:
implications for
h umans consuming cassava (Manihot esculents ) . H u m a n
Biology
60(4):597-614.
Njoh, J.
1990.
Tropical ataxic neuro p a t h y in Liberians.
Trop. Geogr. Med.
42(1):92-94.
Palmer, I. and O. Olson.
1979.
Partial preven t i o n by
c y anide of selenium p o i s oning in rats.
Biochemical
B iophysical R e s ea r c h Comm.
90(4):1379-1386.
Papa, L.
1990.
U.S. EPA, ORD, R e s e a r c h Physiologist.
Personal communic a t i on w i t h R. Sills, M i c h i g a n
D e p a r t m e n t of Natural Resources.
Pearsall, L. and P. Chrostowski.
1990.
The oral
b i o a v a i l a b i li t y of cyanide.
U n p ublished report.
P r e p a r e d by Clement Assoc., Inc., for Boston Gas Co.,
Boston M A .
Philbrick, D. et al.
1979.
Effect of p r o l onged cyanide and
thiocy a n a t e feeding in rats.
J. Toxicol. Env. Health
5:579-592.
Tewe, 0. and J. Maner.
1981a.
L o n g -term and carry-over
effect of dietar y inorganic cyanide (KCN) in the life
cycle performance and metab o l i s m of rats.
Toxicol.
A p p l i e d Pharmacol.
58:1-7.
.
32

Tewe, 0. and J. Maner.
1981b.
Performance and
pathophysiologic a l changes in pregnant pigs fed cassava
diets containing different levels of cyanide.
Res.
Vet. Sci.
30(2): 147-151.
U.S. Environmental Protection A g e n c y ( EPA). 1985a.
Drinking Water Criteria Document for Cyanide.
Final
Draft.
N T I S . EP A - 6 0 Q / X - 8 4 - 192-1.
PB 86-117793.
U.S.

Environmental Protection Agen c y (EPA).
1985b.
Integrated Risk Information System (IRIS d a t a b a s e ) .
Chemical file for Cyanide, free (57-12-5).
V e r i f i c a t i o n Date 8/5/85.
Last Rev i e w e d 8/5/85.

U.S. Environmental Protection Agen c y (EPA).
1990.
Federal
Register 55(143):30370-30448.
July 25, 1990.
National
P r imary and Secondary Drinking Water Regulations;
Synthetic Organic Chemicals and Inorganic Chemicals.
.
Proposed Rule.

33

34

/

S e p t ember 6, 1991
GREAT LAKES INITIATIVE
HUMAN HEAL T H C R ITERIA FOR
P ,P 7- D I C H L O R O D I P H E N Y L T R I C H L O R O E T H A N E
CAS NO.

(DDT)

50-29-3

Tier l Human Noncance r C r i terion

A r e v i e w of the available literature indicates that the most
app rop r i a t e basis for HNC d e r i v a t i o n for DD T is the N O A E L
from the subchronic rat feeding study of Laug et al.
W e a n l i n g rats

(1950).

(15/sex/group) were fed c o m m e r c i a l - gr a d e DDT

(81% p ,p '- D D T , 19% o,p'-DDT)
p p m for 15-27 weeks.

at levels of 0, 1, 5, 10 or 50

The critical toxic effect was liver

toxicity, demons t r a t e d as r e l a t i v e l y mild d o s e - d e p e n d en t
h i s t o p athologic changes in h e p atocytes at doses of 5 ppm and
higher.

These included hepat o c e l l u la r hypertrophy,

increased cytoplasmic oxyphilia,
cytoplasmic granules.

and p e r i p h e r a l b asophilic

The NOEL w as 1 ppm,

or 0.05 m g / k g

bw/day a s s uming a food c o n sumption rate of 5% bo d y w e i g h t
per day.

The LOAEL was 5 ppm

(0.25 m g / k g bw/day).

T h e datab a s e is judged to be s ufficient for T i e r 1 HN C
derivation.
subchronic

The key study

(Laug et al.,

1950) p r o v i d e s a

(greater than 90 day) N O E L w h i c h is supported and

s u p plemented by other data.

In a 2-year rat d i e t a r y e x posure
35

Preceding Page Blank

I

study (Fitzhugh,

1948) rats were exposed to 10-800 pp m DDT

in feed, resulting in liver lesions at all dose levels with
a LOAEL of 10 ppm (0.5 m g / k g b w / d a y ) .

The available

m a m m a l i a n reprod u c t i o n and developmental studies of DDT
indicate that an H N C derived from the critical effect of
liver t o x icity will be prote c t i v e of potential human
reproductive/ developmental effects

(EPA, 1985).

T he HNC is

based on the subchronic rat N O E L of 0.05 m g / k g bw/day, wi t h
a total uncert a i n t y factor of 100.

An u n c e r t a i n t y factor

for subchronic to chronic conve r s i o n is not included because
of the corroborating chronic study in the database.

This

approach is consistent wi t h the oral RfD deve l o p m e n t by EPA
(1985).

ADE

=

0.05 m q / ka/d

=

0.0005 m g / k g / d

=

0.5 ug/ k g / d

100

Where:

Uncer t a i n t y Factor = 100, composed of:
lOx for intraspecies variability
lOx for interspecies extrapolation

Drink i n g W a t e r Sources:

HNV

=

A D E X Wh x RSC
WC + (FC x BAF)
0.5 ua/kg/d x 70 ka x 0.8_____________

=

2 1/d + (0.015 kg/d x 1,913,8751/kg*)
36

0.00098 ug/1

(rounded off to 1.0 ng/1

(Tier 1))

N o n d r i n k i n g Water Sources:

HNV

=

APE x W h x RSC
W C + (FC

X

BAF)

0.5 uq/kq/d x 70 kg x 0.8___________________
0.01 1/d + (0.015 kg/d x 1,913,875 1/kg*)

=

Where:

0.00098 ug/1

(rounded off to 1.0 ng/1

(Tier 1))

RSC = 0.8; the substance is persi s t e n t and

b ioaccumulative

*BAF = 1,913,875, provided by EPA-Duluth and M i n n e s o t a PCA.

References:
Fitzhugh, O. 1948.
Use of DDT insecticides on food
products. Industrial and Engineering Chemistry.
40(4):704-705.
Laug, E., A. Nelson, 0. Fitzhugh and F. Kunze.
1950.
Liver
cell alteration and DDT storage in the fat of the rat
induced by dietary levels of 1-50 p p m DDT.
J.
Pharmacol. Exp. Therap.
98:268-273.
U.S. Environmental Protection Agency (EPA). 1985.
Integrated Risk Information System (IRIS). Chemical
file for DDT (50-29-3). Ver i f i c a t i o n Date 12/18/85.
Last Revised 9/30/87.

37

Tier 1 Human Cancer Criterion
A r eview of the available literature for DDT carc i n o g e n i ci t y
reveals a lack of adequate epidemiological data and an
extensive database of chronic oral rodent bioassays.

These

studies indicate that the induction of liver tumors is the
most consistent and significant tumorigenic r e sponse to DDT
in rodents.

EPA (1987) has class i f i e d the weig h t of

evidence of DDT carci n o g e n i ci t y as B2 based on m u ltiple
posit i v e studies in two species

(mice and r a t s ) , wi t h

ancil l a r y evidence including p r o m oting activity,
g e n o t o x i c i t y , and structural re l a t i o n to other rodent liver
carcinogens.

Therefore, the data are sufficient for Tier 1

HCC derivation.

The animal bioas s a y p r o v iding t he highest slope factor
estim a t i o n is the m u l t i g e n e r a ti o n m ouse feeding study of
T arjan and K emeny

(1969).

The predominant tumor types were

leukemias and lung tumors; a significant liver res p o n s e was
not seen.

EPA (1980) deri v e d ambient w a t e r q u a l i t y criteria

from the slope factor of 8.422

(mg/kg/day)

* from this

study.

EPA (1986a) evaluated the c a r c i n o genicity of DDT a nd other
r e lated compounds and d etermined that the T a r j a n a nd Kemeny
(1969)

study was not the most appropriate basis for

q u a n t i t a t i v e risk assessment.

The study's findings we r e not
38

consistent with the numerous other p ositive b i o assays in
terms of the organ site (lung/leukemia versus liver)

and the

slope factor

This

(about an order of m a g n i t u d e g r e a t e r ) .

slope factor was judged to be a statistical outl i e r in
relation to the liver tumor induction data from six key
studies, and the q u ali t y and val i d i t y of the study was also
questionable.

EPA (1986a) derived a slope factor from the

consistent finding of liver tumor induction in rats and
mice,

for which the six key studies pr o v i d e d slope factors

w ithin a 13-fold range.
E-l

(mg/kg/day)

The r e c ommended slope factor of 3.4

^ was derived as the g e o m etric me a n of ten

slope factors from those six studies
Terracini et al.,
and Turusov,

(Turusov et al.,

1973; Thorpe and Walker,

1975; Cabral et al.,

1973;

1973;

Tomatis

1982; Rossi et a l . , 1977).

The a v e r aging procedure was followed because no further
database refinement or rejection could be logically made,
and the geometric average of the values w as v i e w e d as the
best rational estimate of the slope factor

(EPA,

1986a).

The EPA's CRAVE w o r k gr o u p has r eviewed and a ccepted this
appr oach to slope factor e stimation as a m e t h o d to include
all relevant data

(EPA, 1987).

This averaging approach to slope factor estima t i o n u t i l izing
multiple studies, species,

strains and sexes has not

g e n e r a l l y been recommended in earlier EPA guide l i n e s
1980; 1 9 8 6 b ) .

However, more recently,
39

EPA (1989) has

(EPA,

stated:

"Occasionally,

in situations where no single study

is judged most appropriate, yet several studies collectively
support the estimate, the g e o m etric mean of estimates from
all studies may be adopted as the slope.

This pr a c t i c e

insures the inclusion of all r e levant data"

(EPA, 1989).

the specific case of DDT, the a v e r aging process as applied
to the best available studies m a y be the most reasonable
m e a n s of q u a n t i tativ el y c h a r a cterizing the c a r c i n o genicity
of D D T (Schoeny,

1991; Holder,

1991; Bayard,

1991).

The Tier 1 H uman Cancer Criteria for DDT are der i v e d from
the slope factor of 3.4 E-l

(mg/kg/d)

1 b ased on rodent

liver tumor induction in the six k ey studies.

RAD = 1 x 1Cr^ _____________

=

2.94 X 10 5 mg/kg/d

3.4 x 10 ^ (mg/kg/d) ^

-

29.4 ng/kg/d

D r i nking Water Sources:

HCV = RAD x Uh_______

= 29.4 nq/ko/d x 70 ko_________________

VC + (FC x BAF)

2 l/d + (0.015 kg/d x 1,913,875 l/kg*)

■

0.0716 ng/l (rotnded off to 0.07 ng/l (Tier 1>)

40

In

N o ndrinking Water Sources:

HCV = RAD x Uh_____
WC + (FC x BAF)

=

29.4 ng/kq/d x 70 kg_________________
0.01 l/d + (0.015 kg/d x 1,913,875 l/ltg*)

= 0.0716 ng/l (rounded off to 0.07 ng/t (Tier 1))

Where:

*BAF = 1,913,875, p rovided by EPA-Duluth and

Minnesota PCA.

References:
Bayard, S.
1991.
T o x i c o l o g i s t/ S t a t i s t i c i a n w i t h the U.S.
EPA Office of Research and Development, H u m a n Health
A s s e s s m e n t Group.
Personal c o m m u n i c a t i on w i t h R.
Sills, M i c h i g a n Department of Natural Resources.
Cabral, J. et al.
1982.
Effects of long-term intake of DDT
on rats. Tumori 68:11-17.
Holder, J.
1991.
Toxicologist with the U.S. E P A Office of
R e s earch and Development, Human Health A s s e s s m e n t
Group.
Personal c o m munication w i t h R. Sills, Mi c h i g a n
D epartment of Natural Resources.
Rossi, L. et al.
1977.
Long-term a d m i n i s t r a t io n of DDT or
phenobarbital-Na in W i star rats.
Int. J. Cancer.
19:179-185.
Schoeny, R.
1991.
U.S. EPA Environmental Criteria
A s s e s s m e n t Office, Chair of the Canc e r R i s k Assess m en t
Verifi c a t i o n Endeavor (CRAVE) workgroup.
Personal
communication with R. Sills, Mi c h i g a n D e p a r t m e n t of
Natural Resources.
Tarjan, R. and T. Kemeny.
1969.
M u l t i g e n e r a ti o n studies on
DDT in mice.
Food Cosmet. Toxicol.
7:215-222.
Terracini, B. et al.
1973.
The effects of long-term
feeding of DDT to BALB/c mice.
Int. J. Cancer.
11:747-764.

41

Thorpe, E. and A. Walker.
1973.
The t oxicology of
dieldrin.
II. Comparative long-term oral tox i c i t y
'
studies in mice wi t h dieldrin, DDT, phénobarbital,
beta-BHC and gamma-BHC.
Food Cosmet. Toxicol.
1 1 :433­
442.
Tomatis, L. and V. Turusov.
1975.
Studies on the
c a r c i n ogenicity of DDT.
Gann M o n o graph on Cancer
Research.
17:219-241.
Turusov, V. et al.
1973.
Tumors in CF-1 mice exposed for
six consecutive generations to DDT.
J. Natl. Cancer
Inst.
51:983-998.
U.S. Environmental Prote c t i o n A g e n c y (EPA). 1980.
45
Federal Register No. 231, pp. 79347-79356.
Appendix c
- Guidelines and M e t h o d o l o g y Used in the P r e p a r a t i o n of
the Consent Decree Water Criteria Documents.
U.S. Environmental Prote c t i o n A g e n c y (EPA).
1986a.
Asses s m e n t of the C a r c i n o genicity of Dicofol
(Kelt h a n e ) , DDT, DDE, and DDD (TDE). OHEA/ORD.
E P A / 600/6-86/001.
PB 87-110904.

The

U.S. Environmental Protection A g e n c y (EPA).
1986b.
51
Federal Register No. 185, pp. 33992-34003.
G uidelines
for Carcinogen Ri s k Assessment.
U.S. Environmental Protection A g ency (EPA).
1987.
Intergrated Risk Information System (IRIS d a t a b a s e ) .
Chemical file for DDT (59-29-3).
V e r i f i c a t i o n Date
6/24/87.
Last R e v i s e d 5/1/91.
U.S. Environmental Protection A g ency (EPA).
1989.
Risk
A s s e s s m e n t Guidance for Superfund.
V o l u m e 1.
Human
H e a l t h Evaluatio n Manual (Part A).
Interim Final.
OERR.
EPA/540/1-89/002.

42

October 23,

1991

GREAT LAKES INITIATIVE
TIER 1 HUMAN HEAL T H CR I T E R I A FOR
DIELDRIN
CAS NO. 60-57-1
Tier 1 TTiiman N o n c ancer Criterion
A review of the available literature indicates that the most
appropriate study for HNC d erivation for die l d r i n is a two
year study conducted by Walker et al.
study,

(1969).

In this

25 Carworth Farm "E" rats of each sex were

administered 0.1,

1.0 or 10.0 p pm d ieldrin in their diet and

45 rats of each sex were used as controls.

At th e end of

two years, the females exposed to 1.0 and 10.0 p p m had
increased liver weight s and liver-to-body w e i g h t ratios.
H i s t opathological examination of these animals found changes
in perenchymal cells w h i c h included focal p r o l i f e r a t i o n and
focal hyperplasia.

A N O A E L of 0.1 p pm (estimated to be

0.005 mg/kg/day) was deter m i n e d from the study.

In support

of this v a l u e a systemic N O E L of 0.005 m g / k g / d a y was
calculated for dogs in the same study.

Studies examining the reproductive effects of d i eldrin are
lacking (EPA, 1987).

A review of studies w h i c h examine the

developmental effects of dieldrin in m i c e

(Chernoff et al.,

1975; Dix et al.,

1977) and rats (Harr et al.,

Chernoff et al.,

1975)

1970;

suggest that exposure levels which

43

may result in adverse developmental effects are high e r than
the N O A E L determined in the W a lker et al.

The q u a lity of the Walker et al.

(1969)

sufficient to derive a Tier 1 HNC.
by EPA (1987)

(1969)

study.

study was deemed

This study was also used

to derive the oral RfD for dieldrin.

was d e rived from the N O A E L (0.005 mg/kg/day)

The HNC

u s i n g an

unc ert a i n t y factor of 100 to account for intraspecies
var iab i l i t y and interspecies extrapolation.

ADE

=

0.005 ma/kq/d

= 0.00005 mg/ k g / d

= 50 ng/kg/d

100

Where:

Uncertainty Factor = 100, composed of:
lOx for intraspecies variability
lOx for interspecies extrapolation

Drinking Water Sources:

HNV = ADE x Wh x RSC = 50 n a / k a / d x 70 k g x 0 .8 ______________
W C + (FC X BAF)

= 6.6 ng/1

2 1/d + (0.015 k g / d x 28,171 1/kg*)

(rounded off to 7 ng/1

44

(Tier 1))

N o n d r i n k i n g Water Sources:

HNV = APE x Wh x RSC = 50 nq/kq/d x 70 kq x 0.8_____________
W C + (FC x BAF)

= 6 . 6 ng/1

Where:

0.01 1/d +(0.015 kg / d x 28,171 1/kg*)

(rounded off to 7 ng/1

(Tier 1))

RSC = 0.8; the substance is p e r s i s t e n t and
bioaccumulative.

*BAF = 28,171, provided by EPA-Duluth and M i n n e s o t a PCA.

REFERENCES:
Chernoff, N . , R.J. Kavlock, J.R. Kathrein, J.M. Du n n and
J.K. Haseman.
1975.
Prenatal effects of d i e l d r i n and
p h o t o -dieldrin in mice and rats.
Toxicol, Appl.
Pharmacol.
31:302-308.
Dix, K.M., C.L. Van Der Paus and W. B. McCarthy.
1977.
T o x icity studies with dieldrin:
t e r atological studies
in mice dosed orally with HEOD.
T e r a t o l o g y 16:57-62.
Harr, J . R . , R.R. Claeys, J.F. Bone and T.W. McCorcle.
1970.
Dieldrin toxicosis:
Rat reproduction.
Am. J. Vet.
Res.
31:181-189.
U.S. Environmental Protection A g e n c y (EPA). 1987.
Integrated Risk Information System (IRIS d a t a b a s e ) .
Chemical file for dieldrin (60-57-1).
Verification
Date 4/16/87,
Last Revised 9/1/90.
Walker, A.I.T., D.E. Stevenson, J. Robinson, E. T h o r p e and
M. Roberts.
1969.
The t oxicology and pha r m a c o d y n am i c s
of dieldrin (HEOD): Two year oral e x p o sures of rats
and dogs.
Toxicol. Appl. Pharmacol.
15:345-373.

45

Tier 1 bii*» ti Cancer Criterion

A c c o r d i n g to EPA (1987a), there are inadequate data
available to ascertain whet h e r d ieldrin is a human
carcinogen.

However, chr o n i c studies have shown that

d i e l d r i n induces the formation of liver tumors in seven
strains of mice w h e n admi n i s t e r e d orally.

Additional

support for d i e l d r i n 7s carci n o g e n i ci t y is p r o v i d e d by its
structural similarit y to other compounds

(i.e. h e p t a c h l o r

and chlordane) which have been found to induce tumo r s in
rodents.

Dieldrin has also produced a po s i t i v e re s p o n s e in

several mutage n i c i t y studies.

The w e i g h t - o f - e vi d e n c e for

dieldrin carci n o g e n i c i t y is sufficient for B2
h u m a n carcinogen)

cl a s s i f i c a t io n (EPA, 1 9 8 7 a ) .

(probable
T he data are

sufficient to derive a Tier 1 HCC.

Six k e y studies

(Davis, 1965 as reevaluated by R e uber and

cited in Epstein,

1975; W a l k e r et al.,

Walker,

1978; Tennekes et a l . , 1981; M e i e r h e n r y

1973; NCI,

1972; T h o r p e and

et al., 1983) have r e ported liver tumor i n d u ction in mice
e x p o s e d orally to dieldrin.

EPA (1987a; 1987b) c a l c u l a t e d

13 d i f f e r e n t slope factors u sing data from these studies.
The calcu l a t e d slope factors we r e w i t h i n an e i g h t - f o l d
range.

EPA (1987a; 1987b)

c alculated a single oral slope

factor of 1.6 x 101 (mg/kg/day)-1 by taking the g e o metric
46

mean of the 13 slope factors co m p u t e d from t he k e y studies.
This m e t h o d of computing a slope factor is u s e d "in
situations w h e r e no single study is judged mo s t appropriate,
yet several studies collectively support the estimate..."
(EPA,

1989).

Accordin g to EPA (1989), the a d v antage of this

m e t h o d of d e t e r m i n i n g the slope factor is that all relevant
data are u s e d in the computation.

RAD = l x 10~5_______________

= 6 x 10” 7 m g / k g / d = 0.6 ng/kg/d

1.6 x 101 (mg/kg/d)” 1

Drinking Water Sources:

H C V = RAD x Wh________ = 0.6 na/kq/d x 70 kg
WC + (FC x BAF)

= 0.099 ng/1

2 1/d + (0.015 k g / d x 28,171 1/kg*)

(rounded off to 0.1 ng/1

(Tier 1))

N o n d r i n k i n g W a t e r Sources:

H C V = R A D x Wh________ = 0.6 nq/ka/d x 70 ka____________________
W C + (FC

X BAF)

= 0.099 ng/1

0.01 1/d +(0.015 k g / d

(rounded off to o.l ng/1

X 28,171 1/kg*)

(Tier 1))

*BAF = 28,171, provide d by EPA-Duluth and M i n n e s o t a PCA.
47

REFERENCES:
Davis, K.J.
1965.
Pathology report on mice fed aldrin,
dieldrin, heptachlor or heptachlor epoxide for two
years.
Internal FDA m e m o r a n d u m to Dr. A. J. Lehman.
July 19.
As cited in:
Epstein, 1975; EPA, 1987a.
Epstein,
1.

S.S., 1975.
The c a r c i n o genicity of dieldrin.
Sei. Total Environ.
4:1-52.

Part

Meierhenry, E.F., B.H. Reuber, M.E. Gershwin, L.S. H s i e h and
S.W.French.
1983.
D i e l drin-induced m a l l o r y bodies in
hepatic tumors of mice of d i f f erent strains.
Hepatology.
3:90-95.
National Cancer Institute.
1978.
Bioassays of a l drin and
dieldrin for possible carcinogenicity.
DHEW
P ublication No. (NIH) 78-822.
National Cancer
Institute Carcinogenesis Technical R e port Series, No.
22.
NCI-CG-TR-22.
Tennekes, H . A . , A.S. Wright, K.M. Dix and J.H. Koeman,
1981. Effects of dieldrin, diet and bedding on enzyme
function and tumor incidence in livers of m a l e CF-1
mice.
Cancer Res.
41:3615-3620.
Thorpe, E. and A.I.T. Walker.
1973.
The t oxicology of
d i e l d r i n ( H E O D ) . Part II.
Comparative long-term oral
toxic o l o g y studies in m i c e w i t h dieldrin, DDT,
phenobarbitone, b e ta-BHC and gamma-BHC.
Food Cosmet.
Toxicol.
11:433-441.
U.S. Environmental Protection Agency ( EPA). 1987a.
Integrated Risk Information S y stem (IRIS d a t a b a s e ) .
Chemical file for chlordane (57-74-9).
Verification
Date 3/5/87.
Last Revi s e d 1/1/91.
U.S.

Environmental Protection A g e n c y (EPA).
1987b.
C a r c i n o genicity Assess m e n t of Aldr i n and Dieldrin.
Prepa r e d by Carci n o g e n A ssessment Group, O f f i c e of
H e a l t h a n d Environmental Assessment, Washington, DC for
H a z a r d Evaluation Division, Office of Pesticide
Programs, Office of Pesticides and Toxic Substances.
OHEA-C-205.

U.S. Environmental Protection Agency (EPA).
1989.
Risk
A s s e s s m e n t Guidance for Superfund.
V o l u m e 1. Human
H ealth Evaluation Manual (Part A).
Interim Final.
OERR.
E P A / 540/1-89/002.

48

Walker, A.I.T., E. Thorpe and D.E. Stevenson.
1972.
The
toxicology of dieldrin (HEOD). I. Lo n g - t e r m oral
toxicity studies in mice.
Food Cosmet. Toxicol.
11:415-432.

49

50

Oct o b e r 23,

1991

GREAT LAKES INITIATIVE
T I E R 1 HUMAN HEALTH C R I T E R I A FOR
2,4-DIMET H Y L P HE N O L
CAS NO.

105-67-9

Tier l Human N o n c ancer C r i terion

A r e v i e w of the available literature indicates that HNV
d e r i v a t i o n for 2 , 4-dimethylphenol

(2,4-DMP)

is most

a p p r o p r i a t e ly based on the subchronic oral m o u s e study
condu c t e d by EPA (1989).

Groups c o n s i s t i n g of 30 ma l e and

30 female albino m i c e were a d m i n istered 2,4-DMP by gavage at
dose levels of 0, 5, 50 or 250 m g / k g/day for 90 days.

At

day 30, an interim sacrifice was p e r f o r m e d on at least 8
males and 9 females from each group.

Effects e x amined

included mortality, clinical signs, body weights,
consumption,

ophthalmology,

food

hematology, cli n i c a l chemistry,

organ weights, and gross h i s t o p a t h o l o g y .

Toxicologically

relevant clinical signs observed only after w e e k 6 at 250
m g / k g / d a y in both sexes included squinting,
prostration,

lethargy,

and ataxia, wi t h onset shortly a f t e r dosing.

Statistically significant

lower

me a n c o r p u s c u l a r v o l u m e and

m e a n corpuscular hemoglobin c oncentrations we r e obs e r v e d in
female m i c e at 250 rag/kg/day during the final b ut n ot during
the interim sacrifice.

At interim sacrifice, t he blood urea
51

Preceding Page Blank

nitrogen

(BUN)

levels for females at 50 and 250 mg / k g / d a y

were significantly lower than the vehicle controls, w h i l e at
the final sacrifice,

the BUN levels for females at 50

m g / k g/day were significantly higher than the vehicle control
group.

For only the low-dose

(5 mg/kg/day) m a l e s at the

interim sacrifice, cholesterol levels were s i g nificantly
higher than the vehicle control group.
weights w e r e observed in low-dose

Increased adrenal

(5 mg/kg/day) but not mid-

to h i g h -dose females when compared to vehicle control
animals.

Since the r eported changes in BUN, serum

c holesterol and adrenal weights w e r e not dose- or timedependent,

they m a y be interpreted to be spurious findings.

The N O A E L and LOAEL for this study were 50 and 250
mg/kg/day,

respectively, based on clinical signs and

h e m a t ological changes.

The d a t abase is judged to be sufficient for Tier 1 HNC
deriva t i o n because the key study (EPA, 1989) pro v i d e s a
subchronic NOAEL.

However, there is a paucity of

supplemental and supportive data.

No useful chronic,

r e p roductive or developmental studies are available.
overall findings from the 90-day study

(EPA, 1989)

The

compare

favorably w i t h the results of a 14-day mice g a vage study
(EPA, 1987; as cited in EPA,
the same laboratory.

1989; EPA, 1990)

c o n ducted at

In the 14-day study, the only

toxicological signs observed in males and females
52

administered 250 mg/kg / d a y were lethargy, prostration,
ataxia.

and

This is the same dose at w hich critical effects

were found in the 90-day study (EPA, 1989).

The H N V is derived from the N O A E L dose of 50 m g / k g / d a y from
the 90-day gavage mouse study by EPA (1989) wi t h an
u n c e r t a i n t y factor of 3000.

This approach is consistent

with the derivation of the oral R f D for 2,4-DMP by EPA
(1990).

ADE = 50 mq/ka/d = 0.017 mg/kg/day
3,000

Where:

Uncert a i n t y Factor = 3,000, com p o s e d of:
lOx for intraspecies v a riability
lOx for interspecies extrap o l a t i on
lOx for subchronic to chronic e x t r a p o l a t i on
3x for substantial gaps in the database

Drinking Water Sources:

H N V = ADE x Wh x RSC
WC + (FC x BAF)

= 0.274 mg/1

= 0.017 mq/ k a / d x 70 ka________
2 1/d + (0.015 kg/d x 156 1/kg*)

(rounded off to 0.3 mg/1

53

(Tier 1))

Nondr i n k i n g Water Sources:

HNV = APE x Wh x RSC

UC + (FC x BAF)

= 0,017 mg/kg/d x TO kg_________

0.01 L/d + (0.015 kg/d x 156 l/kg*)

= 0.51 mg/l (rounded off to 0.5 mg/l (Tier 1))

Where:

*BAF = 156, provided by EPA-Duluth and M i n n e s o t a

PCA.

NOTE: A R e l ative Source Contribution

(RSCJ factor has not

been u t i l i z e d in these draft calculations.

54

REFERENCES :
U.S. Environmental Protection A g e n c y (EPA). 1990.
Integrated R i s k Information System (IRIS d a t a b a s e ) .
Chemical file for 2 , 4-dimethylphenol (105-67-9).
V e rification Date 2/21/90.
Last Re v i e w e d 2/21/90.
U.S. Environmental Protection Agency (EPA).
1989.
NinetyDay Gavage Study in A l b i n o Mice U sing 2,4D i m e t h y l p h e n o l . Study No. 410-2831, p r e p a r e d by
Dynamac Corporation, Rockville, MD, for the Offi c e of
Solid Waste and Emergency Response, Washington, DC.
U.S. Environmental Protection A g e n c y (EPA). 1987.
Fourteen-Day Gavage Study in Albi n o Mi c e U sing 2,4Dimethylphenol.
Study No. 410-2830, p r e p a r e d by
Dynamac Corporation, Rockville, MD, for the Office of
Solid Waste and Emergency Response, Washington, DC.
As
cited in EPA (1989, 1990).
U.S. Environmental Protection Agen c y (EPA).
1980.
Ambi en t
Water Quality Criteria for 2,4-Dimethylphenol.
Office
of Water Regulati o n s and Standards, Criteria and
Standards Division, Washington, DC.
E PA 440/5-80-044.
PB81-117558.

55

56

Octo b e r 23, 1991
GREAT LAKES INITIATIVE
TIER 1 H UMAN HEALTH CRI T E R I A FOR
2 , 4 - DINITR0PHEN0L
CAS NO. 51-28-5
Tier 1 TTunian Noncancer Criterion
A r eview of the available literature on the toxic effects
and therapeutic use of 2,4-dinitrophenol

(2,4-DNP)

indicates

that the HNC derivati o n is m o s t a p p ropriately based upon the
human d o s e -response following exposure to 2,4-DNP as
r e v iewed by Horner

(1942).

Numerous studies on 2,4-DNP and its toxic effects on humans
are available

(Horner,

1942; SRC, 1981).

Common l y - r e po r t e d

toxic effects included g a s t rointestinal dist u r b a n c e s
(nausea, vomiting,

loss of appetite), cutaneous rashes,

neuritis, agranulocytosis of the bone marrow,

and jaundice.

Liver and k idney and cardiovascular damage w as rarely
reported.

Evidence of cardiovascular effects w as limited to

abnormal electrocardiograms indicating functional
abnormalities of the heart, although f r a gmentation of the
h e a r t m u s c l e was reported in cases of fatal poisoning.

Nine

cases of m o r t a l i t y resulting from 2,4-DNP po i s o n i n g were
cited.

Death usually occurred w i thin 24 hours after the

onset of such toxic m a n i f estations as dizziness,
dyspnea, h i g h temperature,

intense thirst, a nd excessive

perspiration.
57

Preceding Page B lank

fatigue,

In the study by Horner (1942), bilateral c ataract formation
was frequently observed in patients receiving 2,4-DNP as a
weight - l o s s agent.

The study reported that cataracts

developed in more tha n 164 persons after the use of
d i n i t r o p h e n o l , an estimated incidence of 0.86 percent.

The

study did not include a control group, however the
resear c h e r noted that this type of cataract is not expected
to occur in some of the age groups which e x h ibited cataracts
in the study.

Formation of cataracts o ccurred e i ther d u ring

dosing or within several months to a year after the final
dose w a s taken.

Cataracts were o bserved in patients

receiving as little as 2 m g / k g bw/day w h i c h was the lower
range of the recommen d e d thera p e u t i c dose for obesity.
L O A E L d e t e r m i n e d from the Horner

This

(1942) study w as deemed

sufficient for the deriva t i o n of a Tier 1 HNC.

In a 6-month feeding study, ma l e rats (from the B r eeding and
L a b o r a t o r y Institute, Brooklyn, NY) were a d m i n istered 2,4DNP at d i e t a r y levels of 0, 100, 200, 500 and 1000 p p m for
178-179 days

(Spencer et a l . , 1948).

There w e r e 14, 12, 12,

9 and 14 rats p e r diet a r y level, respectively.

An

additional 10 rats were fed 2000 p pm but after 24 days this
group experi e n c e d 40% m o r t a l i t y and the r e m a ining animals at
2000 p p m w e r e sacrificed and examined at this time.

These

animals w e r e emaciated and had empty gastrointestinal
tracts, enlarged spleens with hemosiderosis, t e s t i c u l a r
58

atrophy,

and increased levels of blood urea nitrogen.

Rats

fed 1000 ppm 2,4-DNP suffered a r e d uction in body w e ight
gain of 10-15%,

a slight de p l e t i o n of body fat, a very

slight increase in the average w e i g h t of t he kidneys,
very slight decrease in the w e ight of the heart.

and a

Blood urea

nitrogen levels were elevated in 2/14 animals at 1000 ppm.
R e d u c e d g r o w t h occurred at 500 p pm and a significant
increase

(between 91% and 92% above controls)

in kidney

w e ights occurred at all diet a r y concentrations.

The authors

concluded that the mal e rats m a i n t a i n e d for six m o n t h s on
diets containing 200 ppm (and presu m a b l y 100 ppm)
appreciable ill effects.

showed no

However, because t h e r e was a

statistically significant increase in k i d n e y weig h t s at all
d i etary concentrations,

the dose of 100 p p m m a y be

consid e r e d the LOAEL for this study.

Using a food

consumption value of 0.08 k g / k g b w (EPA, 1988), the LOAEL
for the Spencer et al.

(1948)

study was 8 m g / k g bw/day.

This is very close to the L OAEL of 2.0 m g / k g b w /day w hich
was c alculated using the h u m a n data from H o r n e r

(1942).

EPA

(1980) derived an Acce p t a b l e Daily Intake (ADI) from an
estimated N O A E L of 5.4 mg / k g / d a y (100 p pm group)
study by Spencer et al.

from the

(1948).

In a t eratology study wi t h 2,4-DNP, G i b s o n (1973) re p o r t e d
that n e ither intraperitoneal
oral

(7.7 and 13.6 mg/kg/day)

(25.5 and 38.2 mg/kg/day)

59

nor

doses of 2,4-DNP administered

to p r e gnant Swiss-We b s t er mi c e d u r i n g early organ o g e n e s is
(days 10-12 of gestation) p r o d u c e d morph o l o g i c al defects.
However, the higher intraperitoneal dose was e m b ryotoxic and
the h i g h e r intraperitoneal and oral doses p r o d u c e d overt
signs of t o x icity (hyperexcitability and hyperthermia)

in

the d a m s .

The HNV is derived from the L OAEL (2.0 m g / k g bw/day)
d e t e r m i n e d from the h u m a n data summarized by H o r n e r
using an u n c e r t a i n t y factor of 1000.

(1942)

This approach is

consistent w i t h the deriv a t i o n of the oral R f D for 2,4-DNP
by EPA (1986).

A D E = 2 m g / k g / d = 0.002 m g / k g / d = 2 ug/kg/d
1000

Where:

U n c e r t a i n t y F a ctor = 1000, c o mposed of :
lOx for subc h r o n i c to chronic conversion
lOx for intraspecies v a r iability
lOx for L O A E L to N O A E L conversion

D r i n k i n g W a t e r Sources:

HNV = ADE x Wh x RSC
WC + (FC

X BAF)

= 2 ua/k a / d x 70 kg__________________
2 1/d + (0.015 kg / d

60

X 4.B 1/kg*)

= 67.6 ug/1

(rounded off to 0.07 mg/1

(Tier 1))

N ondrinking Water Sources:

HNV = A P E x Wh x RSC

= 2 uq/kq/d X 70 kq_____________________

WC + (FC x BAF)

0.01 1/d + (0.015 k g / d x 4.8 1/kg*)

= 1707 ug/1

Where:

(rounded off to 1.7 mg/1

(Tier 1))

*BAF = 4.8, provided by EPA-Duluth and Minnesota

PCA.

NOTE:

A Relative Source Contribution

(RSC)

factor has

not been utilized in these draft calculations.

REFERENCES:
Gibson, J.E.
1973.
T e r a t o l o g y studies in m i c e w i t h 2secbutyl-4, 6-dinitrophenol ( d i noseb). Food Cosmet.
T o x i c o l . 11:31-43.
Horner, W.D.
1942.
D i n itrophenol and its r elation to
formation of cataracts.
Arch. Ophthal.
27:1097-1121.
Spencer, H.C., V.K. Rowe, E.M, A d a m s and D.D. Irish.
1948.
Toxicological studies on laboratory animals of certain
alkyl dinitrophenols used in agriculture.
J. Indus.
Hyg. Toxicol.
30:10-25.
Syracuse Research Corp o r a t i o n (SRC), Center for Chemical
Hazard Assessment.
1981.
Information Profiles on
Potential Occupational Hazards:
Nitrophenols.
Prepared for National Institute for Occ u p a t i o n a l Safety
and Health (NIOSH), Rockville, MD.
PB89-215842/XAD.
P H S - N I O S H — 210-79-0030.

61

U-S. Environmental Protection A g e n c y (EPA). 1988.
Recommendations For A n d Docum e n t a t i on Of Biological
Values For Use In Risk Assessment.
PB88-179874.
U.S. Environmental Protection A g e n c y (EPA).
1986.
Integrated Risk Information System (IRIS d a t a b a s e ) .
Chemical file for 2,4-dinitrophenol (51-28-5).
V e rification Date 2/5/86.
Last R e viewed 2/5/86,
U.S. Environmental Protection Agen c y (EPA).
1980.
Ambi e n t
W a t e r Quality Criteria Document for Nitrophenols.
Prepared by the Office of Health and Environmental
Assessment, Environmental Criteria and A s s e s s m e n t
Office, Cincinnati, OH for the Office of Water
R e gulations and Standards, Criteria and Standards
Division, Washington, DC.
EPA 440/5-80-063.

62

Octo b e r 31, 1991
GREAT LAKES INITIATIVE
T I E R 1 H U M A N HEALTH CRITERIA FOR
HEPTAC H L O R
CAS NO. 76-44-8

Tier l Human Noncancer criterion

A r e view of the available literature indicates that the most
appropriate study for HNC deriv a t i o n for h e p t a c h l o r is a
two-year study conducted by Vel s i c o l Chemical Corpo r a t i o n
(1955) as cited by EPA (1987).
rats

In this study,

CF strain

(20/sex/group) w e r e fed diets c o n t a i n i n g 0, 1.5,

7, or 10 ppm heptachlor.

3, 5,

The N O E L for m a l e rats w a s 3 ppm

(0.15 mg/kg/d) with the liver-to-body weig h t ratio reported
as the sensitive endpoint.
was 5 p p m

The L E L for this critical effect

(0.25 mg/kg/d).

Two studies suggest that exposure levels w h i c h ma y cause
adverse effects on reproduction are h i g h e r than the NO E L
d e t e r m i n e d in the study cited above.

E PA (1987) c ited a

N O E L of 0.25 m g / k g / d in a o n e - g eneration rat r e p r o duction
test

(Velsicol,

1955) and a NO E L of 0.5 m g / k g / d in a three-

g e n e r a t i o n rat reprodu c t i o n test
Green

(Velsicol,

1967).

However,

(1970) found adverse effects on r e p r o d u c t i o n in rats

which were administere d heptac h l o r in feed at 5 ppm
63

(approximately 0.25 m g / k g / d ) .

This value was c onsidered a

LOAEL and no NOAEL was e s tablished in this study.
respect to developmen t al toxicity,

Yamaguchi et al.

Wi t h
(1987)

found no t eratogenic effects in the offspring of female rats
dosed o rally w i t h 5, 10 or 20 m g / k g heptac h l o r from days 7 ­
17 of gestation.

The q u a lity of the Velsicol

(1955) study and suppor t i n g data

was d e emed sufficient to derive a Tier l HNC.

This study

was also used by EPA (1987) to derive the oral RfD for
heptachlor.

A D E = 0.15 m q /kq/d = 0.0015 m g / k g / d = 1.5 ug/kg/d
100

Where:

U n certainty Factor = 100, composed of:
lOx for intraspecies variability
lOx for interspecies e x t rapolation

Drinking W a t e r Sources:

HNV

=

ADE

X

wh

X

RSC

W C + (FC x BAF)

= 0.29 ug/1

=

1.5 ua/ k a / d x 70 ka x 0.8____________
2 1/d + (0.015 kg/d x 19,097 1/kg*)

(rounded off to 0.3 ug/1

64

(Tier 1))

Nondrinking W a t e r Sources:
HNV = APE x Mh x RSC

= 1.5 uq/k<3/d x 70 kg x 0.8___________

UC + (FC * BAF)

0.01 t/d + <0.015 Icg/d x 19,097 l/kg*)

= 0.29 ug/l (rounded off to 0.3 ug/l (Tier 1))

Where:

RSC = 0.8; the substance is persi s t e n t and

bioaccumulative.

*BAF = 19,097, provided by EPA-Duluth and M i n n e s o t a PCA.

REFERENCES:
Green, V.
1970.
Effects of Pesticides on Rat and Chick
Embryo.
In:
Hemphill, D. (Ed.).
1970.
Trace
Substances in Environmental Health-Ill.
P r o ceedings of
Univer s i t y of Missouri's 3rd Annual Conference on Trace
Substances in Environmental Health, June 24-26, 1969.
U.S. Environmental Prote c t i o n A g ency (EPA). 1987.
Integrated Risk Information Syst e m (IRIS d a t a b a s e ) .
Chemical file for heptachlor (76-44-8).
Verification
Date 4/16/87.
Last Revised 3/1/91.
V e l sicol Chemical Corporation.
1955.
M R I D No. 0062599.
Available from EPA.
Write to FOI, EPA, Washington, DC
20460.
V e l s i c o l Chemical Corporation.
1967.
M R I D No. 00147058.
A v a i lable from EPA.
Write to FOI, EPA, Washington, DC
20460.
Yamaguchi, M . , S. Tanaka, K. Kawashima, S. N a k a u r a and A.
Takanaka. 1987.
Effects of hepta c h l o r on fetal
development of rats.
Natl. Inst. Hyg. Sci.
105:33-36.

65

Tier 1 Human Cancar Criterion
There are inadequate data available to ascertain whe t h e r
h eptachlor is a human carcinogen.

However, h eptachlor

exposure has caused a significant increase in h e p a t o c e l l u la r
carcinomas in two strains of mice.

In addition, hepta c hl o r

is struct u r a l l y related to other compounds

(i.e., di e l d ri n

and chlordane) w h i c h have been found to induce the formation
of liver tumors in mice.

H eptachlor has p r oduced negative

results in gene m u t at i o n assays, mouse d o minant lethal
assays and in vitro D N A repair assays
1987).

(EPA,

1980; 1986;

A c c o r d i n g to the weig h t of e v idence a pproach

e m p loyed by EPA (1986; 1987; 1990), there is sufficient
evide n c e to classify hepta c h l o r as a B2 carcinogen (probable
human carcinogen).

T here is also sufficient evidence to

d e rive a Tier 1 HCC.

Two key studies

(Davis, 1965 as cited by Epstein,

1976; NCI,

1977) have repor t e d hepat o c e l l u la r tumors in mi c e exposed
orally to heptachlor.

EPA (1986; 1987; 1990) calcu l a t e d

four slope factors using data from these studies.
factors ranged from 0.83 to 14.9

(mg/kg/d)- 1 .

calcu l a t e d a single slope factor of 4.5

The slope

EPA (1987)

(mg/kg/day)

1 by

taking the geometric mean of the four slope factors from the
key studies.

This m e t h o d of computing a slope factor is

used "in situations w h e r e no single study is judged most
appropriate, yet several studies collectively support the
66

estimate ..."

(EPA, 1989).

The advantage of this m e t h o d of

d e t e r m i n i n g the slope factor is that all r e l e v a n t data are
used in the computations

(EPA,

1989).

R A D = 1 x 10~5________ = 0.0000022 m g / k g / d = 2 . 2
4.5

ng/k g / d

(mg/kg/d)-1

D r i nking W a t e r Sources:

H C V = RAD x Wh________ = 2.2 na/ka/d x 70 ka__________________
WC + (FC

X

= 0.534 ng/1

BAF)

2 1/d + (0.015 kg / d

(rounded off to 0.5 ng/1

X

19,097 1/kg*)

(Tier 1))

Nondri n k i n g W a t e r Sources:

HCV = RAD x Uh_______ = 2 . 2 no/ka/d x 70 kg_________________
UC + (FC * BAF)

0.01 l/d + (0.015 kg/d x 19,097 t/kg*)

= 0.538 ng/l {roinjed off to 0.5 ng/l (Tier 1))

*BAF = 19,097, p r o vide d by EPA-Duluth and M i n n e s o t a PCA.

REFERENCES:
Davis, K.
1965.
P a t h o l o g y Report on Mice Fed Aldrin,
Dieldrin, Heptach l o r and Hepta c h l o r Epoxide for Two
Years.
Internal FDA m e m o r a n d u m to Dr. A. J. Lehman,
J u l y 19.
Epstein, S.S.
1976.
C a r c i n o genicity of h e p t a c h l o r and
chlordane.
Sei. Total Environ.
6:103-154.

67

National Cancer Institute (NCI).
1977.
B i o a s s a y of
H e p t a c h l o r for Possible Carcinogenicity.
NCI
Carcinogenesis Tech. Rep. Ser. No. 9.
U.S. Environmental Prote c t i o n A g e n c y (EPA). 1980.
Ambient
W a t e r Quality Criteria for Heptachlor.
Criteria and
Standards Office.
Washington, DC.
E PA 440/5-80-052.
U.S.

Environmental Protec t i o n A g e n c y (EPA).
1986.
C a r c i n ogenicity A s s e s s m e n t of Chlordane and
H e p t a c h l o r / He p t a c h l o r Epoxide.
C a r c i n o g e n A s s e s s m en t
Group.
O f f i c e of H e a l t h and Environmental Assessment,
Washington, DC.

U.S.

Environmental Pr o t e c t i o n A g e n c y (EPA). 1987.
Integrated Risk Information System (IRIS d a t a b a s e ) .
Chemical file for h eptachlor (76-44-8).
Verification
Date 4/1/87.
Last Rev i s e d 1/1/91.

U.S. Environmental Protection A g e n c y (EPA). 1989.
Risk
A s s e s s m e n t Guida n c e for Superfund.
V o lume 1. Human
H e a l t h Evalua t i o n Manual (Part A ) . Interim Final.
OERR.
E P A / 540/1-89/002.
U.S. Environmental Prote c t i o n A g ency (EPA). 1990.
Dri n k i n g
Water Criteria Document for Heptachlor, H e p t a c h l o r
Epoxide and Chlordane.
Revised November, 1990.
ECAOCIN-406.

68

Octo b e r 31,

1991

GREAT LAKES INITIATIVE
TIER 1 HUMAN HEALTH C R I T E R I A FOR
HEXACH L O R O B EN Z E N E
CAS NO, 118-74-1
Tier 1

yppcancer Criteria

A r eview of the available information on h e x a c h l o r o b e n z e n e
toxicity,

including reviews by EPA (1980; 1985a;

1985b;

(HCB)

1988),

indicates that the database is sufficient for Tier l HNC
derivation.

The best available data c o n s i s t of labor a t o r y animal

studies.

The p r i n ciple human data on HCB to x i c i t y consist of w i d e s p r e a d
toxic effects among several thousand Turkish c itizens exposed to
HCB via consum p t i o n of fungicide-treated grain during 1955-1959.
The r e s u lting effects included porphyria cutanea tarda
neurotoxicity,

(PCT),

liver damage, and increased infant mortality.

The

exposure has been estimate d at 50-200 m g / d a y over an extended
period, w i thout further de s cription of th e d o s a g e e s t i m a t i o n
m ethod (Cam and Nigogosyan,

1963).

The h u m a n d a t a c a nnot be used

for q u a ntitative risk assess m e n t because a c curate ex p o s u r e data
are not available

(EPA, 1988).

The avai lable literature indicates that HCB is a pote n t
developmental toxicant in several animal species.
(1982) exposed rats to 0, 60, 80, 100,

120 and 140 p p m H CB in

feed (doses w e r e approxima t e ly 4.5-10 m g / k g / d a y ) .

69

K i t c h i n et al.

T h e y r eported

a dose- d e p e n d en t increase in mo r t a l i t y of pups in the F l a and Flb
litters.

Grant et al.

(1977) c o n ducted a 4-generation

r e production study w i t h rats at food HCB levels in the diet of 0,
10, 20, 40, 80,

160,

320 and 640 ppm.

They concluded that 20 ppm

(about 1.5 mg/kg/day) was a NOAEL, w h i l e 40 p p m (about 3
mg/kg/day)

resul t e d in increased liver weig h t s and aniline

h ydroxylase activities in weanlings.

Rush et al.

(1983)

exposed m i n k to 0, 1 or 5 p pm in feed

0.16 or 0.78 mg/kg/day),

resulting in p r o f o u n d effects on kit

survivability to w e a n i n g at the hi g h dose.
percent,

M o r t a l i t y was 8.2

4.1 percent and 77.4 perc e n t among controls,

and high dose groups, respectively.
1984b)

(about

Bleavins et al.

low dose,
(1984a,

also reported that mink, as well as ferrets, are high l y

sensitive to the developme n t al effects of HCB.

M i n k w e r e found

to be more sensitive than ferrets, w h i l e bo t h a ppeared mo r e
sensitive than rats according to p u b l i s h e d data.

The mo s t

profound effects r e p o r t e d were d e c r e a s e d m i n k b irth w e i g h t s at
adult d i e t a r y levels as low as 1 p p m and a dos e - r e l a t e d increase
in k i t m o r t a l i t y at three weeks of age among both m i n k and
ferrets at levels as low as 1 p p m (about 0.14 and 0.11 m g / k g / d a y
for m i n k and ferrets, r e s p e c t i v e l y ) .

Additionally,

effects were

seen on the levels of hypo t h a l a m i c dopamine of m i n k kits and on
h y p o t h a l a m i c s e r o tonin in adult mink.

T hese changes we r e

s t a t i stically s ignificant at levels as low as 1 p p m in feed.
NOAEL was not reported.

;

70

A

Arnold et al.

(1985) exposed male and female rats to d i e t a r y HCB

levels of 0, 0.32,

1.6, 8.0 or 40 p pm for 90 days p r i o r to mating

and until 21 days after pa r turition (at w e a n i n g ) .

The offspring

were exposed in utero, from maternal nursing, and from their
diets for the remainder of their lifetime.
period was 130 weeks.
0.08 m g / k g / d a y ) .

T he total study

A NO A E L was reported at 1.6 p p m (about

At 8 p p m

(0.29 mg/kg/day) the p a rental

(Fo)

males demon s t r a t e d increased heart and liver wei g h t s and the FI
generation had an increased incidence of hepatic centr i l o b u l ar
basophilic chromogenesis.

The 40 p pm FI groups s h owed increases

in pup mortality, hepatic centrilobular basop h i l i c chromogenesis,
and severe chronic nephritis

(males o n l y ) .

The effects of HCB on adult animals has been further demo n s t r a t e d
in many other studies, a few of which report NOAELs.
Goodman et al.

(1977) exposed rats via the diet to 0, 0.5, 2, 8

and 32 m g / k g bw/day for up to 15 weeks.

A N O A E L w as rep o r t e d at

0.5 mg/kg/day, while at the higher dose levels,
porphyrin,

Kuiper-

increased tissue

increased organ weights and increased s everity of

centrilobular liver lesions were noted.

G rant et al.

(1974)

exposed rats to HCB at diet a r y levels of 10, 20, 40, 80 a nd 160
p p m for 9-10 months.
20 p p m

Porphyria was induced at levels as low as

(about 1 m g / k g / d a y ) .

The data selected for HNC determination are from the A r n o l d et
al.

(1985) study.

This study involved the e x posure of adult

71

S prague-Dawley rats and subsequent e xposure of the o f f s p r i n g in
utero, via lactation, and via the diet.

Cross - f o s t e ri n g studies

have d e m o n s t r a t e d that the neonate is p a r t i c u l a r l y sensitive to
the toxic effects of HCB.

The t r ansfer of HCB to n e onates via

the m i l k of exposed adults has also been shown to be significant
(Bailey et al.

1980; Bleavins et al. 1982).

The A r n o l d et al.

(1985) study d e m o n s t r a t e d NOAELs of 0.32 and 1.6 p p m in feed
(estimated to be 0.016 and 0.08 m g / k g / d a y ) .

Therefore,

the N OAEL

of 0.08 mg/kg/day, w i t h an unce r t a i n t y factor of 100 (lOx for
each inter- and intraspecies extrapolation)
derivation.
data

is us e d for HNC

Consideration was also given to the m i n k and ferret

(Rush et al.,

1983; Bleavins et al.,

1984a,

1984b) which

d emonstrate that these species are h i g h l y sensitive to the
d e v e lopmental toxic effects of HCB.

A d v e r s e effects on the

develo p m e n t of mink and ferrets have been r e ported at doses only
slightly h i g h e r than the rat N O A E L of 0.08 mg/kg/day.

However,

the rat N O A E L is utilized p r e f e r e n t i a ll y because the SpragueDawley rat, u nlike the min k or ferret,

is a huma n - s u r r o ga t e

species w h i c h has been exte n s i v e l y studied as an animal m o d e l for
t o x icity testing, and because the A r n o l d et al.
of v e r y g o o d quality.

(1985) study is

The selection of this k e y s t u d y is

c o n s i s t e n t w i t h the develo p m e n t of the RfD for HCB by E PA (1988).

A D E = 0.08 m a / k a / d = 0.0008 mg/kg/d = 0.8 ug/k g / d
100

72

Where:

Uncer t a i n t y factor = 100, composed of:
lOx for intraspecies v a riability
lOx for interspecies extrapolation

D r i nking Water Sources:

HNV = A P E

Wh

X

RSC = 0.8 u a / k q / d

W C + (FC

X

BAF)

X

= 0.014 ug/1

70 k a

X

0.8_____________

2 1/d + (0.015 kg/d

X

208,590 1/kg*)

X

(rounded off to 10 ng/1

(Tier 1))

Nondri n k i n g W a t e r Sources:

HNV = APE x W h x RSC = 0.8 ua/ka/d x 70 ka x 0.8________________
W C + (FC x BAF)

= 0.014 ug/1

Where:

0.01 1/d + (0.015 kg/d x 208,590 1/kg*)

(rounded off to 10 ng/1

(Tier 1))

RSC = 0.8; the substance is p e r s i s t e n t and
bioaccumulative.

*BAF = 208,590, provided by EPA-Duluth and M i n n e s o t a PCA.

73

REFERENCES:
Arnold, D.L. et al.
1985.
L o n g - t e r m toxicity of
h e x a c h l o robenzene in the rat and the effect of dietary
v i tamin A.
Fd, Chem. Toxic.
23(9):779-793.
Bailey, J , , V. Knauf, W. Mueller and W. Hobson.
1980.
T r ansfer
of h e x a chlorobenzene and poly c h l o r i n at e d biphenyls to
nursing infant rhesus monkeys:
Enhanced toxicity.
Environ.
Res. 21(1):
190-196.
Bleavins, M.R., W.J. Breslin, R.J. A ulerich and R.K. Ringer.
1982.
Excretion and placental and mamm a r y t ransfer of
hexachlo r o b en z e n e in the European ferret (Mustela putorius
f u r o ) . J. Toxicol. Environ. Health.
10:929-940.
Bleavins, M . , R. Auler i c h and R. Ringer.
1984a.
Effects of
chronic dietary hexac h lorobenzene e xposure on the
r e p roductive performance and survivability of m i n k and
European ferrets.
Arch.
Environ.
Contam. Toxicol.
13:357-365.
Bleavins, M. et al.
1984b.
Effects of dietary hexach l o r o b en z e n e
exposure on regional brain biogenic amine concentrations in
m i n k and European ferrets.
Toxicol. Environ. Hlth.
14:363­
377.
Cam, C. and G. Nigogosyan.
1963.
A c q u i r e d toxic po r p h y r i a
cutaneatarda due to hexachlorobenzene.
R e port of 348 cases
caused by this fungicide.
J. Am. Med. Assoc.
183:88-91.
Grant, D. et al.
1974.
Effects of he x a c h l o r o b en z e n e on liver
p o r p h y r i n levels and micro s o m a l enzymes in the rat.
Environ. Physiol. Biochem.
4:159-165.
Grant, D . , W. Phillips and G. Hatina.
1977.
Effect of
hexac h l o r o b en z e n e on repr o d u c t i o n in the rat.
Arch.
Environ. Contam. Toxicol.
5 ( 2 ) :207-216.
Kitchin, K, et al.
1982.
Of f s p r i n g m o r t a l i t y and m a t e r n a l lung
p a t h o l o g y in female rats fed hexachlorobenzene. Toxicol.
23:33-39.
Kuiper-Goodman, T. et al.
1977.
subacute t oxicity of
hexac h l o r o b en z e n e in the rat.
Toxicol, and Appl. Pharmacol.
40:529-549.
Rush, G. et al.
1983.
Perinatal hexach l o r o b en z e n e tox i c i t y in
the mink.
Environ. Res.
31:116-124.

74

U.S. Environmental Protection Agency ( EPA). 1980.
A m b i e n t Water
Quality Criteria for Chlorinated Benzenes.
EPA 440/5-80028.
U.S. Environmental Protection Agen c y (EPA).
1985a.
Drinking
Water Criteria Document for Hex a c h l o r o b en z e n e (Final D r a f t ) .
EPA - 600/X-84-179-1.
PB-86-117777.
U.S. Environmental Protecti o n Agen c y (EPA).
1985b.
H e alth
Asses s m e n t Document for Chlorinated Benzenes.
E P A / 600/884/015F.
U.S. Environmental P rotecti o n A g e n c y (EPA).
1988.
Integrated
Risk Information System (IRIS d a t a b a s e ) . Chemical file for
h e x a chlorobenzene (118-74-1).
V e r i f i c a t i o n Date 5/26/88.
Last Revised 4/1/91.

Tier l Human cancer criterion

A r eview of the available literature indicates that there are
inadequate epidemiological studies and sufficient animal
c a r c i n ogenicity data,

supporting a B2 w e i g h t - o f - e vi d e n c e

c l a s s ification (EPA, 1989).

The animal bioassays, w h i c h have

been c o m p r e hensively reviewed and summarized by EPA (1980; 1985a;
1985b; 1989),

indicate that HCB induces tumors of the liver

predominantly, w i t h neoplas m induction of the thyroid and kidney
also reported.

The data are judged sufficient for Tier 1 HCC

derivation.

EPA (1991) d e r i v e d an oral slope factor of 1.6 p er (mg/kg)/day
from a chronic rat bioassay de m o n s t r a t i ng h e p a t o c e l l u la r
carcinoma induction

(Erturk et al.,

1986).

This slope factor is

among the h i ghest of those derived for H CB from 14 di f f e r e n t
datasets, which fell within a range of 8.3 E-2 to 1.7 E+0
75

(EPA,

1989).

This dataset was also selected for slope factor

estimation because the study was w e l l - c o n d u c te d and the tumors
were m a l ignancies of the primary target organ
In the key study,

Erturk et al.

published as Lambrecht et al.,

(liver c a n c e r s ) .

(1986; abstracts previ o u s l y
1983a; 1983b) exposed groups of 94

S p r a g u e-Dawley rats/sex/do se to HCB via feed at 0, 75 or 150 ppm
in the d i e t for up to two years.

Treated animals of both sexes

surviving past 12 months showed significant increases in liver
and renal tumors.

Females were far more susceptible to hepato-

c a rcinogenicity while males we r e g e n e r a l l y more sensitive to
renal carcinogenicity.

The slope factor of 1.6 per (mg/kg)/day

is derived from the induction of h e p a t ocellular c arcinomas in
female rats.

This is consistent wi t h EPA (1989).

RAD = 1 x 10~5________ = 6.2 x 10-6 m g / k g / d = 6.2 ng/kg/d
1.6

(mg/kg/d)” *

Drinking W ater Sources:

H C V = RAD x Wh________ = 6.2 nq/ko/d x 70 kg__________________
W C + (FC x BAF)

= 0.14 ng/1

2 1/d + (0.015 kg/d x 208,590 1/kg*)

(rounded off to 0.1 ng/1

76

(Tier 1))

N ondrink ing Water Sources:

HCV = RAD x Wh________ = 6.2 ng/ka/d x 70 kg_______________________
W C + (FC x BAF)

= 0.14 ng/1

Where:

0.01 1/d + (0.015 kg/d x 208,590 1/kg*)

(rounded off to 0.1 ng/1

(Tier 1))

*BAF = 208,590, provided by E PA-Duluth and M i n n e s o t a PCA.

REFERENCES:
Erturk, E. et a l . 1986.
O n c o genicity of h e x a c h l o r o b e n z e n e . In:
Hexachlorobenzene:
Proc. int. S y m p . , C.R. Morr i s and J.R.P.
Cabral, Eds.
IARC Scientific Publ. No. 77, Oxford
U n i v e r s i t y Press, Oxford.
pp. 417-423.
Lambrecht, R . , et al.
1983a.
Renal tumors in rats chron i c a l l y
exposed to h e x achloro b en z e n e (HCB). P r o ceedings of the
A m e r i c a n A s s o c i a t i o n for Cancer Re s e a r c h 24:59.
Lambrecht, R . , et al.
1983b.
H e p a t o c a r c i no g e n i c i t y of
c h r o n i c a l l y administer e d h e x a c h l o r o b en z e n e in rats.
Federa t i o n Proceedings.
4 2 ( 4 ) :786.
U.S. Environmental Protection Agen c y ( EPA). 1980.
A m b i e n t Water
Q u a l i t y Criteria for C h l orinated Benzenes.
EPA 440/5-80028.
U.S. Environmental Protecti o n A g e n c y (EPA).
1985a.
Drinking
W a t e r Criteria Document for H e x a c h l o r o b en z e n e (Final D r a f t ) .
EPA-600/X-84-179-1.
NTIS: PB 86-117777.
U.S. Environmental Protecti o n Agen c y (EPA).
1985b.
H e alth
A s s e s s m e n t Document for Chlorinated Benzenes.
EPA/600/884/015F.
U.S.

Environmental P rotecti o n Agen c y (EPA).
1989.
Integrated
Risk Information System (IRIS d a t a b a s e ) . Chemical file for
hexac h l o r o b en z e n e (118-74-1).
V e r i f i c a t i o n Date 3/1/89.
Last R e v i s e d 3/1/91.
77

78

October 31, 1991
GRE A T LAKES INITIATIVE
TIER 1 HUMAN H E A L T H CR I T E R I A FOR
HEXACHL O R O E TH A N E
CAS NO. 67-72-1

Tier 1 iTiiin»n Noncancer Criteria

A r eview of the available literature indicates that the most
a ppropriate basis for H NV d e r i v a t i o n for hex a c h l o r o e th a n e
(HCE)

is the NOAEL from a 16-week dietary study in rats

(Gorzinski et al.,

1985; Gorzinski et al., 1980, as cited in

EPA,

1991).

In this study ma l e and female CDF Fischer 344

rats

(10/sex/group) were administered a di e t c o n t a i n i n g HCE

at t arget levels of 0, 3, 30 and 100 m g / k g / d a y for 16 weeks.
EPA (1991) reported that actual dose levels we r e a nalyzed to
be a p p r o ximately 0, 1.3, 20 and 82 mg/kg/day.

From analysis

of eating patterns and measu r e m e n t of the t i m e - r e l a t e d loss
of HCE from the diets, a conservative estimate of exposure
was determined by the investigators as 0, 1, 15 and 62
mg/kg/day

(Gorzinski et al., 1985).

The results indicate

that male rats were slightly more sensitive than female rats
to the n ephrotoxic properties of HCE.

Renal t o xicity

observed at 15 and 62 mg / k g / d a y in male rats i ncluded pale
and m o t t l e d kidneys; significant increases in absolute and
relative kidney weights; slight to m oderate renal tubular
79
--

-------- ------- ^

P receding Page B lank |
J

a t rophy and degenerat i o n w i t h or without p e r itubular
fibrosis; a slight to mo d e r a t e increase in renal tubular
c y toplasmic clumping and droplet formation; and scattered or
isolated renal tubules w i t h slight h y p ertrophy and/or
dilation of the proximal c onvoluted tubules.

Liver weights

were increased in mal e rats given 62 mg/kg/day.

The liver

exhibited a slight sw elling of the h e p atocytes in males
g i v e n 15 or 62 mg/kg/day.

Evidence of renal toxicity in

female rats consisted of v e r y slight renal tubular atrophy
and d e g eneration observed histo p a t h o l og i c a l l y at the highest
dose level.

Female rats given 62 m g / k g / d a y also h ad an

increase in relative liver w e i g h t ratios u n a c c o m p a n i ed by
m i c r o s c o p i c alterations.

Based on this study, a N O A E L of 1

m g / k g / d a y was derived for liver and kidn e y t o xicity in male
rats.

W h i l e EPA (1991)

indicates a N O A E L of 1.3 mg / k g / da y

b a s e d on the analyzed low dose, th e e s t i mated N O A E L of l.o
mg/kg/day

(Gorzinski et al.,

1985; EPA, 1987)

is us e d in the

H N V derivation.

In a chronic (78-week) gavage study wi t h rats and mice, the
National Cancer Institute

(NCI, 1978) adm i n i s t e r e d H CE in a

cyclic m anner to 50 male and 50 female O s b o r ne-Mendel rats
and contin u o u s l y to 50 male and 50 female B6C3F1 mice.

The

rats r e c e i v e d H C E in corn oil at doses of 250 and 500
mg/kg/day,
weeks,

5 days per we e k for a p e r i o d of 22 c o n secutive

followed by a 1-week, t r e a t m e n t - f re e interval.

80

Thereafter, until the end of the 78 weeks, the rats were
intubated for 4 consecutive weeks followed by 1 t r e a t m e n t ­
free week,

in a cyclical pattern,

HCE treatment.

for a total of 66 w e e k s of

The t i m e - w e i g h ted-average doses for the rats

for the 78-week perio d were 212 and 423 mg/kg/day.

The mice

were intubated orally with HCE in corn oil at initial levels
of 500 and 1000 mg/kg/ d a y for 8 weeks w i t h these doses
increased to 600 and 1200 mg/kg/day, respectively,
remaining 70 experimental weeks.

for the

A t i m e - w e i g h t ed - a v e r a g e

dose of 590 and 1179 m g / kg/day for the low and hi g h doses,
respectively, was reported.

The dosi n g regimes were

followed by an observation peri o d of 33 or 34 weeks for rats
and 12 or 13 weeks for mice.

Renal tubular nephr o p a t h y was

observed during histop a thological e x amination at the
t e rmination of the study in all groups of trea t e d animals.
In rats, significant p a t h o l o g y and m o r t a l i t y at both dose
levels in the m a l e s pr e c l u d e d the deve l o p m e n t of a N O A E L or
LOAEL for HCE.

For the mice, due to the o ccurrence of

hepat o c e l l u la r carcinoma and n o n - n eoplastic toxic
nephr o p a t h y in both sexes at both dose levels, nei t h e r a
NOAEL nor a LOAEL could be determined.

Because of the inconclusive nature of results from the NCI
(1978) study, additional toxicological and c arcinogenesis
studies were conducted by administering HCE in corn oil by
g a vage to groups of male and female F344/N rats

81

(50/sex/group)

5 days per w e e k for 2 years

(NTP, 1989).

The

male rats received doses of 0, 10 or 20 m g / k g / d a y w h i l e the
females received doses of 0, 80 or 160 mg/kg/day.

The

foremost toxic effect was kidney toxicity, d e m o n s t r a t e d by
increased incidences of m i n e r a l i z a t io n and h y p e r p l a s i a of
the pelvic transitional epith e l i u m in dosed male rats,
increased severity of renal t u bule h y p erplasia in hi g h dosed
male rats, and increased incidence and s everity of renal
tubule hyperplasia in female rats.
bw/day for m a l e rats.

The LOAEL was 10 m g / k g

In this study,

it was hyp o t h e s i z e d

that the increased sensitivity of ma l e rats to the renal
t o x icity of HCE was a result of the accumulation of <*2 u “
g l o b u l i n in h y a l i n e d roplets synthesized by the liver and
secreted into the blood (EPA, 1991).

It is then apparently

filtered through the g l o meruli and p a r t ially reabs o r b e d
t h r o u g h the proximal tubules.

In the presence of HCE, as

well as several nonpolar hydrocarbons such as dec a l i n and
gasoline, a 2u“g l o buli n accumulates in hya l i n e dro p l e t s in
the renal t u bular cells.

a 2 u -Globulin is an e x c r etory

p r otein in male but not female rats.

This may e x p l a i n the

m ale's greater sensitivity to k i dney damage from HCE.

In a 13-week rat study, also by NTP

(1989), groups of 10

F 344/N rats of each sex were administered 0, 47, 94, 188,
375 or 750 mg/kg HCE in corn oil by gavage,
13 weeks.

5 d a y s / w e e k for

Five/10 male rats and 2/10 female rats at 750

82

m g / k g / d a y died before the end of the study.

T he final mean

body w e ight of male rats that received 750 m g / k g / d a y was 19%
lower than that of vehicle controls.

Compoun d - r e la t e d

clinical signs for both sexes included h y p e r a c t i v i t y at
doses of > 94 m g / k g/da y and convulsions at £ 375 mg/kg/day.
The relative weights of liver, h e a r t and k i d n e y were
increased for exposed males and females.
were seen in all dosed male groups,
increased w i t h dose.

Kidn e y lesions

and the severity

Papillary necrosis and tubular cell

necrosis and degenerat i o n in the kidn e y and hemor r h a g i c
necrosis in the u r inar y bladder we r e o b served in the five
male rats at 750 mg/kg / d a y which died before the end of the
study.

At all lower doses in males, hyal i n e droplets,

tubular regeneration,

and granular casts were present in the

kidney.

No chemical-r e la t e d k i dney lesions were obs e r v e d in

females.

Foci of hepat o c e l l u la r necrosis we r e o b s e r v e d in

several male and female rats at > 188 mg/kg/day.

Weeks et al.

(1979)

studied the effects of rep e a t e d exposure

to H C E vapor in 25 male and 25 female rats, 4 m a l e dogs,
male guinea pigs,

20 ma l e or female quail and 22 pre g n a n t

rats per exposure group.
hours/day,

10

The animals were expo s e d for 6

5 d a y s /week for 6 weeks and doses w e r e analyzed

at 0, 15, 48 or 260 ppm of the HCE v apor
145, 465 or 2515 m g / m 3 ; EPA, 1991).

83

(equivalent to 0,

T o x i c effects at the

h i ghest concentrations included tremors and. other n eurotoxic
signs.

No effects were observed at < 465 m g / m 3 .

Weeks et al.

(1979) pe r f o r m e d an oral study,

doses of 100,

320 and 1000 mg / k g / d a y were a d m i n istered by

g avage to rabbits for 12 days.

in w h i c h HCE

The two highest doses

resulted in liver d e g e n e r a t i o n and necrosis, toxic tubular
nephrosis of the convo l u t e d tubules of the cortico m e d u ll a r y
region of the kidney, minimal tubular nephrocalcinosis,
d e c r e a s e d body weights.

and

The N O A E L for this study was 100

m g / k g / d a y based on the effects of HCE on the kidneys of male
rabbits.

The d a t abase is judged to be sufficient for Tier 1 HNC
derivation.

The k e y study

(Gorzinski et a l . , 1985) provides

a subchronic N O A E L wh i c h is supported and supplemented by
chronic t o x icity data (EPA 1989; EPA,
1989; Weeks et a l . , 1979).

1991; NCI,

1978; NTP,

The HNC is based on the

subchronic r a t N O A E L of 1 m g / k g / d a y (0.71 m g / kg/day
c o n v e r t e d for 5 d a y a d m i n i s t r a t i o n / w e e k ) , wi t h a total
u n c e r t a i n t y factor of 1000.

T he L OAEL of 15 mg / k g / d a y

resulted in m a l e rat renal toxicity.

It m ay be a r gued that

the h i g h sensitivity of this e ndpoint is p e c u l i a r to male
rats, secondary to hyaline drop l e t formation and a 2 u g l o b u l i n accumulation.

However,

at a L O E L of 15 mg/kg/day.

liver affects also occurred

The use of the N O A E L of 1

84

m g / k g / d a y for risk assessment is c onsistent wi t h the oral
RfD d evelopment by EPA (1987) and the Lif e t i m e H e alth
A d v i s o r y (EPA, 1991).

A D E = Q .71 m o /ka/d = 0.00071 mg/k g / d = 0.71 ug/k d / d
1,000

where:

Uncert a i n t y Factor = 1,000, c o mposed of:
lOx for intraspecies v a r iability
lOx for interspecies e x t rapolation
lOx for subchronic exposure du r a t i o n

D r i nking W a t e r Sources:

HNV = ADE x Wh x RSC
W C + (FC

X BAF)

= 0.71 ua/ko/d x 70 ka x 0.8
2 1/d + (0.015 kg / d

= 2.45 ug/1 (rounded off to 2 ug/1

(Tier 1))

Nond r i n k i n g W a t e r Sources:

HNV * ADE x Wh x RSC

= 0.71 uo/kg/d x 70 kg x 0.8_________

WC + (FC * BAF)

0.01 l/d + (0.015 kg/d * 950 L/kg*>

= 2.79 ug/l (rounded off to 3 ug/l (Tier 1))

Where:

RSC = 0.8; HCE is bioaccumulative.

85

X 950 1/kg*)

Where:

*BAF = 950 1/kg, p r o v i d e d by EPA-Duluth and

M i n n e s o t a PCA.

REFERENCES:
Gorzinski, S.J., R.J. Nolan, S.B. McCollister, D.C. Morden,
E.A. Hermann, D.A. Dittenbar, R.V. Kainis, J.E. Battjes
and R.J. Kociba.
1980.
Hexachloroethane:
Res u l t s of
a 16-Week T o x ici t y Study in the Diet of CDF Fischer 344
Rats.
T o x i c o l o g y Res e a r c h Laboratory, Dow Chemical
U . S . A . , Midland, MI.
As cited in EPA (1991).
Gorzinski, S . J . , R.J. Nolan, S.B. McCollister, R.J, Kociba
and J.L. Mattsson.
1985.
Subchronic oral toxicity,
t issue distri b u t i o n and clearance of hex a c h l o r o e th a n e
in the rat.
Dru g and Chem. Toxicol.
8 ( 3 ) :155-169.
National Cancer Institute (NCI).
1978.
B i oassay of
H e x a c h l o r o e th a n e for Possible Carcinogenicity.
NCI
C a r c i nogenesis Technical Report Series No. 68, NCI- C G T R - 6 8 , DHEW Publication No. (NIH) 78-1318.
National T o x i c o l o g y P r o g r a m (NTP). 1989.
T o x i c o l o g y and
C arcinogenesis Studies of Hex a c h l o r o e th a n e (CAS No. 6 7 ­
72-1) in F344/N Rats (Gavage S t u d i e s ) . NTP Te c h n i c a l
Report.
N T P - T R - 3 6 1 , N I H / P U B - 8 9 - 2 8 1 6 , Order No. PB90170895, 117 pp.
U.S. Environmental Prote c t i o n A g e n c y (EPA).
1991.
Hexachloroethane.
Heal t h Advisory. O f fice of Dri n k i n g
Water, Washington, DC. PB91-159657/XAD.
U.S. Environmental Prote c t i o n A g e n c y (EPA).
1989.
Health
and Environmental Effects Document for
Hexachloroethane.
E n v ironmental Criteria and
A s s e s s m e n t Office, Cincinnati, OH.
EPA/600/8-88/043.
PB88-178736/GAR.
ECAO-CIN-G041.
U.S. Environmental Prote c t i o n Agency (EPA).
1987.
Integrated Risk Information System (IRIS d a t a b a s e ) .
Chemical file for hex a c h l o r o e th a n e (67-72-1).
V e r i f i c a t i o n Date 4/16/87.
Last Rev i e w e d 4/16/91.
Weeks, M.H., R.A. Angerhofer, R. Bishop, J. T h o m a s i n o and
C.R. Pope.
1979.
The toxicity of h e x a c h l o r o e t h a n e in
laboratory animals.
Amer. Ind. Hyg. Assoc. J.
40(3) :187-199.

86

Tier 1 Human Cancer Criterion
A review of the available literature for H CE carcinogenicityreveals a lack of adequate epidemiological data and two
chronic oral rodent bioassays

(NCI,

1978; NTP,

1989).

EPA

(1986) has classified H C E as a class C c a r c i n o g e n (possible
h u m a n c a r c i n o g e n ) , based on the observation of carcinomas in
one mouse strain after oral exposure (NCI, 1978).

The data

are judged to be sufficient for Tier l H CC derivation.

In a NCI study (NCI,

1978), Osborne-Mendel rats and B6C3F1

mice were orally intubated wi t h HCE in corn oil.

Groups of

50 rats per sex per dose were administered H C E over a 78week p eriod w i t h an exposure p r otocol involving intermittent
treatment-free intervals.

Th e tim e - w e i g h t ed - a v e r a g e doses

were 212 or 423 mg/kg/day.

The rats were then obs e r v e d for

an additional 33-34 weeks.

Groups of 50 mice p er sex per

dose were a d ministere d HC E 5 days p er w e e k for 78 w eeks at
t i m e-weighted-average doses of 590 or 1179 mg/kg/day,
were then observed for an additional 12-13 weeks.

and

Due to an

u n u s u a l l y h i g h morta l i t y rate among the m a l e control mice,
the results in treated groups were compared against both the
v e hicle control group from this study as well as a pooled
vehicle control group from several concu r r e n t studies.

A

stat i s t i c a l ly signifi c a n t increase in the incidence of
h e p a t ocellular carcinoma was reported in both sexes of the
mice

(only males exhibited a dos e - r e l a t e d trend) while

87

tumo r i g e n i c it y was not o b served in rats of e i t h e r sex.

The

increased incidence w as significant by the C o c h r a n - A r m it a g e
test for both sexes of mice against both control g r oups and
by the Fisher exact tests for both sexes as co m p a r e d to the
p o o l e d controls.

Survival of

low- and h i g h -dose m a l e and female rats in this study was
reduced compared with that of t he vehicle controls.

B e c ause findings from NCI

(1978)

in rats were inconclusive,

additional studies on t o x i c i t y and c a r c i nogenesis we r e
c o n d u c t e d in F344/N rats by a d m inistering HCE in corn oil by
g a vage to g roups of m ales and females for 2 y e a r s
1989).

H C E was admi n istered 5 d a y s / w e e k in c o m

(NTP,
oil by

g a v a g e at 0, 10 or 20 m g / k g bw to groups of 50 m a l e rats,
and at 0, 80 or 160 m g HCE/kg b w to groups of 50 female
rats.

T h e incidences of renal adenomas and carci n o m a s alone

and in combin a t i o n increased in the high dose m a l e group.
One of the carcinomas in the high dose group m e t a s t a s i z e d to
the lung.

No c o m poun d - r e la t e d neoplasms we r e ob s e r v e d in

females.

The incidence of ph e o c h r o m o c yt o m a s of the adrenal

g l a n d in low dose male rats was signi f i c a n t ly g r e a t e r than
that in v e hicle controls, and the incidences for b o t h dosed
groups were greater th a n the mean h istorical control
incidence rates.

The renal lesions were consi d e r e d by NTP

to be indicative of HCE c a r c i n o g e n i ci t y w h i l e the
p h e o c h r o m o c yt o m a s were judged to be supportive e v idence for
88

carcinogenic effects.

On the basis of these data, NTP

concluded that there was clear evidence of carci n o g e n i ci t y
for H C E in the male rat and no evidence of carci n o g e n i ci t y
in female rats.

Renal tubule hyperplasia was obs e r v e d at an

increased incidence in high dose male rats.

T hese lesions

have been described as characteristic of the hyaline droplet
nephr o p a t h y that is a ssociated with an acc u m u l a t i o n of
l i ver-generated a 2il-globulin in the c y t o p l a s m of tubular
epithelial cells

(NTP, 1989).

Using this assumption,

it can

be hypothesized that the male rat renal tumors were a
secondary effect to hyaline droplet f o r m ation and that they
m a y not be relevant to h u m a n risk assessment.

The Tier 1 Human Cancer Criteria for H CE a re d e r i v e d from
the slope factor of 1.4 E-2

(mg/kg/d)-1 based on a dose-

response data-set for h e p a t ocellular carcinoma i n d u ction in
male mice from the NCI study (NCI, 1978; EPA,

RAD = 1 x 10~5________________
1.4 x 10-2

1986).

= 7.14 x 10-4 m g / k g / d

(mg/kg/d)-1

Drinking Water Sources:

HCV = RAD x Wh________ = 7.14
WC + (FC x BAF)

X

10~4 m a / k g / d x 70 ka

2 1/d + (0.015 k g / d x 950 1/kg*)
89

= 3.1 x 10“ 3 mg/1

(rounded off to 3 ug/1

(Tier 1))

N o ndrinking Water Sources:

HCV = ra d x wh______ = 7.14 x 10'* nw/kg/d x 70 tea________
UC + CFC x BAF)

0.01 L/d + (0.015 kg/d x 950 l/kg*)

= 3.5 x 10's mg/t (rounded off to 4 yg/l (Tier 1))

Where:

*BAF = 950 l / k g f p r ovided by EPA-Duluth and
M i n n e s o t a PCA.

90

REFERENCES;
National Cancer Institute (NCI).
1978.
Bio a s s a y of
H e xachloroethane for Possible Carcinogenicity.
NCI
Carcinogenesis Technical Report Series No. 68, NCI-CGTR-68, DHEW Publication No. (NIH) 78-1318.
National Toxic o l o g y Program (NTP). 1989.
T o x i c o l o g y and
Carcinogenesis Studies of Hex a c h l o r o e th a n e (CAS No. 6 7 ­
72-1) in F344/N Rats (Gavage S t u d i e s ) . NTP Technical
Report.
NTP-TR-361, N I H / P U B - 8 9 - 2 8 1 6 , Order No. PB90170895, 117 pp.
U.S.

Environmental Prote c t i o n A g e n c y ( E P A ) . 1986.
Integrated Risk Information System (IRIS d a t a b a s e ) .
Chemical file for hexachl o r o e th a n e (67-72-1).
Verifi c a t i o n Date 7/23/86.
Last Re v i e w e d 7/23/86.

91

92

Oct o b e r 31,

1991

GRE A T LAKES INITIATIVE
HUMA N HEALTH C RITERIA FOR
LINDANE
(G A M M A - H E X A C H L O R O C Y C L O H E X A N E )
CAS NO. 58-89-9
Tier 1 Human Noncancer Criterion

A r eview of the available literature indicates that the most
appropriate study for the deriv a t i o n of the H N V for lindane
is a subchronic study c o n d ucted by Zoecon C o r poration
as evaluated by EPA (1991)

(1983)

and summarized by EPA (1986).

this study, W i s t a r KFM- H a m (outbred)

SPF rats

In

(20/sex/dose)

were administered 0, 0.2, 0.8, 4, 20 or 100 p p m lindane in
the feed.

Fifteen ani m a l s /sex/group were s acrificed after

12 weeks.

The r e m a ini n g rats were fed the control diet for

an additional six weeks before sacrifice.

Rats exposed to

20 and 100 ppm lindane had a greater incidence of liver
hypertrophy,

kidney tubular degeneration, h y a l i n e droplets,

tubular distension,

interstitial n e p hritis and basophilic

tubules than did the controls.
4 ppm.

The N O A E L for this study was

This dose was estimated to be e quivalent to 0.29

m g / k g / d for the male and 0.33 mg/ k g / d for the female rats.

Two chronic studies which e xamined the effects of lindane on
rats and dogs were cited by EPA (1986).

A t w o-year study by

Fitzhugh (1950) reported a N O A E L of 2.5 m g / k g / d in Wistar
rats with liver weights and liver damage e v a l uated as the
93
Prec ed in g p a g e W a n k

endpoints.
al.

In a two-year study in beagle dogs, R i v e t t et

(1978) reported a N O A E L of 1.6 mg/ k g / d for liver

toxicity.

A r e v i e w of the datab a s e on d e v elopmental and r e p r o ductive
effects of lindane suggests that these effects may occur at
levels h igher than the N O A E L calcu l a t e d in the study
conducted by Zoecon C o r poration
(1978a)

(1983).

Palmer et al.

found no adve r s e effects on r e p r o ductive function

and d e v e l o p m e n t following exposure of female rats to lindane
in the feed at levels of 1.25, 2.5 and 5 m g / k g / d for three
generations.

Khera et al.

(1979)

found no repr o d u c t i v e

effects in w i s t a r rats exposed to lindane at levels ranging
from 6.25 to 25 mg/kg from the 6th to the 15th day of
gestation.

No adverse effects were found in a

terat o g e n i c it y study on p r egnant rabbits fed lindane on
g e s t ation days 6-18 at levels of 5, 10 and 15 m g / k g
et al.,

1978b).

However,

Sircar and Lahiri

that even the lowest exposure group

(Palmer

(1989) r eported

(3.75 mg/kg/d)

of Swiss

m i c e r e c e i v i n g lindane during g e s t a t i o n exper i e n c e d
reproductive failure.

The q u ality of the study c o n d ucted by Zoecon Corpo r a t i o n
(1983) was deemed sufficient to d e rive a Ti e r 1 HNC.

The

results of studies wh i c h examine the r e p r o ductive or
d e v e l opmental effects of lindane are either negative or
94

indicative of possible effects at doses su b s t a n t i a l ly higher
than the NOAEL reported by Zoecon Corporation
A l t h o u g h subchronic in duration

(1983).

(12 w e e k s ) , the key study is

supported by chronic studies in the database.

This study

was also used by EPA (1986) to derive the oral RfD for
lindane.

The HNC was derived from the female rat NOAEL

(0.33 mg/kg/d) u s i n g an u n certainty factor of 1000 to
account for intraspecies variability,

interspecies

extrapolation and the extrapolation from a subchronic to
chronic study.

The magnitude of this unce r t a i n t y factor is

expected to result in adequate prote c t i o n from any potential
reproductive or developmental effects as well as chronic
n o n c ancer effects.

ADE = 0.33 m a / k a / d = 0.00033 mg/k g / d = 0.33 ug/kg/d
1000

Where:

U n certainty Factor = 1000, co m p o s e d of:
lOx for subchronic to chronic e x t r a p o l a t i on
lOx for intraspecies v a r iability
lOx for interspecies extrapolation

Drinking Water Sources:

HNV = A D E x Wh x RSC

= 0.33 uq/ k q / d x 70 kq x 0.8_________

W C + (FC x BAF)

2 1/d + (0.015 kg / d X 1,628 1/kg*)
95

= 0.69 ug/1

(rounded off to 0.7 ug/1

(Tier l ) )

Nondri n k i n g Water Sources:

H N V = A P E x W h X RSC

= 0.33 uc/kq/d it 70 ka x 0.8____________

W C + (FC x BAF)

0.01 1/d +(0.015 kg/d x 1,628 1/kg*)

= 0.76 ug/1

Where:

(rounded off to 0.8 ug/1

(Tier 1))

R S C * 0.8; the substance is b i ©accumulative.

*BAF = 1,628, p r o v i d e d by EPA-D u l u t h and M i n n e s o t a PCA.

REFERENCES:
Fitzhugh, O.G., A.A. N e l s o n and J. P. Frawley.
1950.
The
c h ronic toxicit i e s of technical benzene hexa c h l o r i d e
and its alpha, beta and gamma isomers.
J. Pharm. Exp.
Ther.
100:59-66.
Khera, K.S., C. Whalen, G. Trivett and G. Angers.
1979.
T e r a t o g e n i c i t y studies on pesticidal formulations of
dimethoate, d iu r o n and lindane in rats.
Bull. Environ.
Contain. Toxicol.
22 (4-5): 522-529.
Palmer, A.K., D.D. Cozens, E.J.F. Spicer and A.N. Worden.
1978a. Effects of lindane upon repr o d u c t i v e function in
a 3-generation study in rats.
10(l):45-54.
Palmer, A . K . , A.M. Bottomley, A.N. Worden, H. Fr o h b e r g and
A. Bauer.
1978b.
Effect of lindane on p r e g n a n c y in
the rabbit and rat.
Toxicol.
9(3):239-247.
Rivett, K.F., H. Chesterman, D.N. Kellett, A.J. N e w m a n and
A.N. Worden.
1978.
Effects of feeding lindane to dogs
for p e riods of up to two years.
Toxicol.
9:273-289.
96

sircar, s. and P. Lahiri.
1989.
Lindane (gamma-HCH)
reproductive failure and fetotoxicity in mice.
Toxicol.
59:171-177.

causes

U.S. Environmental Protection Agen c y (EPA). 1986.
Integrated Risk Information System (IRIS d a t a b a s e ) .
Chemical file for lindane (58-89-9).
Veri f i c a t i o n Date
1/22/86.
Last Revised 3/1/88.
U.S.

Environmental Protection A g e n c y (EPA).
1991.
Data
Evaluation Record (DER) for lindane.
Office ofPesticide Programs.

Zoecon Corporation.
1983.
Unpub l i s h e d report.
M R I D No.
00128356.
Available from EPA.
Write to FOI, EPA,
Washington, D.C.
20460.
Tier 2 Human Cancer level of protection

There are inadequate data available to ascertain whether
lindane is a human carcin o g e n (IARC, 1982; EPA, 1985; ATSDR,
1989).

The preponder a n ce of evidence indicates that lindane

is carcinogenic to mi c e (EPA, 1985).
conducted by T horpe and Walker
al.

(1972) and Hanada et al.

A n imal bioassays

(1973), NCI

(1977), Goto et

(1973) p r o v i d e e vidence that

lindane induces liver tumors.

Possible re l e v a n c e to humans

is indicated by the occurrence of a carc i n o g e n i c m etabolite
(2,4,6-trichlorophenol)

in humans and other species

following exposure to lindane (EPA, 1980; 1985; ATSDR,
1989).

T h e weight-of - e vi d e n c e for lindane carc i n o g e n i ci t y

is report e d l y sufficient for "B2-C" c l a s s i f i c a t io n (EPA,
1985; 1991).

The database was not judged s ufficient for B2

(probable h uman carcinogen)

c l a s s ification b e c a u s e of

limitations in the quality of the b ioassay data and also
97

because the results of mo s t m u t a g e n i c i t y tests have been
negative

(EPA,

1985).

A c c o r d i n g to EPA (1985),

"the weight-

of-evidence appears to be closer to a Category C c arcinogen
than to Categ o r y B2 c a r c i n o g e n " .

The cancer ri s k asses s m e n t

for lindane is u n d e r revi e w by EPA (EPA,

1990).

For this

initiative, the data are s ufficient to d e r i v e a Ti e r 2- level
of p r o t e c t i o n b e cause liver tumor induction has be e n found
in m o r e t h a n one bioassay,
strains of mice.

in both sexes and in mu l t i p l e

A Ti e r 1 cr i t e r i o n is not indicated, due

to the limited q u alit y of t he bio a s s a y data, the lack of
m u t a g e n i c i t y data, and the p e n d i n g a ssessment by EPA.

The T horpe and W a l k e r

(1973) study was used to determine thé

Tier 2 level of p r o t e c t i o n because it p r ovides the best
q u a l i t y data for quan t i t a t i v e ri s k assessment.
study,

In this

30 CF1 m i c e of each sex w e r e exposed to 400 p pm

lindane in their diet for up to 110 weeks.

T he p o o l e d

control group c o n s ist e d of 45 animals of ea c h sex.

Besides

h a v i n g only one expos u r e level, the qua l i t y of t he study was
c o m p r o m i s e d because a low p e r c e n t a g e of tre a t e d mi c e
s u r v i v e d (3% of females and 17% of males) to t he e nd of the
s tudy (EPA 1980; 1985).

T h e r e w as a s i g nificant increase in

the incidence of hepa t i c neoplasms in t r e a t e d m a l e and
female mice.

Liver neoplasms were found in 27/28

t r e a t e d male m i c e and 20/21
c o m p a r e d to 11/45

(24%)

(96%)

(95%) treated female m i c e as

and 10/44

98

(23%)

liver neoplasms in

male and female controls, respectively.

The male m o u s e data

were used to calculate a slope factor of 1.3

(mg/kg/d)

1 via

the linearized multistage model Global 82.

RAD = l x 10~5_________ = 7.6 x 10-6 mg/kg/d = 7.6 ng/kg/d
1.3

(mg/kg/d)-1

Drinking Water Sources:

HCV = RAD

X

Wh________ = 7.6 nq/kq/d x 70 ka__________________

W C + (FC x BAF)

= 20 ng/1

2 1/d + (0.015 kg/d x 1,628 1/kg*)

(rounded off to 20 ng/1

(Tier 2))

Non dr i n k i n g Water Sources:

HCV = RAD x W h ________ = 7.6 nq/kq/d
W C + (FC

X

= 21.7 ng/1

BAF)

X

70 R q ________

0.01 1/d +(0.015 k g / d x 1,628 1/kg*)

(rounded off to 20 ng/1

(Tier 2))

*BAF = 1,628, provide d by EPA-Duluth and M i n n e s o t a PCA.

REFERENCES:
99

A g e n c y for Toxic Substances and Disease R egistry ( A T S D R) .
1989.
Toxicolo g i c al Profile for Alpha-, Beta-, Gammaand Delta-Hexachlorocyclohexane.
U.S. Public Health
Service.
Goto, M . , M. Hattori and T. Mizagawa.
1972.
Contr i b u t i o ns
to ecology. II.
Hepatoma development in mi c e after
a d m i n i stration of HCH isomers in high dosages.
Chemosphere.
1:279-282.
Hanada, M . , E. Kawano, S. K awamura and M. Shiro.
1981.
R a d i a t i o n and photo - i n d u c ed degra d a t i o n of five isomers
of 1,2,3,4,5,6-hexachloro-cyclohexane.
Agric. Biol.
Chem.
4 5 ( 3 ) :659-665.
International A g e n c y for Res e a r c h on Cancer (IARC). 1982.
IARC Monogr a p h s on the Evaluation of the Carcinogenic
Risk of chemicals to Humans.
Suppl.
4:133-135.
N a t ional C ancer Institute (NCI).
1977.
B i oassay of Lindane
for Possible Carcinogenicity.
NCI Carci n o g e n e si s Tech.
Rep. ser. No. 14.
99 p.
NTIS PB-273-480.
Thorpe, E. and A.I. Walker.
1973.
The toxic o l o g y of
d i e l d r i n (HEOD). II. Compa r a t i v e l o n g-term and toxicity
studies in mice w i t h dieldrin, DDT, phenobarbitone,
B e t z - B H C and gamma-BHC,
Food Cosmet. Toxicol.
1 1 :433­
442.
U.S. Environmental P r o t e c t i o n A g e n c y (EPA). 1980.
Ambient
W a t e r Q u ality C riteria for Hexachlorocyclohexane.
Criteria and Standards Office.
Washington, DC.
EPA
444/5-80-054.
U.S. Environmental Protec t i o n A g e n c y (EPA).
1985.
Drinking
W a t e r Criteria D ocument for Lindane.
P r epared by the
O f f i c e of H ealt h and Environmental Assessment.
E n v i ronmental Criteria and Assess m e n t Office,
Cincinnati, OH for the O f f i c e of D r inking Water,
W a s h i n g t o n , D .C .
U.S. Environmental Protec t i o n A g e n c y (EPA).
1990.
Integrated Risk Information S y stem (IRIS d a t a b a s e ) .
Chemical file for lindane (58-89-9).
Last R e v i s e d
8/1/90.
U.S. Environmental Protection Agency (EPA).
Effects Assess m e n t Summary Tables.

100

1991.

Health

October 23, 1991
GREAT LAKES INITIATIVE
TIER 1 HUMAN HEALTH CRITERIA FOR
MERCURY
CAS NO. 7439-97-6
(INCLUDING METHYLMERCURY,

CAS NO. 22967-92-6)

Tier l Human Noncancer C r i t erion

A review of the available literature on the environmental
cycling,

fate, and to xicity of merc u r y and m e r c u r y compounds

indicates that HNC derivation is m o s t appro p r i a t e ly based
u p o n the h u m a n dose-r e s p o n se to methylmercury.
reviews on m e r c u r y toxicity (e.g., WHO,

Numerous

1976; 1990; EPA,

1980; 1984a; 1984b; 1985a) d e scribe the h u m a n dose- r e s p o n se
rel ationship resulting from food-borne e x posure to
met hy l m e r c u ry in Iraq (1971-72), J a p a n (1940s th r u 1960s),
and elsewhere.

These data are judged to be sufficient for

Tier 1 criterion derivation.

Studies of widesp r e a d human food-borne e x posure to
m e t h y l m e r c u ry in fish (Minamata and Niigata, Japan) and in
seed grain (Iraq) have shown that neurological symptoms of
mercury toxicity in adults appear w i t h blood levels of
m e r c u r y in the range of 200 to 500 ng/ml
Strangert,

1976; Clarkson et al.,

101

(Nordberg and

1976; WHO,

1976; 1990;

EPA,

1980; 1984a; 1984b; 1985a).

However, there are a few

studies of workers exposed o c c u p ationally to merc u r y via
inhalation w h i c h suggest that blood merc u r y levels as low as
10-20 ng/ml may result in the development of signs of renal
d y s f u n c t i o n (increased p r o teinurea a nd albuminurea)
abnormal p s ychomotor p e r formance

(Roels et al.,

Piikivi et al., 1984; Buchet et a l . , 1980).

and

1982;

The adult LOAEL

of 200 ng/ml in blood has be e n associ a t e d w i t h an intake
level of 200-500 u g / d

(EPA, 1980; WHO,

1990), a l though the

human adult populati o n ' s varia b i l i t y in merc u r y elimination
rate is significantly bimodal
N o r d b e r g and Strangert,
or 3 ug/kg/d,

(Clarkson et al, 1976;

1976).

The human L O A E L of 200 ug/d,

for the devel o p m e n t of neurological effects

forms the basis for the RfD deri v e d by E PA (1985b)

and the

fish consum p t i o n criteria deri v e d by E PA (1980).

It has

been e s t i mated that less than 5% of the adult p o p u l a t i o n
will experi e n c e neurological effects at these levels

(WHO,

1990).

The risk assessments by EPA (1980) and EPA (1985b) utilized
a total u n c e r t a i n t y factor of 10 in c o n junction w i t h the
L O A E L dose, and both stated that the L O A E L and the risk
assessment addressed the sensitivity and the a dequate
protec t i o n of both pr e - and postnatal exposures.

EPA (1980)

ju stified the 10-fold u n c e r t a i n t y factor as an accounting
for "individual differences in habits of fish consumption

102

and in s usceptibilit y to the toxic effects of methylmercury,
including prenatal exposures".

EPA (1985b) j u s t i f i e d the

10-fold u ncertainty factor "to adjust the L O A E L to what is
expected to be a NOAEL.

Since the effects are

seen in sensitive individuals for chronic exposure, no
additional factors are d e emed necessary".

For the deriva t i o n of the Tier 1 Human No n c a n c e r Criterion,
a total u n c e r t a i n t y factor of 50 will be utilized.

This is

c o m posed of a 10-fold factor to adjust the adult LOAEL to a
p r e s u m e d adult N O A E L and an a dditional 5-fold factor to
protect CNS developme n t during the sensitive fetal life
stages.

The use of a 10-fold factor for L O A E L - t o - N O A E L

c onversion is justified by c o n s i d e r a t i on of th e severity and
i r r e v e rsibility of the effects at the LOAEL, the long
latency of m e r c u r y effects, and the o c c u p ational studies
w h i c h suggest that the t h r e shold m a y be c o n s i d e r a b l y lower
than 200 ng Hg/ml blood.

A n u n c e r t a i n t y factor of 5 is u t i l i z e d to e n sure that the
criterion will be prote c t i v e of the fetal effe c t s of m e r c u r y
exposure via maternal ingestion of m e r c u r y - c o n t a m i n a t e d
fish.

The partic u l a r sensitivity of the fetus h a s been

r e c o g n i z e d in reviews of mercury t o x i c i t y (WHO, 1976;
D'ltri,

1978; EPA,

1980;

1984a;
103

1984b; 1985a).

1990;

T he earliest

of these assessments

(WHO, 1976) developed a dose- r e s p o n se

r e lationship for the adult w hich was not p r e s e n t e d as being
accurate for the mor e sensitive fetal effects.

It was noted

that many infant victims reported from Mi n a m a t a had severe
cerebral involvement

(palsy and retardation)

whereas their

m o thers had m i l d or no m a n i f e s t a t i on s of poisoning.
A l t h o u g h these observations were q u a l i t a t i v e ly confirmed by
animal studies, quant i f i c a t i o n of the d i f f e r e n c e in the
degree of sensitivity between human fetuses and adults has
been elusive.

EPA (1980; 1985b) u t ilized a total

u n c e r t a i n t y factor of 10 and assu m e d that the r e s ulting risk
a ssessments w e r e adequately p r o t e c t i v e of fetal effects.
However, W H O

(1990) r e viewed the database on oral

m e t h y l m e r c u ry ingestion,

including more recent studies,

and

made signif i c a n t advances in d e l i n e a t i n g quant i t a t i v el y the
greater sensit i v i t y of prenatal exposure relative to adult
exposure.

Although WHO

(1990) di d not re c o m m e n d a

p a r t i c u l a r n u meric sensitivity factor for the fetus, their
a ssessment s u fficient l y demonstrates that an additional
u n c e r t a i n t y factor is reasonable and prud e n t to he l p ensure
adequ a t e protection.

T h e y c o n c l u d e d that adult effects

occur at a L O A E L (for 5% increased occurrence rate)
ng/ml blood, or at 50 ug/g in hair.

of 200

Fetal effects on CNS

d e v e l o p m e n t occur at a LOAEL (5% increased occurrence rate)
of 10-20 u g / g as a peak level in maternal hair.

Since the

level of m e r c u r y in maternal blood correlates to the

104

simultaneous level in new hair growth, the ha i r serves as a
fairly reliable indicator of m a ternal blood m e r c u r y levels
during pregnancy.

The data suggest that the fetal effects

LOAEL m a y be 2.5 to 5 times lower than the adult effects
LOAEL.

The HNC is derived from the a d u l t ‘LOAEL dose of 3 ug/kg/d
which is associated with the LOAEL in blood of 200 ng/ml,
and an uncert a i n t y factor of 50.

The m e t h y l m e r c u r y form is

the most significant of the merc u r y compounds from the
standpoint of ambient environmental m e r c u r y and human
exposures and h ealth impacts.

Aqueous c o n c e n t r a t i on s of

mercury, and e speciall y methylmercury, m a y be very low in
ambient waters.

Other forms of mercury, such as elemental

m e r c u r y or m e r c u r y (I), m a y be r e a s o n a b l y anti c i p a t e d to be
transformed p r e d ominan t ly to m e t h y l m e r c u ry in the aquatic
environment via oxidation to merc u r y (II) and
biomethylation.

T h e b i o m e thylation of inorganic m e r c u r y and

the very high propensi t y for methyl m e r c u ry to bioaccumulate
in aquatic organisms result in a hi g h and significant human
exposure potential
1975).

(EPA, 1980; D'ltri,

1990; A n n e t t et al.,

The various forms of m e r c u r y r eleased to and found

in the ambient aquatic environment m ay be assumed to be
converted primarily to methylmercury.

Therefore, the HNC is

expressed as the total recoverable merc u r y concentration.

105

A D E = 3 u a /ka/d = 0.06 ug/kg/d
50
Where:

Uncertainty Factor = 50, c omposed of:
lOx for LOAEL - t o - N O AE L conversion
5x for intraspecies varia b i l i t y (protection of fetal
CNS development)

D r i n k i n g W a t e r Sources:

H N V = A D E x W h x RSC = 0.06 uq/kq/d x 70 ka x 0.8_________
W C + (FC x BAF)
= 0.0017 ug/1

2 1/d + (0.015 kg/d x 130,440 1/kg*)

(rounded off to 2 ng/1 (Tier 1))

N o n d r i n k i n g Water Sources:

HHV - ADE x UH x RSC - 0.06 ug/kg/d x 70 kg x 0.8___________
UC + (FC x BAF) 0.01 l/d + <0.015 kg/d x 130,440 1/kg*)

■ 0.0017 ug/L (ranted off to 2 ng/l (Tier 1))

Where:

R S C = 0.8; the s u b stance is p ersistent and
bioaccumulative,

*BAF - 130,440, provi d e d by EPA-Duluty and M i n n e s o t a PCA.

106

REFERENCES:
Annett, C.S. et al.
1975.
Merc u r y in fish and waterfowl
from Ball Lake, Ontario.
J. Environ. Qual,
4(2):219222

.

Buchet, J.P., H. Roels, A. Bernard and R. Lauwerys, 1980.
Assessment of renal function of wor k e r s exposed to
inorganic lead, cadmium or m e r c u r y vapor.
J. Obcup.
Med.
22:741-750.
Clarkson, T.W., L. Amin-Zaki and S. K. Al-Tikriti.
1976.
An outbreak of me t h y l m e r c u ry p o i s oning due to
c onsumption of cont a m i n a t e d grain.
F ederation
Proceedings.
3 5 ( 1 2 ) :2395-2399.
D'ltri, P.A. and F.M. D'ltri.
1978.
M e r c u r y contamination:
a human tragedy.
Environmental Management.
2(1):3-16.
D'ltri, F.M.
1990.
Mercury conta m i n a t i on - wh a t we have
learned since Minamata.
Environmental M o n i t o r i n g and
Assessment,
v. 16.
Nordberg, G.F, and P, Strangert.
1976.
Estimations of a
dose-response curve for long-term e xposure to
meth y l m e r c u ri e compounds in human beings t a king into
account variabil i t y of c ritical organ c o n c e n t r a t i on and
biological half-time:
a p r e l i m i n a r y communication.
In:
Effects and D o s e-Response R e l a t i o n s h i ps of Toxic
Metals.
1976.
Elsevier Scientific P ublishing Company.
Amsterdam, T h e Netherlands, p. 273-282.
Piikivi, L . , H. Hanninien, T. M a r t e l i n et al.
1984.
Pyschological perfo r m a n c e and long t e r m e x posure to
m e r c u r y vapors.
Scand. J. Work. Environ. H e alth
10:35-41.
,
Roels, J., R. Lauwerys, J.P. Buchet et al.
1982.
Comparison of renal function a nd psych o m o t e r
performance in workers exposed to elemental mercury.
Int. Arch. Occup. Environ. Health 50:77-93.
U.S. Environmental Protection A g e n c y (EPA). 1980.
Ambient
Water Quality Criteria Document for Mercury.
EPA
440/5-80-058.
U.S, Environmental Protection Agency (EPA).
1984a.
Mercury
Health Effects Update:
Health Issue Assessment.
OHEA.
E P A — 6 0 0 /8-84-019 F .
107

U.S.

Environmental Pr o t e c t i o n A g e n c y (EPA). 1984b.
Health
Effects Assessment for Mercury.
EPA/540/1-86/042.
NTIS:
PB86-134533.

U.S. Environmental Protection A g e n c y (EPA). 1985a.
D r i n k i n g Water Criteria Document for Mercury.
Prepared
for O f f i c e of Dr inking Water, by Environmental Criteria
and A s s e s s m e n t Office.
EPA-600/X-84-178-1.
Final
Draft.
PB86-117827.
U.S. Environmental Prote c t i o n A g e n c y (EPA).
1985b.
'
Integrated Risk I n f ormation System (IRIS d a t a b a s e ) .
Chemical file for m e t h y l m e r c u ry (22967-97-6).
Verifi c a t i o n Date 12/2/85.
Last R e v i s e d 2/1/89.
W o r l d H e a l t h O r g a n i z a t i o n (WHO).
1976.
Environmental
H ealth Criteria 1:
Mercury.
WHO, Geneva.
W o r l d H e a l t h O r g a n i z a t i o n ( WHO). 1990.
Environmental
H e a l t h Criteria 101:
Methylmercury.
WHO, Geneva.

108

N ovember 4, 1991
GREAT LAKES INITIATIVE
T I E R I HUMAN H E ALTH CRITERIA FOR
ME T H Y L E N E CHLORIDE
CAS NO. 75-09-2
Tier 1 TTnmww Noncancer Criterion
A r eview of the literature indicates that hepatic and renal
toxicities are characteristic critical effects of m e t h ylene
chloride subchronic and chronic e x posure (EPA, 1989).

From

animal studies on the chronic t o xicity of m e t hylene
chloride, the most appropriate basis for H N V deriva t i o n is
the N O A E L from the chr o n i c oral rat study by the National
Coffee Associ a t i o n
this study,

(NCA, 1982; Serota, et al.,

F344 rats

(85/sex/group)

1986a).

In

r eceived nominal doses

of 0, 5, 50, 125 or 250 m g / kg/day of m e t h y l e n e ch l o r i d e via
d r i nking water exposure for 2 years.

A n induction of liver

t o x icity in the females was observed.

T r e a t m e n t - r el a t e d

histological alteratio n s such as increases in hepat o c e l l u la r
foci and fatty changes in the liver w e r e obs e r v e d in rats of
both sexes at nominal doses of £ 50 mg/kg/day.

No

trea t m e n t - r el a t e d effects were noted in the rats
administered the nominal dose of 5 mg/kg/day.

T he actual

N O A E L doses were 5.85 and 6.47 m g / k g / d a y for m a l e s and
females, respectively.

In addition to the rat drinking water study, Ha z l e t o n Labs
conducted a 24-month study with B6C3F1 m i c e for the National
109

Coffee Association

(NCA, 1983; Serota et al.,

1986b).

In

this study, m i c e were e x p o s e d to nominal doses of 0, 60,
125,

185, and 250 m g / k g / d a y of me t h y l e n e chloride in

d r i n k i n g water for up to 24 months.
h i s t o m o r p h o lo g i c changes,

D o s e - related

such as p r o l i f e r a t i ve hep a t i c

lesions and e n h anced amount of Oil Red 0 p o s i t i v e material,
w e r e o b s erved in groups exposed to the highest dose of
m e t h y l e n e chloride.
mg/kg/day.
rats

The study r e ported a N O A E L of 185

Compared to the 5.85-6.47 m g / k g / d a y N O A E L in

(NCA, 1982; Serota et al.,

1986a), this study

d e m o n s t r a t e s a wide diffe r e n c e in the interspecies
s e n s i tivities to m e t h y l e n e chl o r i d e - i n du c e d t o x i c effects.

In a 2 -year inhalation t o x i c i t y and onco g e n i c i t y s tudy by
D o w C h e m i c a l Co.
D a w l e y rats

(Nitschke et al., 1988), groups of Sprague-

(90 m a l e and 180 female) were e x p o s e d to 0, 50,

200, or 500 p p m m e t h y l e n e c h loride for 6 hours/day,
d a y s / w e e k for 2 years.

5

D u r i n g t he course of the study, all

rats w e r e m o n i t o r e d after each ex p o s u r e for signs of
toxicity,

c h anges in body w e i g h t and food intake.

Samples

of liver t i s s u e w e r e a n alyzed for DNA synthesis as indicated
b y 3 [H]-thymidine uptake.

Rats s e lected for interim

n e c r o p s i e s and all the others

(at the end of the study) were

s u b j e c t e d to extensi v e gross pathologic, histopathologic,
and serum c h e m istry evaluation.

Data on D NA synthesis in

the liver, pathology, h i s t o p a t h o l o g y , mortality,

no

and other

parameters were evaluated for s t a tistically significant
differences between the exposed and controls groups.
Pathologic and histopathologic data of the exposed groups
indicated that the liver and kidney are the prim a r y targets
of methylene chloride toxicity.

An increased incidence of

hepatocellular vacuolization was o bserved in male and female
rats exposed to 500 p p m of methylene chloride.

In addition,

elevated numbers of multi n u c l e a te d h e p atocytes w e r e observed
in female rats exposed to 500 p p m m e t h ylene chloride.
effects of methylene chloride at lower doses

The

(50 and 200

ppm) were comparable with historical controls.

Responses to

chemical insult leveled off by 12 m o nths in that the
responses of female rats exposed to 500 pp m for the first 12
months were comparable to those of female rats exposed to
the same concentration for 24 months.

Based on these

results, the authors concluded that 200 p p m (706.7 m g / m 3 ) is
the N O A E L for methyle n e chloride by the inhalation route.
This exposure m a y be converted to a daily a d m i n istered dose
of a p p r oximately 159 mg/kg/day, a d j usting for 6 hours/day
exposure and assuming that Sprague-Dawley rats breathe
a p p r oximately 0.9 m 3 /kg bw/day (EPA, 1988).

Burek et al.

(1984) reported a 2-year inhalation study of

m e t h y l e n e chloride with Sprague-Dawley rats and Golden
Syrian Hamsters.

In this study, rats and h amsters were

exposed to 0, 500, 1500, and 3500 ppm of m e t h y l e n e chloride

ill

for 6 hours/day,

5 d a y s /week for 2 years.

Liver a nd mammary

glands were the principal target tissues of me t h y l e n e
chloride inhalation toxicity in rats.

Groups exposed to 500

to 3500 p p m methylen e chloride showed increased incidence of
h e p a t o c e l l u la r vacuo l i z a t i on consistent with fatty changes,
and the number of m u l t i n u c l e a te d hepat o c y t e s in the female
rats was elevated.

A f t e r 18 months of e xposure to the

regimen, several chara c t e r i s ti c lesions of liver and mammary
glands w e r e t r ansfor m e d to benign neoplasms

(Burek et a l . ,

1984) .

The d a t abase is judged to be sufficient for Ti e r 1 HNC
derivation.

The k e y study (NCA, 1982; Serota et al. 1986a)

p r o vides a chronic oral N O A E L w h i c h is supported and
supplemented by other oral and inhalation chronic toxicity
data.

EPA u s e d this k e y study in the d e r i v a t i o n of the oral

RfD for r i s k assessm e n t pur p o s e s (EPA, 1 9 8 5 a ) , and t o derive
lifetime h ealth adviso r i e s for m e t h y l e n e chloride
1985b).

For the RfD derivation,

(EPA,

EPA (1985a) us e d the male

and female rat doses, resp e c t i v e l y of 52.58 and 58.32
m<3/kg/day for LOAELs, and 5.85 and 6.47 m g / k g / d a y for NOAELs
for h e patic effects

(NCA, 1982; Serota et al.,

1986a).

HNC is d e r i v e d from the h n o a e l from the key study, 6.47
m g / k g / d a y to female rats.

112

The

A D E = 6.47 m a / kq/d = 0.065 mg/kg/d
100

Where:

Uncertainty factor = 100, composed of:
lOx for interspecies e x t rapolation
lOx for intraspecies variability

Drinking W a t e r Sources:

H N V = ADE x Wh x RSC

= 0.065 ma/ka/d x 70 ka____________

WC + (FC x BAF)

2 1/d + (0.015 kg / d x 2.5 1/kg*)

= 2.23 mg/1

(rounded off to 2 mg/1

(Tier 1))

Nondr i n k i n g W a t e r Sources:

HNV = ADE

X

Wh

X

RSC

W C + (FC x BAF)

- 95.8 mg/1

Where:

= 0.065 mq/ k q / d

X

70 ka

______________

0.01 1/d + (0.015 k g / d x 2.5 1/kg*)

(rounded off to 96 mg/1

(Tier 1))

*BAF =2.5, provided by EPA-D u l u t h and M i n n e s o t a PCA.

113

Note:

A r e l ative source c o n t r i b u t i o n (RSC) factor has not

been utili z e d in these draft calculations.

REFERENCES:
Burek, J.D., K.D. Nitschke, T.J. Bell, D.L. Wackerle, R.C.
Childs, J.E. Beyer, D.A. Dittenber, L.W. Rampy, and
M.J. McKenna.
1984.
M e t hylene chloride:
A two-year
inhalation toxi c i t y and onc o g e n i c i t y study in rats and
hamsters.
Fundam. Appl. Toxicol.
4:30-47.
N a t i o n a l Coffee Asso c i a t i o n (NCA). 1983.
T w e n t y - F o u r Month
Oncoge n i c i t y Study of M e t h y l e n e Chloride in Mice.
P r e p a r e d by Hazleton L a b o ratories America, Inc.,
Vienna, VA.
(U n p u b l i s h e d ) .
N a t ional Coffee A sso c i a t i o n (NCA).
1982.
24-Month Chronic
T o x i c i t y and O n c o g e n i c i t y Study of M e t h y l e n e Chl o ri d e
in Rats.
Final Report.
P repared by H a z l e t o n
L a boratories America, I n c . , Vienna, VA.
(Unpublished).
N a t i o n a l T o x i c o l o g y P r o g r a m (NTP). 1986.
T o x i c o l o g y and
C a r c i nogenesis
Studies of D i c h l o r o m e t ha n e (Methylene
Chloride) in F344/N Ra t s and B6C3F1 M i c e (Inhalation
Studies).
NTP-TRS-306.
Nitschke, K . D . , J.D. Burek, T.J. Bell, R.J. Kociba, L.W.
Rampy, and M.J. McKenna.
1988.
Me t h y l e n e chloride:
A
t w o - y e a r inhalation t o x i c i t y and o n c o g e n i c i t y study in
rats.
Fundam. Appl. Toxicol.
11:48-59.
Serota, D . G . , A.K. Thakur, B.M. Ulland, J.c. Kirschman, N.M.
Brown, R.H. Coots and K. Morgareidge.
1986a.
A twoy e a r d r i n k i n g w a t e r study of d i c h l o r o m e t ha n e on
rodents. I. Rats.
Food Chem. Toxicol.
24:951-958.
Serota, D.G,, A.K. Thakur, B.M. Ulland, J.C. Kirschman, N.M.
Brown, R.H. Coots and K. Morgareidge.
1986b.
A twoy e a r d r i n k i n g w a t e r study of dich l o r o m e t ha n e on
rodents. II. Mice.
Food Chem. Toxicol.
24:959-964.
U.S. E n v i r onmental P r o t e c t i o n A g e n c y (EPA). 1989.
Health
Effects A s s e s s m e n t for M e t h ylene Chloride.
EPA/600-889-092.
Environmental Criteria and A s s e s s m e n t Office
(ORD), Cincinnati, OH.
PB90-142449.

1X4

U.S. Environmental Prote c t i o n Agen c y (EPA). 1988.
R e commendations for and Documentation of Biological
Values for Use in Ri s k Assessment.
PB88-179874.

U.S. Environmental Protection A g ency (EPA).
1985a.
Integrated R i s k Information System (IRIS d a t a b a s e ) .
Chemical file for m e t hylene c hloride (75-09-2).
V e r i f i c a t i o n date 11/6/85.
Last r eviewed 11/6/85.
U.S.

Environmental Protection A g ency (EPA). 1985b.
Healtyh
A d v i s o r y for Dichloromethane.
Prepared b y the Office
of Drinking Water, Washington, D.C.
PB86-118338.

Tier 1 Bum»™ Cancer Criterion

M e t h y l e n e chloride is a class B2 c arcinogen (a probable
human carcinogen)

acco r d i n g to the E PA weight - o f - e vi d e n c e

classification of carcinogenic chemicals

(EPA,

1989a).

Thè

classification rationale is based on sufficient evidence
from animal carcinogenicity.

Two e p i d e m i ological studies on

chemical factory workers exposed to m e t hylene c hloride

(Ott

et al.,

1987)

1983; Friedlander et al., 1978; H e a r n e et al.,

are inconclusive on the h uman carc i n o g e n i ci t y of methylene
chloride.

R e v i e w of these e p idemiological studies and

u p d a t e d evaluation of the cohorts still p r o v i d e inadequate
evidence of h u m a n carc i n o genicity (EPA, 1 9 8 9 b ) .
Experimental carcinogenesis studies indicate that exposure
to m e t h y l e n e chloride by the oral route res u l t e d in a
significant increase in the incidence of h e p a t ocellular
carcinoma and neoplastic nodules in female F344 rats
1982; Serota et al.,

1986a)

(NCA,

and male B6C3F1 mi c e (NCA,
115

1983;

Serota et al,

1986b).

Inhalation studies with m e t hylene

chloride p r o d u c e d an increased incidence of m a m m a r y tumors
in both sexes of Spr a g ue-Dawley (Burek et al.,
and F344 rats

(NTP, 1986).

1980,

1984)

The data are judged to be

sufficient for Tier 1 HCC derivation.

The c a r cinogenic effects of m e t hylene chloride via the oral
r oute were investigated in two separate 2-year studies
sponsored by the National Coffee Assoc i a t i o n (NCA, 1982,
1983; Serota et al.,

1986a,

1986b).

In the 1982 study,

groups of 85 F344 rats of either sex received nominal doses
of 5, 50, 125, or 250 mg / k g / d a y of m e t h ylene c h loride in
d r i nking water.

Female rats r e c eiving 50 and 250 m g / k g / d a y

h a d a sign i f i c a n t ly increased incidence of c o mbined
h e p a t o c e l l u la r carcinoma and n e o p l a s t i c nodules in
compar i s o n to m a t c h e d controls.

M a l e rats, however, d id not

show an increased incidence of liver tumors.
dependent,

A dose-

statistica l ly significant increase in the

incidence of salivary gland sarcoma w as ob s e r v e d in male
rats.

A d o s e - r e l a t e d increase in the ave r a g e n u mber of

b e n i g n m a m m a r y tumors wa s observed in female rats.

The

increased incidence of m a m m a r y tumors was o bserved in male
rats, albeit to a lesser degree.

The National C offee Asso c i a t i o n in its s ubsequent study
(NCA,

1983; Serota et al.,

1986b) exposed B6C3F1 m i c e of

116

e ither sex to 0, 60, 125, 185, or 250 m g / k g / d a y m e t h ylene
chloride in drink i n g water.

A statistically significant

increase in the incidence of combined hepat o c e l l u la r
carcinoma and neoplas t i c nodules was ob s e r v e d in male mice
exposed to 125 and 185 mg/kg/day.

However, on l y a marginal

increase in the incidence of tumorigenesis and reduced
average survival time was observed in the 250 m g / k g / d a y
group.

Q u a ntitative cancer risk estimates of m e t h y l e n e chloride are
based o n NTP inhalation studies in rats and mi c e
1986).

(NTP,

In this study, groups of 50 male an d female F344/N

rats and B6C3F1 m i c e were exposed to 0, 1000, 2000, and 4000
ppm (rats), and 0, 2000, and 4000 p p m (mice) for 6 hrs/day,
5 d a y s /week for 102 weeks.

Female rats, and to a lesser

degree m a l e rats, dem o nstrated a stati s t i c a l ly significant
increase in the incidence of m a m m a r y g l a n d neoplasms.

In

mice, m e t h y l e n e chloride elicited an e n hanced com b i n e d
incidence of hepatoce l l u la r adenomas and c a r c i n o m a s in the
male

(22/50, 24/49,

40/48) mice.

33/49) and female (3/50,

16/48, and

Similarly, both male and female m i c e displayed

an increased incidence of alve o l a r / b r on c h i o l a r adenomas and
carcinomas (NTP, 1986).

In an inhalation study reported by D ow Chemical Company
(Burek et al.,

1980,

1984),

Sprague-Dawley rats and Syrian
117

G o l d e n hamsters of both sexes were exposed to 0, 500,
or 3500 p p m m e t h ylene chloride for 6 hrs/day,
for 24 months.

1500,

5 d a y s /week

A stati s t i c a l ly significant increased

incidence of benign tumors in female hamsters expo s e d to
3500 p p m was attributed to increased longevity in that
group.

A statistical ly significant increase in salivary

g l a n d sarcoma was observed in male rats exposed to 3500 ppm
methy l e n e chloride.

Th e finding of m e t h y l e n e chloride-

induced salivary gland tumors in male rats is c o mplicated by
the o b s e r v a t i o n that these rats had appar e n t l y contra c t e d a
viral disease,

sialodacryoadentitis,

in the salivary glands

d u r i n g the earlier phase of the e x posure regimen (Burek et
al.,

1980, 1984).

Based on these uncertainties,

exper i m e n t a l results from this study were considered
inconclusive on t h e c a r c i n o g e n i ci t y of m e t h y l e n e chloride.
In a subsequent inhalation study by D ow Chemical Company
(Nitschke et al., 1982), limited evidence of mamm a r y
f i broma/fibrosarcoma was o b served in ma l e and female rats
exposed to 0, 50, 200, or 500 p p m of m e t h y l e n e c h loride for
2 years.

EPA (1989b) d e r i v e d a reco m m e n d e d oral slope factor from the
arith m e t i c m e a n of two slope factors d e r i v e d fr o m the
induction of liver tumors in female mice by inhalation
1986) and in male mice by d r inking w a t e r e x posure
1983; Serota et al.,

1986b).

(NTP,

(NCA,

These individual slope factors
118

were 2.6 x 10-3

(mg/kg/d)-1 and 1.2 x 10-3

r e s pectively (EPA, 1 9 8 9 b ) .
(1989b)

(mg/kg/d)- 1 ,

This a pproach recom m e n d e d by EPA

is utilized for Tier l HCC derivation, u t i l izing an

arithmetic mean slope factor of 7.3 x 10-3

(mg/kg/d)- 1 .

RAD = 1 x 10-5 = 1 x 10-5______________
q^*

7.3E-3

(mg/kg/day)-1

= 0.00137 m g / k g/d a y

D r i nking W a t e r Sources:

H C V = RAD x Wh_______ = 0,00137 ma/kcr/dav x 70 ka____________
W C + (FC x BAF)

= 0.047 m g / 1

2 1/day + (0.015 kg/d a y x 2.5 1/kg*)

(rounded off to 0.05 mg/1

(Tier 1))

Nondri n k i n g W a t e r Sources:

HCV = RAD x Wh________ = 0.00137 m a / k q / d a v x 70 k g_______
W C + (RC x BAF)

0.01 1/day +(0.015 k g / d a y x 3.5

1/kg*)
= 2.02 mg/1

(rounded off to 2 mg/1

119

(Tier 1))

Where:

*BAF = 2.5, pr o v i d e d by EPA-D u l u t h a nd M i n n esota

PCA.

REFERENCES:
Burek, J.D., K.D. Nitschke, and T.J. Bell.
1980.
Me t h y l e n e
Chloride:
A Two - Y e a r Inhalation Tox i c i t y and
Oncog e n i c i t y Study in Rats and Hamsters.
Toxic o l o gy
R e s e a r c h Laboratory, Health and Environmental Sciences,
Dow Chemical Company, Midland, MI.
Burek, J.D., K.D. Nitschke, T.J. Bell, D.L. Wackerle, R.C.
Childs, J.E. Beyer, D.A. Dittenber, L.W. Rampy, and
M.J. McKenna.
1984.
M e t hylene chloride:
A two-year
inhalation toxicity and oncogenicity study in rats and
hamsters.
Fundam. Appl. Toxicol.
4:30-47.
Friedlander, B . R . , F.T. Hearne, and S. Hall.
1978.
E p i d e miologic investigation of employees c h r onically
e x posed to methy l e n e chloride — m o r t a l i t y analysis.
J. Occup. Med.
20:657-666,
Hearne, F.T., F. Grose, J.W. Pifer, B.R. Friedlander, and
R.L. Raleigh.
1987.
M e t h y l e n e chloride mo r t a l i t y
study: Dose-resp o n se c h a r acterization and animal model
comparison.
J. Occup. Med.
29:217-228.
N a t i o n a l C offee Assoc i a t i o n (NCA).
1983.
T w e n t y - F o u r Month
O n c o g e n i c i t y Study of M e t h y l e n e C h loride in Mice.
P r e pared by Hazleton Laboratories America, I n c . ,
Vienna, VA.
(Unpub l i s h e d) .
National Coffee Assoc i a t i o n (NCA). 1982.
24 - M o n t h Chronic
T o x i c i t y and O n c o g e n i c i t y Study of M e t h y l e n e Chloride
in Rats.
Final Report.
Prepared by H azleton
Labora t o r i e s America, Inc., Vienna, VA.
(Unpublished).
Nitschke, K.D., J.D. Burek, T.J. Bell, L.W. Rampy, and M.G.
McKenna.
1982.
M e t h y l e n e Chloride:
A Two - Y e a r
Inhalation Toxic i t y and O n c o g e n i c i t y Study. T o x i c o l o g y
R e s e a r c h Laboratory, Health and Environmental Sciences,
D o w Chemical Company. Midland, MI. (Final R e p o r t ) .
Natio n a l Toxicology Prog r a m (NTP). 1986.
T o x i c o l o g y and
Carcinogenesis
Studies of D i chloromethane (Methylene
Chloride) in F344/N Rats and B6C3F1 Mi c e (Inhalation
Studies).
N T P - T R S -306.

120

Ott, M.G. L.K. Skory, B.B. Holder, J.M. Bronson and p.R.
Williams.
1983.
Health evaluation of employees
occupationally exposed to methylene chloride —
mortality.
Scanc. J. Work Environ. Health.
9:8-16.
Serota, D.G., A.K. Thakur, B.M. Ulland, J.C. Kirschman, N.M.
Brown, R.H. Coots and K. Morgareidge.
1986a.
A twoyear d r i nking water study of dich l o r o m e t ha n e on
rodents. I. Rats.
Food Chem. Toxicol.
24:951-958.
Serota, D.G., A.K. Thakur, B.M. Ulland, J.C. Kirschman, N.M.
Brown, R.H. Coots and K. Morgareidge.
1986b.
A twoyear d r i nking water study of d i c h l o r o m e t ha n e on
rodents. II. Mice.
Food Chem. Toxicol.
24:959-964.
U.S. Environmental Protection A g e n c y (EPA). 1985.
Addendum
to the H e a l t h Asses s m e n t Document for D i c h l o r omethane
(Methylene C h l o r i d e ) . Updated Carc i n o g e n i ci t y
Assessment.
Prepared by the C a r c i n o g e n A s s e s s m e n t
Group, OHLA, Washington, DC.
EPA 600/8-B2/Q04FF.
U.S. Environmental Protection A g e n c y (EPA).
1989a.
Risk
A s s e s s m e n t Guidance For Superfund, Vol 1., H u m a n Health
Evaluation Manua l (Part A). E P A / 5 4 0 / 1 - 8 9 / 0 0 2 . Office
of Emergency and R e medial R e s ponses ( S u p e r f u n d ) ,
Washington, D.C.
U.S. Environmental P rotection A g e n c y (EPA).
1989b.
Integrated Risk Information S y s t e m (IRIS d a t a b a s e ) .
Chemical file for d i c hloromethane (75-09-2).
V e rification Date 4/6/89.
Last R e v i e w e d 4/6/89.

1 21

122

September 6, 1991
GR E A T LAKES INITIATIVE
HUMAN HEALTH CRITERIA FOR
POLYCHL ORINATED BIPHENYLS (PCBS)
CAS NO. 1336-36-3
Tie r 2 Human Noncance r Level of Protection
Studies of low-level oral PCB exposure in several species
have d e monstrated effects on serum chemistry,

liver

toxicity, reproductiv e c apability and other endpoints at
doses of less than 5 m g / k g bw/day.

T he m o s t a p p ropriate

data for use in H N V development are the r h esus m o n k e y data
due to the high sensitivity of the species and the relative
w e a l t h of the database including studies on r e p r o d u c t i o n and
development.

Also, as a n onhuman pri m a t e the rhesus m o n k e y

m a y serve as the m o s t appropriate m odel species for
p o t e ntial h u m a n effects.

Adult male and female rhesus mon k e y s were administered
A r o c l o r 1248 in the di e t at levels of 2.5 an d 5.0 p p m for up
to 18 m o n t h s

(Allen,

Barsotti et al.,

1975; A l l e n a nd Barsotti,

1976; A l l e n et al.,

1980).

1976;

A s s u m i n g that

rhesus monkeys consume daily an amount of food e quivalent to
4% of their body weight, these exposure levels of 2.5 and
5.0 p p m are equivalent to 0.1 and 0.2 m g / k g bw/day,
r e s p e c t i v e l y (EPA, 1985).

After six m o n t h s exposure, the

females were bred with unexposed males.
in 12/12,

Concep t i o n occurred

8/8 and 6/8 of the adult females re c e i v i n g 0, 2.5
123

Preceding page blank

and 5.0 ppm, respectively.

The number of live infants born

at 0, 2.5 and 5.0 ppm was 12, 5 and 1, respectively.
Exposure of the females continued until three mont h s after
parturition.

Infants we r e allowed to remain w i t h their

m o t h e r s and nurse for a m i n i m u m of four months,

resulting in

t r ansmammary as well as t r a n s placental exposure.

At both

dose levels

(dose-specific responses not d i s t i n g u i s h e d ) ,

adult females develop e d acne, alopecia (hair l o s s ) ,
erythema,

swelling of the eyelids, abnormal menstrual

cycles, and abnormal s e r u m chemistries.
that d i e d after 173 days

Two t r e a t e d females

(2.5 p p m group) or 310 days

(5 ppm

group) were found at nec r o p s y to have signs of liver
t o x icity including focal areas of necrosis.

Trea t e d animals

were n o t e d to appear mo r e susceptible to t he o p p ortunistic
intestinal p a t h o g e n Shigella flexneri type IV.
the e x posed g roups
weights

Offspring of

(combined) dem o n s t r a t e d de c r e a s e d birth

(399 ± 22 g. vs. 507 ± 59 g. in controls) a nd

h y p e r p i g m e n ta t i o n of the skin.

T hree of the 6 infants died,

w h i c h w a s attrib u t e d to PCB toxicity.

These included the

only infant from the 5 p p m g roup and two of the five infants
from the 2.5 p p m group.
r u d i m e n t a r y thymuses,

Necro p s i e s of these infants showed

small spleens, u n d e r d e v e l o pe d splenic

lymph nodes, h y p o c e l l u l a ri t y of the bone m a r r o w a nd fatty
infiltration of liver cells, among other effects.
contin u a t i o n of these studies,
al.

In a

Barsotti (1980) a nd A l l e n et

(1980) reported that in subsequent b reeding trials

12 4

during the recovery period for these same adult female
monkeys,

effects on reproduction and o f f spring development

were still apparent for greater than one year.

Barsotti

(1980) and Barsotti and V a n M i l l e r

(1984)

administered diets containing 0, 0.25 or 1.0 p pm Aroclor
1016 to groups of 8 adult female rhesus m o n k e y s for seven
m onths prior to breeding, through g e s t a t i o n and a 4 -month
nursing period.

The total exposure peri o d w as 87 ± 9 weeks.

Exposure did not result in signs of overt tox i c i t y in adult
females.

All treated females conceived, carr i e d their

fetuses to term and delivered v i able offspring.
w e i ghts from the control,

The birth

0.25 and 1.0 p p m groups were 512 ±

64, 491 ± 24 and 422 ± 29 g . , respectively.

The newborn

weights in the 1.0 p p m group w e r e signif i c a n t ly less than
the controls

(p less than 0.01).

Experimental groups of

infants gained w e ight consistently, a nd the infant weights
among the 1.0 p p m g rou p we r e not signif i c a n t ly lower than
the control group at wean i n g (864 ± 97g vs. 896 ± 9 0 g ) .

The

authors d etermined that d u ring the p r e - b r e e d i n g exposure
period, the 0.25 and 1.0 p pm treated females con s u m e d 1.7 ±
0.3 m g/kg bw/7 months and 6.1 ± 0.9 m g/kg bw/7 months, or
approximately 0.008 and 0.03 mg/kg bw/day, respectively.

B o wman et al.

(1981) reported that offspring of female

rhesus monkeys fed diets containing 0.5 or 1.0 p p m Aroclor
125

1248 three days per w e e k or 2.5 p p m d aily
doses w e r e 0.006,
respectively)
controls.

(estimated average

0.013 a n d ' 0.085 m g / k g bw/day,

d i s p l a y e d gre a t e r locomotor ac t i v i t y than

However, g roup sizes w e r e small

(n = 3-7), the

q u a n t i t a t i v e differences in ac t i v i t y we r e not dose-related,
and the v a r i a b i l i t y w i t h i n ea c h g r o u p was n o t e d to be
substantial.

Becker et al.

(1979)

found that g r oups of 1-2

rhesus m o nkeys fed diets c o n t a i n i n g 3, 10, 30 or 100 ppm of
PCBs as A r o c l o r 1242 for several months had d o s e - d e p e n d en t
findings of gastric lesions,
r e duced hemoglobin,
mortality.

lack of body w e i g h t gain,

persistent leukocytosis,

-

and early

These effects occ u r r e d even in the animal

r e c e iving the lowest dose of 3 p p m

(0.12 m g / k g bw/day),

w h i c h expired after 245 days of dosing.

The s ubstantial studies of A r o c l o r 1248 in rhes u s mon k e y s
e s t a blish a subchronic L O A E L for m a r k e d systemic toxicity,
repro d u c t i v e and dev e l o p m e n t al effects at 2.5 p p m
bw/day).

(0.1 m g / k g

One study u t i lizing Aroc l o r 1016 indicates a LOAEL

for neona t a l w eight depres s i o n at 1.0 p p m (0.03 m g / k g
bw/day) w i t h a N O A E L for this effect at 0.25 p p m (0.008
m g / k g bw/day)
1984) .

(Barsotti,

1980; Barsotti and VanMiller,

None of these studies were chronic in duration,

g e n e r a l l y s p a nning less than 10% of the ex p e c t e d lifespan of
about 20 years (Gold et al.,

1984).

The c o m p o s i t i o n of

A r o c l o r 1016 is prim arily di-, tri-, and t e t r a c h l o r o isomers

126

of biphenyl, w i t h an average chlorine p e r c e n t a g e
is very similar to Aroclor 1242

(EPA, 1980).

(41%) that

Other Aroclor

mixtures composed of mo r e highly chlorinated congeners have
inadequate data to identify the approximate t h r eshold level
for the sensitive systemic and r e p r o d u c t i ve/developmental
effects,

EPA (1985) considered the poor m e t a b o l i s m of PCBs

and their bioaccumulation tendency, and t he s everity of
effects seen at the subchronic L O A E L of 0,1 m g Aro c l o r
1 2 4 8 /kg bw/day,
Daily Intake

and de clined r e c o m m e n d a t io n of an Acceptable

(ADI).

The d a t abase is judged insufficient for Tier 1 Human
N o n c ancer Criterion development. A Tier 2 level of
protec t i o n is d e rived from the Aroc l o r 1016 N O A E L in rhesus
monk eys at 0.25 p p m (approximately 0.008 m g / k g bw/day).

The

Tier 2 level of protec t i o n is intended to be applicable to
all PCB isomers and A r o c l o r mix t u r e s (i.e., total PCBs)
until a m o r e appropria t e m e t hodology m a y be developed.
particular,

In

the dose-response for chronic a nd reproductive/

deve lopmental effects of the more h i g h l y chlor i n a t e d PCBs
needs to be investigated and characterized.

A total

uncert a i n t y factor of 1,000 is used in t he calculation:

ADE

=

0.008 ma/kcr/d

=

8 x 1 0~6 m g / k g / d

1,000

127

=

8 ng/kg/d

Where:

U ncertainty factor = 1,000 composed of:
lOx for intraspecies variability
lOx for interspecies extrapolation
lOx for subchronic exposure duration

D r i nking W a t e r Sources:

HNV - APE » Uh » RSC
WC * (FC x BAF)

- 8 rw/ko/d k 70 fca x 0.B _________________
2 l/d + (0.015 kg/d x 1,776,860 l/kg*)

• 0.017 ng/L (rowded off to 20 pg/l (Tier 2))

N o n d r i n k i n g Water Sources:

HMV » APE x Mh x RSC

» 8 ng/ko/d x 70 ka > 0.8________________

WC + (FC x BAF)

0.01 L/d ♦ (0.015 kg/d x 1,776,860 l/kg*>

s 0.017 ng/L Crcunded off to 20 pg/l (Tier 2))

Where:

RSC = 0.8; the substance is persi s t e n t and
bioaccumulative.

*BAF = 1,776,860, provided by EPA-Duluth and M i n n e s o t a PCA.

References:
Allen, J.R. 1975.
Response of the n o n - human p r i m a t e to
p o l y c h l o r i n at e d biphenyl exposure.
Fed. Proc. 34:
1675-1679.
Allen, J.R. and D.A. Barsotti.
1976.
The effects of
t ransplacental and mammary m o vement of PCBs on infant
rhesus monkeys.
Toxicology.
6:331-340.

128

Allen, J.R., D.A. Barsotti and L.A. Carstens.
1980.
Residual effectsof p o l y c h l orinated biphenyls on adult
n o n human primat e s and their offspring.
J. Toxicol.
Environ. Health.
6(1):55-66.
Barsotti, D.A., R.J. M a r l a r and J.R. Allen.
1976.
Reproductive dys function in rhesus mon k e y s expo s e d to
low levels of poly c h l o r i n at e d biphenyls (Aroclor
1248).
Fd. Cosmet. Toxicol.
14:99-103.
Barsotti, D.A.
1980.
Gross, clinical and rep r o d u c t i v e
effects of polyc h l o r i n at e d biphenyls (PCBs) in the
rhesus monkey.
Diss. Abstr. Int.
41(10):3744-5.
Barsotti, D.A. and J.P. VanMiller.
1984.
A c c u m u l a t i o n of a
commercial p oly c h l o r i n at e d biphenyl m i x t u r e (Aroclor
1016) in adult rhesus monkeys and their nursing
infants.
Toxicology.
30(1):31-44.
Becker, G.M., W.P. M c N u l t y and M. Bell.
1979.
P o lychlorinated biphenyl induced m o r p h o l o g i c changes in
the gastric mucosa of the rhesus monkey.
Lab. Invest.
40(3):373-383.
Bowman, R.E., M.P. Heiro n i m u s and D.A. Barsotti.
1981.
L o c o m o t o r hypera c t i v i t y in PCB-e x p o s e d rhesus monkeys.
Neurotoxicology. 2(2):251-68.
Gold, L.S., et al.
1984.
A c a r c i nogenic p o t e n c y database
of the standardized results of animal bioassays.
E n v i r onmental H e a l t h Perspectives.
58:9-319.
U.S. Environmental P rotection A g e n c y (EPA). 1985.
Drinking
W a t e r Criteria Document for Polyc h l o r i n at e d Biphenyls
( PCBs). Environmental Criteria and A s s e s s m e n t Office.
EPA-600/X-84-198-1.
PB-86-118312,
Tier 1 Human Cancer Criterion
PCBs

(as a class) h a v e sufficient c a r c i n o g e n i ci t y w eight-of-

evidence for a B2 classification

(probable h u m a n carcinogen)

b a s e d on the induction of h e p a t o c e l l u la r carcin o m a s in three
strains of rats and two strains of mice and inadequate yet
suggestive evidence of excess risk of liver c a ncer in humans
(EPA, 1987).

The data are judged sufficient for Ti e r 1 HCC
124

derivation.

A l t houg h animal feeding studies demon s t r a t e the

carc i n o g e n i ci t y of commercial PCB preparations,

it is not

known which of the PCB congeners in such m ixtures are
responsible for these effects.

EPA (1987) de v e l o p e d a

carci n o g e n i ci t y risk assessment for PCBs wi t h a slope factor
derived from A r o c l o r 1260 data, clearly stating the intent
that the assessment be c onsidered r e p r e sentative for all PCB
mixtures.

The application of this a pproach to r egulatory

p r o grams is a pruden t approach to ensure adeguate prote c t i o n
of p ublic health.

A r e v i e w of the available c a r c i n o g e n i ci t y data indicates
that the most approp r i a t e studies for q u a n t itative cancer
risk assessment are the bioassays of K i m b r o u g h et al
and N o r b a c k and Welt m a n

(1985).

(1975)

These studies u tilized

d i f f erent rat strains -- Sherman rats in the Ki m b r o u g h et al
(1975) study, Spragu e - D a w le y rats in the N o r b a c k and Wel t m a n
(1985) study —

but otherwise ha d several similarities.

B o t h u t i l i z e d large numbers of animals in chronic Aro c l o r
1260 feeding studies w i t h only one exposure group.

Dosed

g r oups r e c e i v e d 100 p p m for 630 days in the b i o a s s a y by
K i m b r o u g h et al.

(1975), while Norback and W e l t m a n (1985)

admini s t e r e d 100 p p m for 16 months followed by a 50 p pm diet
for an additional 8 months, then a basal diet for 5 months.
The p r e d o m i n a n t neoplastic effect in each study w as the

130

increased incidence of h e p a t ocellular neoplasms in female
rats.

Using the linearized multistage procedure,
estimated slope factors of 7.7
(mg/kg/d)

(mg/kg/d)

EPA (1987)

1 and 3.9

1 from the data of Norb a c k and W e l t m a n

K i m b rough et al.
slope factors,

(1975), respectively.

7.7

(mg/kg/d )

(1985) and

The larger of these

, was s elected by EPA (1987)

as the p r e f e r r e d slope factor estimate.

Although the Norback and Welt m a n (1985) study included a
test protocol of part i a l l y hepa t e c t o m i zi n g some of the
animals,

EPA (1987) noted that the study had favorable

qualities.

The rat strain used (Sprague-Dawley)

is known to

have a low incidence of spontaneous h e p a t ocellular
neoplasms, the study duration spanned the natural life of
the animal, and concur r e n t m o r phologic liver studies showed
the sequential progre s s i o n of liver lesions to
h e p a t ocellular carcinomas.

E x t rapolation m o d e l i n g utilized

a female rat liver tumor incidence rate of 45/47 in the
dosed group.

This includes 7 animals which h ad earlier

undergone partial hepatectomy, and the liver tumor incidence
for this subgroup was unreported.

Exclusion of this group

would have very little impact on the r e s u l t i n g slope factor,
and the tumor promoting effect of the par t i a l
hepat e c t o m i za t i o n should be minimal
131

(Hiremath,

1991).

The

Tier 1 H u m a n Cancer C r i terion for PCBs is b ased on the slope
factor of 7.7

(mg/kg/d)

N o r b a c k and W e l t m a n

1 derived from the rat bi o a s s a y of

(1985).

RAD = 1 x j r * _____ _ » 1.3 x 10 6 mg/kg/d
7.7 (mg/kg/d) 1

= 1.3 ng/kg/d

Drinking W a t e r Sources:

HCV

=

RAP x Uh______
WC ♦ (FC x BAF)

» 3.4 x 10

•3

■

1.3 rw/ka/d x 70 ka__________________
2 l/d + (0.015 kg/d x 1,776,860 L/kg*>

ng/t (rounded off to 3 pg/l (Tier 1))

N o n d r i n k i n g W ater Sources:

HCV = RAD x Uh
WC ♦ (FC x BAF)

» 1.3 nq/fco/d x 70 ko___________________
0.01 L/d ♦ (0.015 kg/d x 1,776,860 L/kg*)

-3
=> 3.4 x 10 ng/l (rouided off to 3 pg/l (Tier 1))

Where:

*BAF = 1,776,860, p r o v i d e d by EPA-D u l u t h and

M i n n e s o t a PCA.

References:
Hiremath, C.
1991.
Toxicologist, U.S. EPA O f f i c e of
R e s e a r c h and Development.
Personal c o m m u n i c a t i on with
R. Sills, M i c h i g a n Department of Natural Resources.

132

Kimbrough, R.D. et al.
1975.
Induction of liver tumors in
Sherman strain female rats by Aro c l o r 1260.
J. National
Cancer Institute.
55(6):1453.
Norback. D. and R.H. Weltman.
1985.
P o l y c h l o r i n at e d
biphenyl induction of h e p a t o c e l l u la r carcinomas in the
Sprague-Dawley rat.
Env. Heal t h Persp.
60:97-105.
U.S.

Environmental Protection Agen c y (EPA). 1987.
Integrated R i s k Information System (IRIS d a t a b a s e ) .
Chemical file for p o l y c h l o r i n at e d biphenyls (PCBs)
(1336-36-3).
Ver i f i c a t i o n Date 4/22/87.
Last Revised
1/1/90.

133

134

October 31, 1991
GREAT LAKES INITIATIVE
TIER 1 HUMAN HEALTH CRI T E R I A FOR
P E N T A C H LOROPHENOL
CAS NO. 87-86-5
Tier 1 Hinnjin Noncancer Criterion
A r e v i e w of the available literature indicates that HNC
derivation for pentac hlorophenol

(PeCP) is mo s t

a p p r opriately based on the chronic oral rat study by Schwetz
et al.

(1978).

Twenty-five rats/sex were a d m i n istered PeCP

in the diet for two years at levels resulting in doses of l,
3, io or 30 mg PeCP/kg bw/day.

The test substance was

r e p r e s entative of Dowicide EC-7, a comm e r c i a l l y available
and purif i e d grade of PeCP.

A n a c c u m ulation of pig m e n t in

the liver and kidneys was observed in females r e c e iving 10
or 30 mg/kg / d a y and in males receiving 30 mg/kg/day.

The

N O A E L was 3 mg/kg/day.

The chronic rat N O A E L at 3 m g / k g / d a y is s u p p orted by several
subchronic and reprodu c t i on/development studies
1985b).

J o h n s o n et al.

(EPA, 1985a;

(1973) adm i n i s t e r e d 3, 10 or 30

mg/kg b w/day purified PeCP to rats for 90 days v ia feed.
Increased liver weight s were o b served at 10 or 30 mg/kg/d,
and increased k idney weights o c curred at 30 mg/kg/d.
N O A E L was 3 mg/kg/day.

K i m b rough a nd Linder

The

(1978)

administered purified PeCP to rats via diet a r y levels of 20,
100 or 500 p p m for eight months.
135

Preceding page blank

Only the high e s t exposure

of 500 p p m (approximately 25 m g / k g bw/day) re s u l t e d in
h e p a t ocellular changes.

K i d n e y wei g h t s were el e v a t e d over

controls at all dose levels including 20 pp m (approximately
1 m g / k g b w / d a y ) , but without a dos e - r e l a t e d increase.
G o l d stein et al.

(1977) reported a N O A E L at 5 mg/kg bw/day

(100 p p m in feed) to female rats over eight months, with
h e p atic and body w e ig h t effects at 25 mg/kg bw/day (500 ppm
in f e e d ) .

Reproducti v e/ d e v e l o p m e n t a l studies ha v e r e ported

a v e r y low t e n dency for p l a c ental t r ansfer (Larsen et al.,
1975), a lack of tera t o g e n i c effects, and fetotoxicity at 15
or 30 m g / k g bw/day (Schwetz et al., 1974; 1978).

A

stati s t i c a l ly signifi c a n t increase in delayed skull
ossifi c a t i o n has been r e ported at doses as low as 5 m g / kg
b w /day (Schwetz et a l . , 1974), but no effects on
reproduction,

neonatal growth,

survival,

or d e v e l o p m e n t

occurred at 3 m g/kg bw/day (Schwetz et al., 1978).
(1985b)

The EPA

concluded that 3 m g / k g bw/day could be c o n s i d e r ed a

N O E L for P eCP's fetotoxicity.

The q u a l i t y of the ke y study and supporting da t a b a s e are
judged to be sufficie n t for Tier 1 H NC development.

The

d e r i v a t i o n of the HNC from the chronic rat N O A E L at 3
mg/kg/day, w i t h lOx uncer t a i n t y factors for inter- and
intraspecies extrapolation,

is consistent w i t h the RfD

d e v e l o p m e n t by EPA ( 1 9 8 5 a ) .

136

A D E = 3 m a /ka /d = 0.03 mg/kg/d
100

Where:

Uncertainty Factor = 100, composed of:
lOx for intraspecies variability
lOx for interspecies e x t rapolation

'

Drinking Water Sources:

H N V = A D E x Wh x R S C = 0.03 m a / k a / d x 70 k a _____________

W C + (FC x BAF)

= 0.179 m g / 1

2 1/d + (0.015 kg / d x 650 1/kg*)

(rounded off to 0.2 mg/1

(Tier 1))

Nondri n k i n g Water Sources:

HNV = APE x Wh x RSC

= 0.03 ma/ k a / d x 70 ka________________

W C + (RC x BAF)

0.01 1/d + (0.015 kg/d x 650 1/kg*)

= 0.215 mg/1

Where:

(rounded off to 0.2 m g / 1

(Tier 1))

* B A F = 650, provided by EPA-Duluth and M i n n e s o t a

PCA.

137

NOTE:

A R e l ative Source C o n t ribution

(RSC) factor has not

been u t i lized in these draft calculations.

REFERE N C E S :
Goldstein, J.A. et al.
1977.
Effects of pentac h l o r o ph e n o l
on h e p a t i c drug - m e t a b o l i z i n g enzymes and p o r phyria
r e l a t e d to c o n t a m i n a t i on w i t h chlor i n a t e d d ibenzo-pd i oxins and dibenzofurans.
Biochem. Pharmacol.
26:1549-1557.
Johnson, R.L., et al.
1973.
C h l orinated diben z o d i o x in s and
pentachlorophenol.
Environ. H e a l t h Perspect.
5:171­
175.
Kimbrough, R.D. and R.E. Linder.
1978.
The effect of
technical and p u r i f i e d pen t a c h l o r o ph e n o l on the rat
liver.
Toxicol. Appl. Pharmacol.
46:151-162.
Larsen, R.V. et al.
1975.
P l a cental t ransfer and
t e r a t o l o g y of p e n t a c h l o r o ph e n o l in rats.
E n v ironmental
Letters.
10(2):
121-128.
Schwetz, B.A. et al.
1974.
The effect of p u r i f i e d and
commer c i a l grad e pentac h l o r o ph e n o l on rat embryonal and
fetal development.
Toxicol. Appl. Pharmacol.
28(1):
151-161.
Schwetz, B.A. et al.
1978.
Results of t wo-year t oxicity
and r e p r o d u c t i o n studies on pen t a c h l o r o ph e n o l in rats.
In:
Rao, K.R. (Ed.).
1978.
Pentac h l o r o ph e n o l
Chemistry, Pharmacology, and Environmental Toxicology.
P l e n u m Press, N e w York, NY.
pp. 301-309.
U.S. Envir o n m e n t al P r o t e c t i o n A g e n c y (EFA). 1985a.
Integr a t e d R i s k I n f ormation Syst e m (IRIS d a t a b a s e ) .
Chemical file for Pen t a c h l o r o ph e n o l (87-86-5).
V e r i f i c a t i o n Date 5/20/85.
Last Revised 5/7/91.
U.S. Environmental Protec t i o n A g e n c y (EPA). 1985b.
D r i n k i n g W a t e r C riteria Document for Pentachlorophenol.
P r e p a r e d for the Office of D rinking Water, by the
Environmental Criteria and A s s e s s m e n t Office.
EPA600/X-84-177-1.
PB-86-118015.

138

Tier 1 Human Cancer Criterion

A r eview of the available literature on the c a rcinogenicity
of pentachlorphenol

(PeCP)

indicates a lack of evidence of

h uman or animal carcinogenicity prior to N TP (1989).

As

p o i nted out in NTP (1989), p rior studies were ge n e r a l l y
limited by study design flaws.
evidence provided by NTP

EPA has c o n c l u d e d that the

(1989) w o u l d support c lassification

of PeCP into Group B2; p r obable h uman c arcinogen (EPA, 1989/
1990) .

The conclusions of NTP (1989) are that under the

conditions of the 2-year feeding studies, there wa s clear
evidence of carcinogen i c a c tivity for m a l e and female B6C3F1
mice e x posed to PeCP as Dowicide EC-7, and for m a l e mice
exposed to PeCP as a technical grade composite.
Additionally, there was some evidence of carcinogenic
activity for female mice exposed to the P e C P t e c hnical-grade
composite.

The database is judged to be s ufficient for Tier

1 HCC derivation.

The study design of NTP (1989)

involved e x posure via feed

for 103 weeks to groups of 50 mice/sex, w i t h g r oups of
35/sex serving as controls for each grade of PeCP studied.
The grades of PeCP selected for the chronic bioassays were
commercial samples

(Dowicide EC-7 and a t e c h n i c al-grade

c o m p o s i t e ) , considered to be representative of PeCP forms
139

w h ich humans are exposed to.

Exposure levels in feed were

0, 100 or 200 p p m te c h n i c al-grade PeCP or 0, 100, 200 or 600
pp m Dowicide EC-7.

There was clear evidence that

a dministration of the t e c h n i c al-grade composite re s u l t e d in
increased incidences of h e p a t o c e l l u la r and adrenal m e d u l l a r y
neoplasms in male mice, and some evidence of induction of
h e p a t o c e l l u la r tumors and hem a n g i o s a r co m a s in female mice.
There was clear evidence that the administration of Dowicide
EC-7 r e s ulted in hep a t o c e l l u la r tumors and adrenal me d u l l a r y
pheoc h r o m o c yt o m a s in both sexes and hema n g i o s a r co m a s in
female mice.

A m o n g the three types of tumors induced by
p e n t a c h l o r o p h e n o l , the E PA Science A d v i s o r y Board c onsidered
the heman g i o s a r co m a s to be the tumor of gre a t e s t concern
(EPA, 1990).

To giv e prefe r e n c e to the h e m a n g i o s a r co m a data

and because some male groups experienced sign i f i c a n t early
loss, only the female mice are u s e d in the q u a n t i t a t i v e risk
assessment.

P ooled tumor incidence was utilized, with

exclusion of animals which died p r i o r to the first tumor
observation.

The slope factor of 1.2 E-l p er (mg/kg)/day is

c a l c u l a t e d as the ge o m etric me a n of the slope factors for
each p e n t a c h l oropheno l preparation.

This a p proach is

c o n s i s t e n t w i t h EPA (1990).

R A D = 1 x 10~5_____________ = 8.3 3 x 10“ 5 mg/ k g / d
140

1.2 E-l

=83.3

(mg/kg/d)-l

ng/kg/d

Drinking Water Sources:

HCV = RAD x Wh________ = 83.3 na/ka/d x 70 ka_____________
WC + (FC

= 496 ng/1

X

BAF)

2 1/d + (0.015 kg/d

(rounded off to 0.5 ug/1

X

650 1/kg*)

(Tier 1))

N o n d r i n k i n g Water Sources:

H C V = RAD x Wh________ = 83.3 na/ka/d x 70 kg_________________
W C + (RC x BAF)

= 597 ng/1

Where:

0.01 1/d + (0.015 kg/d x 650 1/kg*)

(rounded off to 0.6 ug/1

(Tier 1))

*BAF = 650, provided by EPA-Duluth and Minnesota

PCA.

REFERENCES:
NTP.

1989.
Toxicolo g y and Carcinogenesis Studies of Two
Pentachlorophenol Technical-Grade Mix t u r e s in B6C3F1
Mice (Feed Studies).
U.S. DHHS.
Technical Report
Series No. 349.

141

U.S.

Environmental Protec t i o n A g e n c y (EPA). 1989.
54 FR
22062-22160.
National Pri m a r y and Secondary Drinking
W a t e r Regulations; Proposed Rule.
M ay 22, 1989.

U.S. Environmental Prote c t i o n A g e n c y (EPA).
1990.
Integrated Risk Information System (IRIS database),
chemical file for P e n t a c h lorophenol (87-86-5).
V e r i f i c a t i o n Date 8/2/90.
Last Revi s e d 5/7/91.

142

Oct o b e r 23,

1991

G R E A T LAKES INITIATIVE
TIER 1 HUMAN HEALTH C R ITERIA FOR
2 , 3 , 7 , 8 -TETRACHLORODIBENZO-P-DIOXIN (2,3,7,8- T C D D ).
CAS NO. 1746-01-6
Tier 1 Human Noncancer Criterion
Of the many subacute and chronic studies available for
2 , 3 , 7 , 8-TCDD,

a few stand out as supporting Tier 1 criterion

derivation.

In a two-year t oxicity and o n c o g e n i c i t y study,

rats were a d m inistered doses of 0, 0.001, 0.01 and 0.1 ug/kg
bw/day of 2 , 3 , 7 , 8-TCDD via diet

(Kociba et al.,

1978).

A n imals given the high dose exhibited increased mortality,
decreased w eight gain, slight d epression of erythroid
parameters,

increased urinary e x c r etion of p o r p h y r i n s and

delta-ami n o le v u l i n i c acid and increased s erum levels of
certain enzymes.
in liver,

H i st o p a t h o l og i c or gross effe c t s w e r e seen

lymphoid,

lung and v a scular tissues.

tumor incidence was also seen.

A n increased

Similar effects, but to a

lesser degree, w e r e seen in m i d - d o s e animals.

A N O A E L of

0.001 ug/kg / d a y (1 ng/kg/day) was r eported in this study.

A N O A E L of 0.001 u g/kg bw/day via feed e x posure w as also
reported in a t h r ee-ge n e r at i o n rat r e p r o d u c t i o n study
(Murray et al.,

1979).

At 0.1 ug/kg/day, d e c r eases in F Q

genera t i o n fertility and F^^ generation litter size were
reported.

At 0.01 ug/kg/day,

significant de c r e a s e s in

fertility were seen in the F^ and F 2 generations; other
14 3

effects included dec r eased litter size at birth, d e c r eased
gestational survival and de c r e a s e d n e onatal grow t h and
survival.

The reproductive c apacity of the low dose rats

did not appear to be significantly a f fected in any
generation.

However, a réé v a l u a t i o n of t hese data using

diffe r e n t statistical met h o d s indicated that both lower dose
levels r e s ulted in significant reductions in offspring
survival indices,

increases in liver a nd k i dney w e i g h t of

pups, decre a s e d thymus w e i g h t of pups, decreased neonatal
w e ights and increased incidence of dilated renal pelvis
(Nisbet and Paxton,

1982).

Nisbet and Paxton (1982)

c o n c luded that 0.001 u g / k g / d a y (1 ng/kg/day) was no t a N O E L
in the M u r r a y et al.

(1979) study.

the data of M urray et al.

Kimmel

(1988) consi de r e d

(1979) to be s uggestive of a

p a t t e r n of d e c r eased o f f spring survival a n d increased
o f f s p r i n g renal patho l o g y even at 0.001 ug/kg/day, although
the p o o l i n g of data fr o m di f f e r e n t gene r a t i o n s by N i s b e t and
Paxton

(1982) was considered b i o l o gically inappropriate.

Studies by Schantz et al.

(1979) and A l l e n et al.

(1979)

suggest that rhesus m o n k e y s are m o r e sensitive to 2,3,7,8T C D D than r a t s .

When m o n k e y s w e r e adm i n i s t e r e d 50 ppt

2,3,7,8-TCDD in feed for 7 to 20 months, d e c r eases in
fertility,

increases in abortions an d other toxic effects

(alopecia, hyperkeratosis, weight loss, de c r e a s e d h ematocrit
and w h i t e blood cell count and increased s erum levels of
144

SGPT) w e r e noted.

The 50 ppt dietary residue level

corresponds to a daily dose of 1.5 ng/kg bw/day (EPA,
Therefore,

1984).

1.5 ng/kg/day can be considered a L O A E L for

rhesus monkeys from these studies.

In a continuation of the rhesus monk e y studies by Schantz et
al.

(1979) and Allen et al.

(1979), Bowman et al.

(1989a,

1989b) have evaluated the effects of 5 and 25 ppt 2,3,7,8T C D D in feed on reproduction and on behavior, respectively.
Breeding of the animals after 7 and 24 m o n t h s of exposure
resulted in impaired reproductive success at 25 pp t but not
at 5 ppt

(approximately 0.67 and 0.13 n g / k g bw/day,

respectively).
years,

The exposures were dis c o n t i n u e d after 4

and a third breeding ten mont h s p o s t - e x p o s u re did not

indicate reproductive impairment (Bowman et al.,

1989a).

The offspring from these breeding experiments were evaluated
for d evelopment and behavioral effects u t i l i z i n g several
t e sting methods

(Bowman et a l . , 1 9 8 9 b ) .

A l t h o u g h t h e r e were

no significant effects of TCDD exposure on birth weight,
growth, or physical appearance of the offspring, some
behavioral test results we r e interpreted to be indicative of
TCDD effects.

These included alterations in the social

behavior between the mothers and their infants and of peer
groups of the offspring after weaning.

However,

the study

groups were very limited in size and the statistical and
biological significance of the findings are unclear.

145

This

study m a y be interpreted to provide only sugges t i v e evidence
of p o s s i b l e behavioral effects.
Bowman et al.

The r e p r o duction study of

(1989a) provides mu c h clearer e vidence of a

L OAEL at 25 ppt

(0.67 ng/kg/day)

and a NOAEL at 5 ppt

(0.13

ng/kg/day).

The EPA has used the equivocal e vidence for a rat L O A E L at
1 ng/kg/day,

supported by an unequivocal rhesus m o n k e y LOAEL

at 1.5 ng/kg/day,
Intake

(ADI)

in the d e v elopment of an A c c e p t a b l e Daily

(EPA, 1984; 1985a) and Drinking Water

Equivalent Level

(DWEL)

(EPA, 1985b; 1990).

In light of the

m o r e recent rhesus m o n k e y study of Bowman et al.

(1989a),

there is improved resolu t i o n of the threshold for the
sensitive effect of r e p r o ductive impairment in this species.
T h e H u m a n N o n c ancer C r i terion is based on t he N O A E L of 0.13
n g / k g/day for reproductive effects from this study.

The

e n t irety of the rhesus m o n k e y studies, supported by the
e v i dence in rats cited above,

is judged sufficient for Tier

1 c r i t e r i o n development.

A D E =■ 0.13 n a /ka/d = 1.3 x 10” 3 ng/kg/d = 1.3 pg/ k g / d
100

Where:

U n c e r t a i n t y Factor = 100, composed of:
lOx for intraspecies variability
lOx for interspecies extrapolation
146

Drinking Water Sources:

H N V = APE x Wh x RSC = 1.3 pg/ka/d x 70 kg x 0.8____________
W C + (FC X BAF)

= 0.097 pg/1

2 1/d + (0.015 kg/d X 50,000 1/kg*)

(rounded off to 0.10 pg/1

(Tier 1))

N o n d r i n k i n g Water Sources:

HNV = APE x Wh x RSC = 1.3 «/kq/d x 70 kg x 0.8__________
VC + (FC x BAF)

0.01 t/d + (0.015 kg/d x 50,000 l/kg*)

= 0.097 pg/l (roLnded off to 0.10 pg/l (Tier 1))

Where:

RSC = 0.8; the substance is p e r s i s t e n t and
bioaccumulative.

*BAF = 50,000, provided by E PA-Duluth and M i n n e s o t a PCA.

REFERENCES:
Allen, J.R. et al. 1979.
R e p r o d u c t i v e effects of
h a l o g e n a t e d aromatic h y d r o carbons on n o nhuman primates.
Ann. N Y Acad. Sci. 320:419-425.
Bowman, R.E., et al.
1989a.
Chro n i c d i e t a r y intake of
2 , 3 , 7 , 8 -tetrachl o r o d i b e n z o - p - d i o x i n (TCDD) at 5 or 25
parts per trilli o n in the monkey:
TCDD k i netics and
d o se-effect estimate of r e p r o ductive toxicity.
Chemosphere.
1 8 (1 - 6 ): 243-252.

147

Bowman, R.E., et al.
1989b.
Behav i o r a l effects in monkeys
e x posed to 2,3,7,8-TCDD tran s m i t t e d m a t e r n a l l y during
g e s t a t i o n and for four months of nursing.
Chemosphere.
18(1-6) :235-242.
Rimmel, G.L.
1988 . A p p e n d i x C.
Rep r o d u c t i v e and
Devel o p m e n t al T o x i c i t y of 2,3,7,8-TCDD.
Repr o d u c t i v e
Effects Assess m e n t Group, OHEA/ORD, EPA.
In:
EPA.
1988.
A Cancer Ri s k - S p e c i f ic Dose E stimate for
2,3,7,8-TCDD.
A p p e n d i c e s A-F.
R e v i e w Draft.
E P A / 600/6-88/007Ab.
‘
Kociba, R. J. et al. 1978.
Results of a two - y e a r chro n i c
t o x i c i t y and onc o g e n i c i t y study of 2,3,7,8t e t r a c h l o r o di b e n z o - p - d i o x i n in rats.
Toxicol. A p p l i e d
Pharmacol.
46:279-303.
Murray, F. J. et al.
1979.
T h r e e - g e n e r a t i o n r e p r o duction
study of rats g i v e n 2 , 3 , 7 , 8 - t e t ra c h l o r o d i b e n z o - p - d i o x i n
(TCDD) in the diet.
Toxicol. A p p l i e d Pharmacol.
50:241-252.
Nisbet, I.C.T. and M.B. Paxton.
1982.
Stat i s t i c a l aspects
of t h r e e - g e n e r a t i o n studies of the r e p r o ductive
t o x i c i t y of TCD D and 2,4,5-T.
T he Am e r i c a n
Statistician.
36(3): 290-298.
Schantz, S. L. et al.
1979.
Toxic o l o g i c al effects p r oduced
in n o n h u m a n pri m a t e s c h r o n i c a l l y exposed to 50 ppt
TCDD. Toxicol. A p p l i e d Pharmacol.
48:A180.
(Abstract
No. 360).
U.S. E n v i r onmental P r o t e c t i o n A g e n c y (EPA).
1984.
Ambient
Water Q u a l i t y Criteria for 2 , 3 , 7 , 8 - T e trachlorodibenzop-dioxin.
O ffi c e of W a t e r Regu l a t i o n s and Standards.
E P A 440/5-84-007.

U.S. E n v i r onmental P r o t e c t i o n A g e n c y (EPA). 1985a.
Heal t h
A s s e s s m e n t Document for P o l y c h l o r i n at e d D ibenzo-pdioxins.
O f fic e of H e a l t h and E n v ironmental
Assessment.
EPA/600/8-84/014F.
U.S. Environmental Prote c t i o n A g e n c y (EPA).
1985b.
D r i nking W a t e r Criteria Document for 2,3,7,8Tetrachlorodibe n z o - p - d i o x i n .
ECAO/ODW.
E P A -600/X-84194-1.
PB 86-117983.

148

U.S. Environmental Protection A g e n c y (EPA). 1990.
55
Federal Register No. 143.
Wednesday, July 25, 1990.
National P r imary and Secondary Dri n k i n g Water
Regulations; Synthetic Organic Chemicals and Inorganic
Chemicals.
Proposed rule.
Tier l winnaTi cancer criterion
The EPA (1984) evaluated the available e p idemiological and
animal bioassay data on the potential c a r c i n o g e n i ci t y of
2 . 3 . 7 . 8- T C D D .

They determined that some case-control

studies provide limited evidence for the h uman
carci n o g e n i ci t y of phenoxy acids and/ o r chlorophenols, which
con tain impurities including 2 , 3 , 7 , 8-TCDD.

T h e y concluded

that t h e evidence for the h uman c a r c i n o g e n i ci t y of 2,3,7,8T C D D based on the epide m i o l o g ic studies is only suggestive
due to the d i f f i c u l t y of e v a l u a t i n g the risk of 2 , 3 , 7 , 8-TCDD
exp osure in the presence of the confo u n d i n g effects of
p h e n o x y acids and/or chlorophenol.

Rec e n t l y p u b l ished

epi dem i o l o g y studies m ay be interpreted to p r o v i d e
suggestive evidence of c a r cinogenicity (Zober et al.,
F i n g erhut et al.,

1991).

1990;

Th e potential us e of t h e s e new

studies for quantitat i v e risk a ssessment h a s not y et been
fully explored.

W i t h regard to animal bioassays, th e EPA

(1984) concluded that several rodent studies e s t a blish that
2 . 3 . 7 . 8- TCDD is an animal c arcinogen in m u l t i p l e species and
organs and is probably carcinogenic in humans.

The weight

of evidence of carcin o genicity is s ufficient for Group B2
cla ss i f i c a t io n

(probable human c a r c i n o g e n ) , and satisfies

the database requirements for Tier 1 c r i t e r i o n derivation.
149

A m o n g the c a rcinoge n i ci t y bioassays, NTP c o n d ucted bioassays
with both Osborne-Mendel rats and B6C3F1 mice

(NTP, 1 9 8 2 a ) ,

Groups of 50 mice and 50 rats of each sex were given
2,3,7,8-TCDD in corn oil-acetone by gavage twice per week
for 104 weeks.

Doses of 0, 0.01,

0.05 or 0.5 u g/kg/week

were a d ministered to rats and ma l e mice while female mice
r e c eived 0, 0.04, 0.2 or 2.0 ug/kg/week.
of 75 rats and 75 m i c e of each sex.
weeks 105-107.

Controls consisted

Animals w e r e k i l l e d at

2,3,7,8-TCDD caused an increased, d ose-

r e lated incidence of follicular-cell adenomas or carcinomas
of the t h yroid in male rats.

A significant increase in

subcutaneous tissue fibromas was also seen in h i g h -dose
males.

High-dose female rats exhibited increased incidences

of h e p a t o c e l l u la r carci n o m a s and n eoplastic nodules,
subcutaneous tissue fibrosarcomas and adrenal cortical
adenomas.

In male and female mice, 2,3,7,8-TCDD induced an

increased d o s e-rela t e d incidence of h e p a t o c e l l u la r
carcinomas.

High-d o s e female mice also exhibited increased

incidences of thyro i d follicular-cell adenomas.

In a d ermal study also c o n d ucted under contract for NTP
(NTP,

1 9 8 2 b ) , 30 ma l e and 30 female Swiss W e b s t e r mi c e were

t r e a t e d w i t h 2,3,7,8-TCDD in acetone for 3 d a y s / w e e k for 104
weeks.

Doses of 0.005 ug and 0.001 ug 2,3,7,8-TCDD were

admini s t e r e d to the clipped backs of m ales and females,
respectively.

A similar group was pretreated wi t h one

ISO

application of 50 ug dimethylben za n t h r a c e n e
before 2,3,7,8-TCDD administration.

(DMBA) one week

2,3,7,8-TCDD induced a

statistically significant increase of fibrosarcomas in the
integumentary system of females given both 2,3,7,8-TCDD
alone and following a single appli c a t i o n of DMBA.

Van M iller et al.
0.001,

0.005,

(1977) administered diets c ontaining 0,

0.05,

1, 50, 500 and 1000 p p b 2 , 3 , 7 , 8-TCDD to

groups of 10 male Spr a g ue-Dawley rats.

Anim a l s received the

diets for 78 weeks and were then p l a c e d on c o n t r o l feed
until they were kille d at w e e k 95.

Al l rats fed the higher

concentrations (1-1,000 ppb) died early.

A variety of

tumors were produced and the total number of animals w i t h
tumors generally increased,

but the small numb e r of animals

limits the value of the data.

Kociba et al.

(1978) administered 2,3 , 7 , 8 - T C D D via the diet

to groups of 50 m a l e and 50 female Sprag u e - D a w le y rats for 2
years.

Control groups c o n s isted of 86 animals of each sex.

The doses administered were 0, 0.001, 0.01 and 0.1
ug/kg/day.

2,3,7,8-TCDD induced an increased incidence of

hepat o c e l l u la r carcinomas and h e p a t o c e l l u la r hyperplastic
(neoplastic) nodules in female rats at the two hig h e s t dose
levels.

The highest dose of 2,3,7,8-TCDD also induced an

increase in the incidence of stratified squamous cell
carcinomas of the hard palate and/or nasal turbi n a t e s in
151

b o t h m a l e s and females, squamous cell carcinomas of the
t ongue in males and squamous cell c arcinomas of the lungs in
females.

Kociba et al.

(1978)

is chosen as the basis for q u a n t itative

cancer r i s k assessment.
principal t arget

The Kociba study found that the

organ for 2 , 3,7,8-TCD D - i n d u ce d tumors was

the liver in female rats, d e m o n s t r a t i n g a dose - r e l a t e d
stati s t i c a l ly significant increase of h e p a t o c e l l u la r
carcinomas and hype r p l a s t i c

(neoplastic)

nodules.

For

quant i t a t i v e risk assessment, the data were adj u s t e d for
early m o r t a l i t y by elimi n a t i n g those animals that died
d u r i n g the first y e a r of the study.

Also,

in the mid-dos,e

group, two of the r eported 20 females w i t h t u m o r s h a d both
nodules and carcinomas;

18 aff e c t e d animals w e r e u s e d as the

input for the dose group.

Using the linearized m u l t i s t a g e

model, the r e s u ltin g slope factor for 2 , 3 , 7 ,8-TCDD is 1.51 x
1 0 5 (mg/kg/day)_ 1 .

However, an independent path o l o g i s t

(Squire) was e n gaged by EPA to reeva l u a t e the
h i s t o p a t h o l o g i c slides from the K o c i b a study (EPA,

1984).

Squire r e p o r t e d high e r tumor incidences t h a n Kociba,
g e n e r a t i n g a slight l y high e r slope factor of 1.61 x 105
(mg/kg/day)“ 1 .
factors,

EPA (1984) used an average of th e tw o slope

1.56 x 10s (mg/kg/day)” 1 , to generate surface water

criteria.

152

In M a r c h 1990 a panel of seven independent path o l o g i s t s
referred to as the Pathology Work i n g Group

(PWG) blindly

reevaluated the female rat liver slides from K o c i b a et al.
(1978).

Liver lesions were c lassified a c c o r d i n g to the

National T oxicology Program's 1986 liver tumor
c l a s s i fication scheme

(Sauer,

1990).

U s i n g the linearized

multistage model, the liver tumor incidence rates reported
by the PWG result in a slope factor of 5.1 x 1 0 4
(mg/kg/day)-1 for liver tumors only, and a slope factor of
7.5 x 104 (mg/kg/day)"1 for pooled s i g n i f i c a n t ly increased
tumors of the liver,

lung or nasal t u r b i n a t e s / ha r d palate.

The latter m e t h o d avoids d o u b l e - c o u n ti n g of tumor - b e a r i ng
animals

(Bayard,

1990).

The H uman Cancer Criterion is based on the p o oled
significant tumors in female rats of K o c i b a et al.

(1978)

with the liver tumor r é é v a luation of the P a t h o l o g y Working
Group

(Sauer,

1990).

The linearized m u l t i s t a g e model

generates a slope factor of 7.5 x 104 ( m g / k g/day)"1 from
these data.

RAD = 1 X

10~5_______________

= 1.33 x 1 0 " 10 m g / k g / d

7.5 x 1 0 4 (mg/kg/d)"1

= 0.133 pg/kg/d

153

D r i nking Water Sources:

H C V = RAD x Wh_______ = 0.133 pg/ka/d x 70 k:cr_______________
W C + (FC x BAF)

= 1.2 x 10“2 pg/1

2 1/d + {0.015 kg/d x 50,000 1/kg*)

(rounded off to 0.01 pg/1

(Tier l))

NondrinJcing Water Sources:

HCV = RAD x Uh
WC + (FC x BAF)

» 0.133 pg/lcg/d x 70 kg______________

0.01 l/d + <0.015 kfl/d x 50,000 l/kg*)

• 1.2 x 10'* ps/t (rouxled o f f t o 0.01 pg/l (Tfer 1))

Where:

*BAF = 50,000, p r o v i d e d by EPA-Du l u t h a nd Minnesota

PCA.

REFERENCES:
Bayard, S.
1990.
T o x i c o l o g i s t/ S t a t i s t i c i a n wi t h the U.S.
EPA O ffice of Res e a r c h and Development, H u m a n Health
A s s e s s m e n t Group.
Personal c o m munication w i t h R.
Sills, M i c higan Depart m e n t of Natural Resources.
Fingerhut, M. et al.
Cancer m o r t a l i t y in work e r s exposed to
2,3,7,8-tetrachlorodibenzo-p-dioxin.
T he N e w England
Journal of Medicine.
2 3 4 ( 4 ) :212-218.
Kociba, R.J. et al.
1978.
Results of a t w o-year chronic
t o x icity and onco g e n i c i t y study of 2,3,7,8t e t r a c h l o rodibe n z o - p - d i o x i n in rats.
Toxicol. Applied
Pharmacol.
46:279-303.

National Toxico l o g y Program (NTP).

154

1982a.

Bio a s s a y of

2.3.7.8Rats and
National
Triangle

tetrachloro di b e n z o - p - d i o x i n in Osborne-Mendel
B6C3F1 Mi c e (Gavage S t u d y ) . NTP-TR-209.
Toxicolo g y Program, U.S. D H H S , Research
Park, NC.

National T oxicology Program (NTP). 1982b.
Carcinogenesis
Bioassay of 2,3,7,8-tetrach l o ro d i b e n z o - p - d i o x i n in
Swiss-Webster Mice (Dermal Study).
NTP-TR-201.
National T oxicolo g y Program, U.S. DHHS, Research
Triangle Park, NC.
Sauer, R.M.
1990.
Pathology Wor k i n g Group:
2,3,7,8T e t r achlorodibenzo - p - d i o x i n in S p r a g ue-Dawley Rats.
Pathco, Inc.
Submitted to the Maine Scientific A d visory
Panel.
U.S. Environmental Protection Agen c y (EPA). 1984.
Ambient
W ater Quality Criteria for 2 , 3 , 7,8-Tetrachlorodibenzo-pdioxin.
EPA 440/5-84-007.
Van Miller, J.P. et al.
1977.
Increased incidence of
neoplasms in rats exposed to low levels of 2,3,7,8tetrachlorodibenzo-p-dioxin.
Chemosphere 6(10):625-632.
Zober, A., P. M e s serer and P. Huber.
1990.
T h i r ty-fouryear m o r t ality follow-up of BASF employees exposed to
2 . 3 . 7 . 8- TCDD after the 1953 accident.
Int. Arch.
Occup. Environ. Health. 62(2):139-157.

155

156

O c t o b e r 31,

1991

GREAT LAKES INITIATIVE
T I E R 1 HUMAN HEALTH CRI T E R I A FOR
TOLUENE
CAS NO.

108-88-3

Tier 1 Human N o n c ance r C r i t erion

A r e view of the available literature indicates inadequate
human data for quanti t a t i v e risk assessment of toluene.
O c cupational exposure,

cigarette smoking and delib e r a t e

inhalation of solvents found in var i o u s p r e p a r a t i o n s

("glue

sniffing") are common means of h u m a n exposure to toluene
(NTP,

1990).

Chronic exposure to tol u e n e v a p o r s at levels

of a p p r oximately 200-800 p pm have been a s s o c i a t e d p r i m a r i l y
w i t h CNS effects, possibly peripheral nervous system
effects, h e patomegaly and hep a t i c function changes, and
renal function affects

(EPA, 1987).

A l t h o u g h these findings

p r o vide q u alitative e v idence of the human t o x i c i t y of
toluene,

specific exposure levels we r e not p r o v i d e d and

the se data do not provide a do s e - r e s p o n se r e l a t i o n s h i p
1987; EPA,

1990; NTP,

(EPA,

1990).

The m a j o r i t y of the subchr o n i c - ch r o n i c studies on toluene
are inhalation studies determining behavioral or
h i s t o p athologic effects

of

toluene

157
Pr e c e d i n g p a g e blank

exposure.

The most

appropriate basis for H N V deriv a t i o n for toluene is the
N O A E L from a 13-week rat gavage study (NTP, 1990).

In this

study, toluene in corn oil was administered by gava g e to
groups of w e a nling F344/N rats and B6C3F1 mice
(10/sex/group)
5000 mg/kg,

at dose levels of 0, 312,

625,

5 days per week for 13 weeks.

1250, 2500 or

All rats at 5000

mg/kg died during the first week, and 8/10 rats at 2500
mg/kg died, two of wh i c h were due to gavage errors.
H i s t o p a t h o l og i c changes we r e observed in the liver, kidney,
brain and u r i nary bladder at > 1250 mg/kg.

The N O A E L for

the rats is 312 mg/kg/day wi t h a LOAEL based on liver and
k i d n e y w e i g h t changes in ma l e rats at 625 mg/kg.

Because

the exposure was for 5 days/week, these doses are converted
to t i me-weighted-aver a g e doses of 223 and 446 mg/kg/day,
r e s p e c t i v e l y (EPA, 1990).

As d e s c ribed above, N TP (1990) also conducted a 13-week
g a v a g e study in B6C3F1 mice.

Al l m i c e that r e ceived 5000

m g / k g d i e d d u r i n g the first week, and 40% of t h o s e that
r e c e i v e d 2500 m g / k g d i e d before the end of the 13-week
g a v a g e study.

Clinical signs observed in mi c e at £ 2500

m g / k g included sub-convulsive jerking, prostration,

impaired

g r a s p i n g reflex, bradypnea, hypothermia, hyp o a c t i v i t y and
ataxia.

The final me a n body weig h t of m a l e s at 2500 m g/kg

was lower t h a n that of vehicle controls.

At £ 1250 mg/kg,

relative liver weight s were increased for mice, but this
158

increase was not stati s t i c a l ly significant.

The N O A E L for

this study was 1250 m g / k g and the L O A E L was 2500 mg/kg.
Adjus t i n g the doses for 5 days/week e x posure provides timew e i g h t e d-average NOAEL and L O A E L doses of 893 and 1786
mg/kg/day,

respectively.

A n o ther subchronic oral t o xicity study was c o n ducted by Wolf
et al.

(1956),

in w h i c h female W i s t a r rats we r e administered

toluene by stomach tube at doses of 0, 118, 354 and 590
mg/kg/day,

5 days/week for a total of 138 doses

(converted

to t i m e - w e i ghted-avera g e doses of a p p roximately 0, 18, 253,
and 422 m g / k g / d a y per EPA,

1990).

No adverse effects were

observed at any dose level in any of the p arameters
monitored:

growth, appearance and behavior, mortality,

o rgan/body weight, blood urea nitrogen levels, bone m a rrow
counts, peripheral blood counts or m o r p h o l o g y of major
organs.

The H N O A E L for this study was 422 m g / k g / d a y as the

time-weig h t ed - a v e r a g e dose.

N Y L A R m i c e were exposed pre- and pos t - n a t a l l y to toluene
p r o vided in the drinki n g w ater at c o n c e ntrations of 0, 16,
80 and 400 p p m (Kostas and Hotchin,

1981).

Rotorod

performance w a s m e a s u r e d at 45 and 55 days of age.

An

inverse dose-response relationship in t he effects was noted
in w h i c h rotorod performance was improved wi t h increasing
dose.

N o effects were observed for the following
159

r e productive measurements:

maternal fluid consumption,

offspring m o r t a l i t y rate, development of eye or ear
openings, or surface-righting response,
H N O A E L of 400 ppm.

resulting in a

As s u m i n g mice consume w ater at

a p p oximately 0.24 1/kg bw/day

(EPA, 1988), the H N O A E L was

appr o x i m a t e ly 96 mg/kg/day.

Nawrot and Staples
b w toluene,

(1979)

administered 0.3, 0.5 or 1.0 ml/kg

3 times/day (equivalent to a p p r o x i m a t e ly 780,

1300 and 2600 mg/kg/day, per EPA, 1990) to p r e g n a n t CD-I
m i c e from days 6-15 of gestation.

No m e t h o d of e x posure was

m e n t i o n e d in this limited information abstract.

Tera t o g e n i c

effects w e r e reporte d at 2600 m g / k g / d a y and increased
e m b r y o l e t h a li t y was rep o r t e d at £ 780 mg/kg/day,

therefore

the L O A E L for this study was 780 mg/kg/day.

N o other s u b c hronic- ch r o n i c oral t o xicity studies were
identified in the av a ilable literature for toluene.
inhalation studies include NTP (1990),
and B6C3F1 m i c e
toluene,

in w h i c h F344/N rats

(60/sex/dose) w e r e exposed to vapors of

6.5 hours/day,

5 d a y s /week for 2 years.

levels w e r e 0, 120 (mice only),
anima l s / g r o up

Chronic

600 or 1200 ppm.

Dose
T en

(except m a l e mice) were removed at 15 months

for toxico l o g i c evaluation.

At 15 months, t h e r e was an

increased incidence and severity in the erosion of o l f actory
epithelium,

and dege n e r a t i o n of respiratory e p i t h e l i u m was

160

increased in the exposed rats,

At the end of the study

inflammation of nasal mucosa and metaplasia of olfactory
epithelium were increased in exposed females rats.
N e phropathy was seen in almost all rats w i t h a severity
somewhat increased in exposed rats.

For mice, no

b i ologically relevant increase in any nonneoplastic lesion
was observed.

Chronic inhalation of toluene w as studied in F344 rats
exposed to 30, 100 or 300 p p m (113, 377 or 1130 m g / m 3 )
toluene 6 hours/day,

5 d a y s/week for 24 m o n t h s

Hardisty,

1980, as cited in NTP,

1983; C U T ,

1990; and EPA,

1987).

(Gibson and

1990; EPA,

A d o s e - related r e d u c t i o n in

hemato c r i t values was reported in female rats exposed to 100
and 300 ppm.

Increased corpuscular h e m o g l o b i n concentration

was reported in females at 300 ppm.

In a perinatal study w i t h CD-l mi c e

(Courtney et al.,

1986),

toluene was administered by inhalation at 200 and 400 ppm
(750 and 1500 m g / m 3 , respectively)

to p r e g n a n t female CD-l

m i c e 7 hours/day from days 6-16 of gestation.

Fetotoxicity

was o b s erved at 400 pp m wi t h a signi f i c a n t shift in the
fetal r i b profile.

A n increased body w e i g h t in the neonates

on day 1 postp a r t u m was observed at 400 ppm.

At 200 ppm,

there was an increase in dilated renal pelves w h i c h the
authors concluded might reflect d e s y n c h r o n i za t i o n of
161

matura t i o n with respect to development and growth.

Ass u m i n g

that m i c e breathe appoximately 1.7 m 3 /kg/day (EPA,

1988),

the 7 h o u r s / d a y 200 p p m LOAEL and 400 pp m FE L convert to
a p p r o x i m a t e ly 370 and 740 mg/kg/day, respectively,

as daily

admini s t e r e d doses.

The Tier 1 HNC is der i v e d from the N O A E L dose of 312 mg/kg
(converted to 223 m g / k g / d a y for 5 days/week administration)
from the 13-week oral rat study by NTP (1990) w i t h an
u n c e r t a i n t y factor of 1000.

T he uncer t a i n t y factor accounts

for inter- and intraspecies extrapolation,
subchron i c - to - c h r o n i c extrapolation.

and for

This a p proach should

be protec t i v e of develo p m e n t al effects, as s u g g ested by the
limited developmental t o x i c i t y data.

This ap p r o a c h is

consis t e n t with the ri s k assessment of tol u e n e for the oral
RfD and t h e d r i nking w a t e r h e a l t h advisory d e v e loped by EPA
(1990; 1987).

A D E = 223 m a / k q / d = 0.223 m g / k g / d a y
1,000

Where:

U n c e r t a i n t y Factor = 1,000, c o mposed of:
lOx for intraspecies v a r i a b i l i t y
lOx for interspecies extrapolation
lOx for subchronic exposure d u ration

162

Drinking Water Sources:

HNV = ADE

X

Wh

X

RSC

WC + (FC x BAF)

= 6.00 mg/1

= 0.223 mq/ka/d

70 kq_______

X

2 1/d + (0.015 kg/d x 40 1/kg*)

(rounded off to 6 mg/1

(Tier 1))

N o n d r i n k i n g Water Sources:

HNV = A P E x W h x RSC
W C + (FC x BAF)

= 25.59 mg/1

Where:

NOTE:

= 0.223 m g / k a / d x 70 ko________
0.01 1/d + (0.015 kg/d X 40 1/kg*)

(rounded off to 26 mg/1

(Tier 1))

*BAF = 40, pro v i d e d by E PA-Duluth and M i n n e s o t a PCA.

A Relative Source Contribution

(RSC) factor ha s not

been u t i lized in these d raft calculations.

REFERENCES:
Chemical Industry Institute of Techn o l o g y ( C U T ) .
1980.
A
24-Month Inhalation Toxicology Study in Fischer-344
Rats Exposed to Atmospheric Toluene.
C U T , R e search
T r i angle Park, NC.
As cited in EPA, 1987; EPA, 1990;
NTP, 1990.
Courtney, K.D., J.E. Andrews, J. Springer, M. Ménache, T.
Williams, L. Dailey and J.A. Graham.
1986.
A
163

p e r i natal study of toluene in CD-I mice.
Toxicol.
6:145-154.

Fundam. Appi.

Gibson, J.E. and J.F. Hardisty.
1983.
Chronic tox i c i t y and
o n cogenicity bioassay of inhaled toluene in Fischer-344
rats.
Fundam. Appl. Toxicol.
3:315-319.
Kostas, J. and J. Hotchin.
1981.
Behavioral effects of
low-level perinatal exposure to toluene in mice.
Neurobehav. Toxicol. Teratol. 3:467-469.
National T o x i c o l o g y P r o g r a m (NTP). 1990.
Toxico l o g y and
Carcinogenesis Studies of Toluene (CAS No. 108-88-3) in
F344/N Rats and B6C3F1 Mi c e (Inhalation S t u d i e s ) . NTPTR. No. 371, N IH P u b lication No. 90-2826.
Nawrot, P.S. and R.E. Staples.
1979.
Embryo-fetal toxicity
and t e r a t ogeni c it y of benzene and toluene in the mouse.
Teratology.
19:41A (abstract).
U.S. Environmental Prote c t i o n A g e n c y (EPA). 1990.
Integr a t e d Ris k Information System (IRIS d a t a b a s e ) .
Chemical file for toluene (108-88-3).
V e r i f ication
Date 6/20/90.
Last Rev i e w e d 6/20/90.
U.S. Environmental P rotection A g e n c y (EPA).
1988.
R e c o m m endation s for and Do c u m e n t a t i on of Biological
V a l u e s for Use in Ri s k Assessment.
PB88-179874.
U.S. Environmental P r o t e c t i o n A g e n c y (EPA).
1987.
Drinking
W a t e r Criteria Doc u m e n t for Toluene.
Pr e p a r e d b y the
Office of Heal t h and Environmental Assessment,
Environmental Criteria a nd A s s e s s m e n t Office,
Cincinnati, O H for the Office of Drinking Water,
Washington, DC.
ECAO-CIN-408.
Wolf, M . A . , V.K. Rowe, D.D. McCollister, R.L. H o l l i n g s w o r th
and F. Oyen.
1956.
To x i c o l o g i c al studies of certain
a l k y l a t e d benzenes and benzene.
A.M.A. Arch. Ind.
Health.
14:387-398.

164

October 28, 1991
GREAT LAKES INITIATIVE
TIER 1 HUMAN HEALTH C R ITERIA FOR
TOXAPHENE
CAS NO. 8001-35-2
Tier i H u m a n Noncancer criterion
A review of the available literature indicates that liver
pathology and immunological effects are the critical
noncancer endpoints for chronic exposure to toxaphene.
study by Lehman (1952, as cited by EPA,

In a

1985; 1987), rats

were e x p osed for a lifetime to 0, 25 or 100 p pm toxaphene in
their diet.

Fatty de g e neration was found in the livers of

rats fed 100 ppm, but no adverse effects we r e o bserved in
animals fed 25 ppm.

The dose of 25 p p m (1.25 mg/kg/d)

considered the NOEL for this study.

However,

was

in a study

c o n d ucted w i t h rats by Fitzhugh and N e lson (1951, as cited
by EPA, 1985; 1987) there was an increase in t h e weig h t of
the liver w i t h minimal cell enlar g e m e n t at d i e t a r y levels of
25 ppm.

The dose of 25 p p m (1.25 mg/kg/d) was c onsidered

the LOEL for this study. Concentrations in food in these two
studies w e r e converted to m g / k g bw/d by ass u m i n g the rats
consumed 5% of their body weight in food per da y (EPA,
1987). A n unpubl i s h e d two year study in m o n k e y s conducted by
Hercules,

Inc. found no clinical or histological effects at

d i etary exposure levels of toxaphene ranging from 0.64 to
0.78 m g / k g bw/d

(EPA, 1980).

Details of this study were not

available for development of this criterion.
165

The effect of toxaphene on the immune system of SwissW e bster mice was examined by A l l e n et al.

(1983).

In the

first part of the study, female w eanling m i c e were fed 10,
100, or 200 ppm toxaphene for eight weeks.
(1987)

A c c o r d i n g to EPA

these values are equiv a l e n t to 1.5, 15 and 30

mg/kg/d, respectively.

T he formation of IgG antibody was

depre s s e d in animals r e c e iving 100 and 200 pp m toxaphene.
Liver / b o d y w e ight ratios were increased in females at the
100 and 200 ppm level.

In the second part of the study,

m a t u r e female mice we r e fed the same amounts of toxaphene
used in the first par t of the study.

T hese animals were

m a t e d t hree weeks after feeding began and were m a i n t a i n e d on
the treatm e n t s until three weeks after p a r t u r i t i o n at which
time the pups w e r e w e a n e d onto the control diet.

The

r e sults of the assays w h i c h were p e r f o r m e d on the offspring
eight w e e k s after bir t h showed suppressed a n tibody formation
in the 100 p p m toxaphene group and enhanced a ntibody
formation in the 200 p p m group.

Phagocytic ability of

m a c r o p h a g e s was significantly reduced in the of f s p r i n g at
all doses.

The reduction in p hagocytic ability of

m a c r o p h a g e s w a s greatest at 100 ppm.

The L O A E L for

immunological effects in the offspring o c curred w h e n dams
w e r e fed 10 p p m (1.5 mg/kg/d) toxaphene.

However, the

actual dose r e c eived by the offspring cannot be estimated
accura t e l y because the offspring received t o x a phene

16«

transplacentally,

in the milk and p o s s i b l y in the feed (EPA,

1985).

Several studies have examined the r e p r o d u c t i v e and/or
devel o p m e n t al effects of toxaphene.

In a one gener a t i o n

r e production and devel o p m e n t study by Chu et al.

(1988),

groups of 30 female and 15 male S p r a g u e - D a w le y rats were
e x posed to 0, 4, 20,

100 or 500 p pm t o x a phene in the feed

and m a t e d after 13 and 20 weeks of exposure.

Dams were

e x p osed to the treatment diet t hroughout m a t i n g and
pregnancy.

F l a pups were s e p a rated from the dams three

weeks after birth and placed on the same t r e a t m e n t as their
dams and FQ and Fla animals we r e exposed to t o x a p h e n e for a
total of 26 weeks.
partum.

Flb

pups w e r e k i l l e d 21 da y s p o s t ­

Toxaphene had no effect on reproduction,

size, pup weight,

litter

fertility, ge s t a t i o n or survival.

Adult

F 0 female rats exhibit e d a s i g nificant increase in liver
w e i g h t at 20, 100 and 500 p pm w h e r e a s F Q m a l e s a nd F l a males
and females exhibited a s i gnificant increase in liver
w e i g h t s only at 500 ppm.

H i s t o logical changes w e r e observed

in the liver, k idney and thyroid of the F q and F l a m a l e and
female rats at 4 ppm but these changes did not appear to be
b i o l o g i c a l l y significant.

The changes in these organs at 20

p p m and above were mor e extensive and p r e v a l e n t and were
consid e r e d s ignificant by the researchers.

Th e N O A E L for

male and female Sprague-Dawley rats in this study was
167

therefore 4.0 ppm.

The geometric me a n of the doses given in

the study for m a l e s and females of the F 0 and F l a groups at
4 p p m was calculated to be 0.35 mg/kg/d.

In a three genera t i o n reproduction study by Kenn e d y et al.
(1973), S prague-Dawle y rats were exposed to 25 or 100 'ppm
t o x a phene in the diet.

T he two test groups and two control

groups each consisted of eight males and 16 females.

Adult

rats exposed to 100 p pm had slight cytoplasmic fatty
v a c u o l i z a t i on in their livers.
the 25 ppm dose level.
reproduction,

No effects were observed at

T o x a phene had no effect on

litter size, p up survival or w e a n l i n g body

weights.

No evidence of terat o g e n i c it y was found in this

study.

The N O A E L for systemic effects w as 25 ppm, or 1.8

m g / k g bw/d assuming the rats c o nsumed 7% of their body
w e i g h t in food p e r day (EPA, 1988).

Chernoff and Carver (1976) adm i n i s t e r e d relat i v e l y high
doses of toxaphene to pr e g n a n t CD rats in order to examine
the effect of the chemical on fetal development.

T o x a phene

was a d m i n i s t e r e d in corn oil by gastric intubation on days 7
t h r o u g h 16 of gestation at doses of 15, 25 or 35 mg/kg/d.
T h e r e w a s a reduction in w e i g h t g a i n of dams at all dose
levels and in fetuses at 25 mg/kg/d, but there w e r e no doser e l a t e d changes in fetal m o r t ality or the occurr e n c e of
anomalies.

In a study conducted by Kavl o c k et al.
168

(1985),

supernumerary ribs were found in the neonates of p r egnant
m i c e treated with 100 and 120 mg/ k g / d toxaphene on d a y 8 of
gestation.

However, this anomaly occurred at doses which

were toxic to dams.

The results of these studies suggest

that teratogenic and fetotoxic effects occur only at doses
w h i c h cause maternal toxicity.

Ac c o r d i n g to EPA (1985),

"toxaphene appears to have a low t e r atogenic potential
unless doses are large enough to induce m a ternal toxicity."

The studies cited thus far suggest that t o x a phene has little
effect on neonate development.

However, toxaphene has been

found to affect the behavior of neonates at v e r y low doses.
In a study by Olson et al.

(1980), pre g n a n t a l bino rats were

exposed to 50 ug/kg bw/d toxaphene via the feed b e g i nning on
day 5 of gestation.

The neonates w e r e exposed to th e same

treatment levels until the study wa s t e r m i n a t e d at 3 months
postpartum.

Early deve l o p m e n t of th e pups was tested on

p o s t natal days 7 t h ro u g h 17 by m e a s u r i n g s w i m m i n g ability
and r i g hting reflexes.

Motivational,

l e arning and retention

tests were run on postnatal days 70 through 90 u s i n g a
symmetrical maze.

Early in development, the trea t e d animals

exhibited retarded maturation as mea s u r e d by their swimming
ability, but by day 16 all groups di s p l a y e d normal swimming
ability.

Toxaphene-f ed animals exhibited a retarded

righting reflex in tests conducted on p o s t natal days 7

16 9

t h rough 17.

Toxaphene t r e atment had no effect on the

results of motivational tests.

The Chu et al.

(1988) study w as considered the k ey study for

risk assessment.

This study used a sufficient number of

doses to e s t a blish a NO E L for liver toxicity.

The primary

weakness of this study was that it was subchronic in
duration.

However, the results found in this study were

c onsistent w i t h the results of several chronic studies in
rats.

These chronic studies we r e not us e d for risk,

a ssessment because th e y either established a N O E L w h i c h was
h igher than the LOEL deter m i n e d in the Chu study (Lehman,
1952; K e n n e d y et al.,

1973) or a NO E L was not e s t ablished

(Fitzhugh and Nelson,

1951).

The Chu et al.

(1988) study

was also better suited for risk assessment bec a u s e it used
four dose levels w h er e a s the chronic studies u s e d o n l y two
dose levels.
mg/kg/d

A l t hou g h the subchronic m o n k e y H N O A E L of 0.78

(Hercules, Inc. as cited by EPA,

1980) w as higher

than the subchronic rat N O A E L OF 0.35 mg/ k g / d (Chu et al.,
1988), the latter study was p r e f e r r e d for risk a ssessment
d u e to the greater extent of the d o s e - r e s p o n se d a t a in rats.

The lowest dose of toxaphene w h i c h was found to p r o d u c e an
a d v e r s e effect in rats was 50 ug/kg

(Olson et al., 1980).

This dose level was not used in the H NV deriv a t i o n for
t o x a p h e n e because the effects measured at this d o s e appeared
170

to be transient and the actual dose re c e i v e d by the neonates
w a s uncertain.

EPA (1985) did not use the O lson et al.

(1980) study to derive heal t h advisories for toxaphene for
the same reasons cited above.

The q u a l i t y of the Chu et al.

(1988) study was deemed

sufficient to derive a Ti e r 1 HNC.
the N O E L

(0.35 mg/kg/d)

The HNV was deri v e d from

determ i n e d for S p r a g u e - D a w le y rats

using an u n c e r t a i n t y factor of 100 to account for
intraspecies v ariabi l i t y and interspecies extrapolation.
additional 10-fold u n c ertainty factor was no t used for
subchronic to chronic e x t rapolation because t here were
several chronic studies w h i c h supported the results of the
Chu et al.

(1988) study.

A D E = 0.35 m g / k a / d = 0.0035 m g / k g / d = 3.5 ug/kg/d
100

Where:

U n c e r t a i n t y factor = 100, c omposed of:
lOx for intraspecies v a r i a b i l i t y
lOx for interspecies e x t rapolation

D r i n k i n g W a t e r Sources:

HNV = ADE x Uh x RSC
VC + (FC x BAF)

« 3.5 ua/lco/d x 70 ka x 0,8__________
2 l/d ♦ (0.015 kg/d x 2,117,450 l/kg“)

171

An

■ 0.0062 ug/l (rounded off to 6 ng/l (Tier 1))

Nondr i n k i n g Water Sources:

HNV = APE » Uti X RSC

WC ♦ (FC x 8AF)

* 3.5 ug/kg/d x 70 kg x 0.B____________

0.01 t/d + (0.015 kg/d x 2,117,450 t/kg*)

■ 0.0062 ug/l (rotnded off to 6 ng/L (Tier 1))

*BAF = 2,117,450 prov i d e d by EPA-Duluth and M i n n e s o t a PCA.

REFERENCES:
Allen, A.L., L.D. Roller and G.A. Pollock.
1983.
Effect of
toxaphene exposure on immune responses in mice.
J.
Toxicol. Environ. Hlth.
11:61-69.
Chernoff, N. and B.D. Carver.
1976.
Fetal t o xicity of
toxaphene in rats and mice.
Bull. Environ. Contam.
Toxicol.
15:660-664.
Chu, I., V. Secours, D.C. Villeneuve, V.E. Valli, A.
Nakamura, D. Colin, D.J. Clegg and E.P. Arnold.
R e p r o d u c t i o n study of t o x a phene in the rat.
J.
Environ. Sci. Hlth.
B23(2): 101-126.

1988.

Fitzhugh, O.G. and A.A. Nelson.
1951.
C o m p a r i s o n of
c h r o n i c effects pr o d u c e d in rats by several chlorinated
h y d r o c a r b o n insecticides. Fed. Proc.
10:295.
Kavlock. R . J . , N. Chernoff and E.H. Rogers.
1985.
The
e f f e c t of acute m a ternal t o xicity on fetal d e v elopment
in the mouse.
Terat. Careinog. Mutag.
5:3-13.
Kennedy, G.L. Jr., J.P. Frawley, and J.C. Calandra.
M u l t i g e n e r a ti o n rep r o d u c t i v e effects of three
pestic i d e s in rats.
Toxicol. Appl. Pharmacol.
596.

172

1973.
25:589­

Lehman, A.J.
1952.
Oral toxicity of toxaphene.
Assoc. Food Drug Off.
U.S. 16:47.
Olson, K.L., F. Matsumura and
effects on juvenile rats
levels of toxaphene, and
A and toxicant B.
Arch.
9:247-257.
U.S.

Q. Bull.

G.M. Boush.
1980.
Behavioral
from p e r i natal e x p o s u r e to low
its toxic components, toxicant
Environ. Contam. Toxicol.

Environmental Prote c t i o n Agen c y (EPA). 1980.
Ambient
Water Q u a lity Criteria for Toxaphene.
EPA 440/5-80076.

U.S. Environmental Protection A g e n c y (EPA).
1985.
Drinking
Water Criteria Document for Toxaphene.
E n v ironmental
Criteria and Assess m e n t Office.
Cincinnati, OH.
PB
86-118049.
U.S.

Environmental Protec t i o n A g e n c y (EPA).
1987.
H e alth
Advisories for 16 Pesticides.
O f fice of D rinking
Water, Washington, D.C.
NTIS No. PB 87-200176, 264 pp.

U.S.

Environmental Protection A g e n c y (EPA).
1988.
R e commendations for the D o c u m e n t a t i on of Biolo g i c a l
V a l u e s for Use in Ri s k Assessment.
NT I S No. PB 8 8 ­
179874 .

Tier l winn^Ti c a n c e r C r i t erion
A c c o r d i n g to EPA (1985,- 1987), there are i nadequate data
a v a i l a b l e t o a s c e rtai n whether t o x a phene is a h u m a n
carcinogen.

However, two chronic studies h a v e shown that

toxaphene induces the formation of liver t u mors in B6C3F1
mice.

One of these studies also found that t o x a p h e n e

induces the formation of thyroid tumors in O s b o r n e - M e n de l
rats.

T o x a p h e n e was mutagenic for S almonella t y p h i m u r i u m

strains TA98 and TA100

(Hill,

1977 as cited by EPA, 1985)

and was also found to induce the formation of sister
chromatid exchanges in Chinese hamster lung (DON) cells
(Steinel et al.,

1990).

However,
17 3

toxaphene p r o d u c e d a

n e g a t i v e response in a mod i f i e d dominant lethal a ssay which
used male ICR/Ha Swiss m i c e

(Epstein et al.,

1972).

A c c o r d i n g to EPA (1985; 1987), the w e i g h t - o f - e vi d e n c e for
toxaphene c arcinogeni ci t y is sufficient for B2
clas s i f i c a t io n

(probable h u m a n carcinogen).

T he data are

sufficient to d e rive a T i e r 1 HCC.

In a study conducted by NCI

(1979), 50 O s b o r ne-Mendel

rats/ s e x / g r ou p and 50 B6C3F1 m i c e / s e x / g r ou p were
admini s t e r e d toxaphene in their diets for 80 weeks.

Male

rats recei v e d t i m e - we i g h t ed average (TWA) doses of 112 and
556 ppm, while females r e ceived T W A doses of 540 and 1080
ppm.

Both m a l e and female m i c e received T WA d o s e s of 99 and

198 ppm.

Both rats and mi c e h ad 10 mat c h e d c o n t r ols/sex

w i t h an additional 45 p o o l e d cont r o l s / s e x for rats and 40
additional p ooled con t r o l s / s e x for mice.

M a l e and female

rats e x h i bited a stat i s t i c a l ly significant dos e - r e l a t e d
increased incidence of thyr o i d tumors

(adenomas and

c a r c i n o m a s ) , w h e r e a s treated mice e x h ibited a s t a tistically
signif i c a n t dose-r e l a t e d i n c r eased incidence of liver tumors
(NCI, 1979).

In a study c o n d ucted by Litton Bionetics
EPA,

(1978, as cited by

1987), toxaphene was a d m i nistered to B6C3F1 m i c e

(54

mice/sex/group)

in the diet for 18 months at doses of 0, 7,

20 and 50 ppm.

Animals were observed for a p e r i o d of 6
174

months after treatment.
hepatocellular tumors

An increased incidence of

(adenomas and carcinomas)

was seen in

both sexes and was st a tistically significant in males
adm inistered 50 ppm.

This study, rather than the NCI study,

was used for cancer risk assessment because it utilized more
dose levels and a lower range of doses while still eliciting
a t umorigenic response in the liver.
the same key study and slope factor

EPA (1987) recommends
(1.1 (mg/kg/d)- 1 ) as

u t i lized for HCC derivation.

R A D = l x 10~5 = 9 x 10-6 m g / k g / d = 9 ng/kg/d
-1
1.1 (mg/kg/d)

Drinking Water Sources:

HCV - RAD x Wh
UC + (FC * BAF)

= 9 rw/kq/d x 70 lea_______________
2 l/d + (0.015 kg/d * 2,117,450 l/kg*)

= 0.0198 ng/l (rounded off to 0.02 ng/l (Tier 1))

Nondr i n k i n g W ater Sources:

HCV s RAD x Wh
WC ♦ (FC x BAF)

= 9 ng/kg/d x 70 kg___________________
0.01 l/d + (0.015 kg/d x 2,117,450 l/fcg*)

= 0.0198 ng/l (romded off to 0.02 ng/l (Tier 1))

*BAF = 2,117,450, provided by EPA-Duluth and Minnesota PCA.

175

REFERENCES:
Epstein, S.S., E. Arnold, J. Andrea, W. Bass and Y. Bishop.
1972. Detection of chemical mutagens by the dom i n a n t
lethal a ssay in the mouse.
Toxicol. Appl. Pharmacol.
23:288-325.
Hill, R.N.
1977.
Memora n d u m to Fred Hagemen.
Off. Spec.
Pestic. Rev., U.S. EPA.
December 15.
As cited in:
EPA, 1984.

Litton Bionetics.
1978.
Carc i n o g e n i c e valuation in mice:
Toxaphene.
Pre p a r e d by Litton Bionetics, I n c . ,
Kensington, MD for Hercules, I n c . , Wilmington, DE.
N a t i o n a l Cancer Institute (NCI).
1979.
B i o a s s a y of
T o x a phene for Possible Carcinogenicity,
Carcinogenesis
T e sting Program.
Div i s i o n of Cancer Cause and
Prevention.
NCI, N a tional Institute of Health,
Bethesda, Maryland,
20014.
U.S. D e p a r t m e n t of Health,
E d u c ation and Welfare.
DHEW P u b l i c a t i o n No. (NIH)
79­
837.
Steinel, H.H., A. Ar l a u s k a s and R. S. Baker.
1990.
SCE
induction and c ell-cycle d e l a y by toxaphene.
Mutat.
Res.
230:29-33.
U.S.

Environmental Prote c t i o n A g e n c y (EPA).
1985.
Drinking
W a t e r Criteria D o c u m e n t for Toxaphene.
E n v ironmental
C r i teria and A s s e s s m e n t Office.
Cincinnati, OH.
PB
86-118049.

U.S.

Environmental Prote c t i o n A g e n c y (EPA).
1987.
I ntegrated R i s k I n f ormation S y s t e m (IRIS d a t a b a s e ) .
C h e mical file for toxaphene (8001-35-2).
Veri f i c a t i o n
Date 3/5/87.
Last Rev i s e d 1/1/91.

176

N o v e m b e r 4, 1991
GREAT LAKES INITIATIVE
TIER 1 HUMAN HEALTH CRITERIA FOR
T RICHLOROETHYLENE
CAS NO. 79-01-6

Tier 1 Wiiman Noncancer Criterion

A r e view of the available literature indicates inadequate
human data for quanti t a t i v e oral risk asses s m e n t of
t r i c h l o r oethylene

(TCE).

Humans exposed occup a t i o n a ll y to

TCE in air have been reported to e xperience central nervous
system disorders such as dizziness, headaches,

nausea,

euphoria, palpitations, disturbances of vision,

fatigue,

and

irritability,* disturbances in cardiac rhythm,
g a s trointestinal disorders, toxic effects on the liver, and
cutaneous reactions.
IARC,

(NIOSH,

1973; G r a n d j e a n et al.,

1955;

1979).

A r e v i e w of animal studies indicates that the m o s t
appropriate basis for HNV d erivation for T C E is the N O A E L
from a subchronic drinking water study c o n d ucted by T u cker
et al.

(1982).

In this study, male and female CO-1 mice

were administered TCE in drinking water ad libitum for 4 or
6 months.

The concentrations used w e r e 0, 0.1, 1.0,

2.5,

and 5.0 mg/mL, corresponding to t i m e-weighted average daily

177

doses of 0, 18, 217,

393, and 660 m g / kg/day for male mice

and 0, 18, 193, 437 and 793 mg / k g / d a y for female mice,
respectively,

according to the authors.

F o l lowing 4 months

of exposure,

enlarged livers were o bserved in m ales at the

1, 2.5 and 5.0 mg/1 doses, and in females at the 5.0 mg/1
dose.

A significant increase in k i dney weig h t was seen at

the h i ghest dose in males at 6 months and in females at 4
and 6 months of exposure. The results of this study indicate
a L O A E L value of 216 m g / k g / d a y and a N O A E L of 18 mg / k g / d a y
based on liver effects in male CD-I mice.

Sanders et al.

(1982)

investigated the immune status of CD-I

m i c e u s i n g the same animals and b i oassay as d e s cribed above
(Tucker et al.,
0.05)

1982).

A s t a tistically significant

(p <

finding of depr essed c e l l-mediated immunity was

observed in female mi c e at all four TCE c o n c e ntrations after
4 m o n t h s of exposure.

However, this r esponse

at 4 months

d i d not exhibit a clear d o s e-response relationship, and
after 6 months of exposure the effect was stati s t i c a l ly
s i g nificant at only the highest dose.

In as s e s s i n g bone

m a r r o w function, the ability of bone m a r r o w stem c e l l s from
the T C E e x p osed mice to form colonies in a s emi-solid m e dium
was found to be statistically significantly inhibited at all
dose levels after 4 months and 6 months of exposure.

While

a s t a t i stically significant do s e - r e s p o n se was observed,
biological significance of the in vitro o b s e r v a t i o n is
178

the

questionable,

This study may be interpreted to prov i d e only

suggestive evidence of a L O A E L at 18 m g / k g / d a y for immune
system effects.

The observations reported in the key study are supported by
evidence of h e p a t otox i c it y of T CE from g a vage studies
(Tucker et al.,
al.,

1982; Buben and O'Flaherty,

1984) and inhalation studies

1982; 1981;

Kimmerle and Eben,

study, Tucker et al.

(1982)

1985; Zenick et

(Kjellstrand et al.,

1973).

1983;

In a 14-day gavage

found a s t a tistically

sig nificant increase in liver wei g h t s among m a l e CD-l mice
r e c e iving T C E at 240 mg/kg, but not among m i c e r e c e iving a
dose of 24 mg/kg.

In a subchronic study p e r f ormed by Buben and 0 ' Flaherty
(1985), TCE was admini s t e r e d by gavage in corn oil to male
Swiss-Cox mice 5 days a w e e k for 6 weeks.

D oses were 0,

100, 200, 400, 800, 1600, 2400, and 3200 m g / k g bo d y weight.
Doses of 100 m g / k g or more r e sulted in a statis t i c a l ly
s i gnificant increase in the liver to body w e i g h t ratio when
compared to controls.

In addition, the authors n oted a

dose - r e s p o n se relationship in liver t r i g l y c e r i d e levels and
glucose-6 - p ho s p h a t a s e activity.

The increase in liver size

was a ssociated w i t h hypertrophy of liver cells and a
decrease in t h e DNA concentration in the liver.

179

In another subchronic study,

Zenick et al,

(1984)

a d ministered TCE in corn oil gavage to Long-Evans hooded
male rats for 5 days per week for 6 weeks.

Doses

administered w e r e 0, 10, 100, and 1000 mg/kg/day.

Elevated

liver w eight to bod y weight ratios were o b served in the 100
and the 1000 mg/kg groups, and a reduced body weight gain
was observed in the 1000 m g / k g group.

Results of a 2-year gavage study (NTP, 1988) are not useful
for H N V d e r i v a t i o n because of the hi g h doses used.

Male and

female ACI, August, Marshall, and O s b o r ne-Mendel rats
(50/sex/strain/group) we r e administered TCE in a corn oil
v e hicle at doses of 0, 500, a nd 1000 mg/kg,
for 103 weeks.

5 days per w e e k

Renal tubular cell cytom e g a l y was observed

in 82% to 100% of all dosed animals, and TC E pro d u c e d toxic
n e p h r o p a t h y in 17% to 80% of the d o s e d animals, but in none
of the u n t r e a t e d or vehi c l e controls.
reported.

No liver effects were

R e d u c e d survival r e lative to vehicle controls was

observed in 7/16 do s e d groups, and nephrotoxicity,

central

n e rvous s ystem toxicity charac t e r i z ed by sedation,

loss of

consciousness, tremors, and convulsions were obs e r v e d in all
dosed groups.

EPA (1987a) d e v e lop e d a lifetime h e a l t h a d v i s o r y for TCE
b ased on a rat inhalation study (Kimmerle and Eben,

1973).

Subchronic exposure to TCE by adult rats at 55 p pm (300
180

m g / m 3 ) , 8 hours/day,

5 days per week for 14 w e e k s was

followed by the investigation of indices of to x i c i t y
including hematologic al investigations,
function tests, blood glucose,

liver and renal

and organ / b o d y w e ight ratios.

Liver weights were found to be elevated, w h i l e other test
values were not diff erent from controls.

T he e l evated liver

w e ights were attribut e d to hyd r o p i c changes or fatty
accumulation.

The LOAEL exposure is e s t imated to be

equivalent to 270 mg/kg/day.

The r e f e rence dose

(RfD)

d e t e r m i n e d by EPA (1987a) on the basis of this study was
0.00735 mg/kg/day.

Other E PA documents that evaluate TCE

toxicity

1985; 1987b; 1988a) p r e s e n t cancer risk

(e.g. EPA,

characterization,

but do not r e c o mmend a k e y s tudy or

critical effect for n o n c ancer assessment.

A number of other inhalation studies c o r r o b o r a t e the results
of the Kimmerle and Eb e n (1973) study.

K j e l l s t r a n d et al.,

(1983), e x posed male and female NHRI m i c e

(10/sex/group)

TCE at concentrations of 0, 37, 75, 150, a nd 300 p p m
199, 403, 806, and 1612 m g / m 3 ) for 30 days.

to

(0,

T he critical

toxic effect observed was a change in liver weight, which
was statistically greater in all expo s e d groups than in
controls.

Although a N O A E L was not identified b y the

authors, the L O A E L was d etermined to be 37 p p m
for liver effects of TCE.

(199 m g / m 3 )

This m ay be c o n v e r t e d to an

approximate administered dose of 338 m g / k g / d a y ass u m i n g that

181

mice breathe approxi m a t e ly 1.7 m 3 /kg bw/day (EPA, 1 9 8 8 b ) .
K jellstrand et al.

(1982) exposed NMRI mice, Sprague Dawley

rats and m o n g olian gerbils to 150 ppm TCE for 30 days. A
m arked increase in liver w e i g h t was found in all three
species.
et al.

Using the same species and exposure,

K j e llstrand

(1981) also o bserved increased k i dney weights among

TCE exposed gerbils, and to a lesser extent in mi c e and rats
exposed t o 150 p p m T C E for 30 days.

The data are judged to be sufficient for Tier 1 HNC
derivation.

The HNC is based on the mouse N O A E L of 18

m g / k g / d a y determ i n e d in the key study (Tucker et al.,

1982).

There exists only suggestive evidence of effects on immune
p a r a m e t e r s at this dose
inhalation studies
al.,

(Sanders et a l . , 1982).

(Kimmerle and Eben,

Subchronic

1973; K j e l l s t r a n d et

1983) corrobora t e the sensitivity of liver effects, but

involve shorter exposure d u r ations than Tucker et al.
(1982), fail to p r ov i d e a NOAEL, and present u n c ertainties
in route - t o - r o ut e ex t rapolation for oral ri s k assessment.
A c c o r d i n g to EPA (1985), T CE does not produce significant
signs of development al t oxicity except at levels w h i c h
affect maternal well being.

Al s o no clinical e v idence of

f e t otoxicity or terat o g e n i c it y from T CE exposure has been
reported.

Therefore, any potential for TCE to cause

r e p roductive/develop m e n t a l effects should be a dequately
p r o t ected by this approach to HNC development.
182

A D E = N O A E L = 18 mg/k q / d a v = 0.018 m g / k g / d a y
UF

Where:

1,000

U n certainty factor = 1,000 c o m p o s e d of
lOx for intraspecies va r i a t i o n
lOx for interspecies extra p o l a t i on
lOx for subchronic to chro n i c e x t r a p o l a t i o n

D r i n k i n g Water Sources:

HNV = APE x Wh x RSC

= 0.018 m a / k g / d a y x 70 ka_________

W C + (FC x BAF)

2 1/d + (0.015 kg / d x 18 l/kg*>

= 0.56 mg/1

(rounded off to 0.6 mg/1

(Tier 1))

N o n d r i n k i n g W a t e r Sources:

H N V = APE x W h x RSC

= 0.018 m a / k a / d a v x 70 ka____________

W C + (FC x BAF)

0.01 1/d + (0,015 k g / d x 18 l/kg*>

= 4.5 mg/1

Where:

(rounded off to 5 mg/1

(Tier 1))

*BAF = 18 provided by EPA-P u l u t h and M i n n e s o t a PCA.

ia 3

NOTE:

A R e l a t i v e Source C o n t r ibution

(RSC) factor has not

been utilized in these draft calculations.

REFERENCES:
Buben, J. and E. O'Flaherty.
1985.
D e l i n e a t i o n of the role
of m e t a b o l i s m in the h e p a t o t o x i c it y of
trich l o r o e t hy l e n e and perchloroethylene: A dose effect
study.
Toxicol. Appl. Pharmacol.
78:105-122.
Grandjean, E . , et al. 1955.
I n v e s tigations into the effects
of e x p osure to tr i c h l o r o e t hy l e n e in m e c h a n i c a l
engineering.
Br. J. Indust. Med.
12:131-142.
International A g ency for R e s e a r c h on Cancer ( I A R C ) . 1979.
IARC M onographs on the E valuation of C a r c i nogenic Risk
of Chemicals to Man.
WHO Publ. Centre, USA. Volume 20.
Albany, NY.
Kimmerle, G. and A. Eben.
1973.
Metabolism, e x c r etion and
t o x i c o l o g y of t r i c h l o r o e t hy l e n e after inhalation.
1.
Experimental ex posure on rats.
Arch. Toxicol. 30:115.
Kjellstrand, P., B. Holmquist, P. Aim, M. Knaje, S. Romare,
I. Jonsson, L. Mansson, and M. Bjerkemo.
19B3.
Trichloroethylene: Further studies of the effects on
body and organ wei g h t s and p l a s m a b u t y r y l c h o l in e s t e r a s e
activ i t y in mice.
Acta Pharmacol, et Toxicol. 5 3 : 3 7 5 ­
384.
Kjellstrand, P . , A. Edstrom, M. Bjerkemo, and B. Holmquist.
1982.
Effects of t r i c h l o r o e t hy l e n e i nhalation on acid
p h o s p h a t a s e in rodent brain.
Toxic. Let. 10:1-5.
Kjellstrand, P . , M. Kanje, L. Mansson, M. Bjerkemo, I.
Mortensen, J. Lanke, and B. Holmquist.
1981.
Trichloroethylene: Effects on body a nd o r g a n weig h t s in
mice, rats and gerbils.
Toxicol. 21:105-115.
N a t i o n a l Institute of O c c u p a t i o n a l Safety and H e a l t h
( N I O S H ) . 1973.
Criteria for a R e c o m m e n d e d Standard for
O c c u p a t i o n a l Exposure to Trichloroethylene.
R e p o r t No.
N I O S H - T R - 0 4 3 - 7 3 . DHEW.
Public H e alth Serv. Cent e r for
D i s e a s e Control.
Cincinnati, OH.

184

N a t ional Toxic o l o g y Program (NTP). 1988T o x i c o l o g y and
C arcinogenesis Studies of T r i c h l o r o e t hy l e n e in Four
Strains of Rats.
National T o x i c o l o g y Program.
Technical Report Series No. 273. U.S. Depart m e n t of
Health and Human Services.
Public H e alth Service,
National Institutes of Health.
Sanders, V., A. Tucker, K. White, B. Kauffmann, P. Hallett,
R. Carchman, J. Borzelleca, and A. Munson. 1982.
Humoral and cell - m e d i a t ed immune status in m i c e exposed
to trich l o r o e t hy l e n e in d r inking water.
Toxicol. Appl.
Pharmacol. 62:358-368.
Tucker, A.N., V. Sanders, D. Barnes, T. Bradshaw, K. White,
L. Sain, J. Borzelleca, and A. Munson.
1982.
T o x i c o l o g y of trichl o r o e t hy l e n e in t he mouse.
Toxicol.
Appl. Pharmacol. 62:351-357.
U.S. Environmental Pr o t e c t i o n A g e n c y (EPA).
1988a.
Health
Effects Assess m e n t for Trichloroethylene.
EPA/600/889/097 ._ Washington, D.C.
U.S. E n v i ronmental Pr o t e c t i o n A g e n c y ( E P A ) . 1988b.
Recom m e n d a t io n s for and Docum e n t a t i on of Biological
Values for use in Ri s k Assessment.
PB88-179874.
U.S. Environmental Protec t i o n A g e n c y ( EPA). 1987a.
Trichlor o e t hy l e n e H e alth Advisory.
Offi c e of Drinking
Water.
U.S. Environmental Prote c t i o n A g e n c y (EPA). 1987b.
Addendum
to the Health A s s e s s m e n t Document for
Trichloroethylene: Updated C a r c i n o g e n i ci t y A s s e s s m e n t
for Trichloroethylene.
E P A / 600/8-82/006. Washington,
D.C.
U.S. Environmental Prote c t i o n A g e n c y (EPA). 1985.
Health
A s s e s s m e n t Docume n t for Trichloroethylene.
E P A / 600/882/006F Washington, D.C.
Zenick, H., K. Blackburn, E. Hope, N. Richdale, M. Smith.
1984.
Effects of tr i c h l o r o e t hy l e n e e x p o s u r e on male
reprod u c t i v e function in rats.
Toxicol. 31: 237-250.
Tier 1 m m « " Cancer Criterion

Six e p i d e m i o l o g ic studies have been pe r f o r m e d to investigate
the carci n o g e n i ci t y of tr i c h l o r o e t hy l e n e

ias

(TCE)

in exposed

workers

(Axelson et al.,

1978; Hardell et al.,

et al., 1979; Novotna et al.,
al,

1980).

1979; Paddle,

1981; Malek

1983; Tola et

Results of those studies we r e inadequate to

attribute cancer incidence to TOE exposure. However, because
they suffer from various
limitations and deficiencies,

they- also fail to provide

adequate evidence that TCE is not a human c arcinogen

(EPA,

1985).

Based on w eight of evidence, EPA (1985,

1987,

1988)

classified TCE in Group B2- Probable Human Carcinogen.

The

evidence r e v iewed by EPA (1985) for c a r c i n o genicity of T CE
in experimental animals includes increased incidence of
h e p a t o c e l l u la r carcinomas in male and female B6C3F1 mice
(NCI,

1976; NTP,

1982,

1986) by gavage, m a l i g n a n t lymphomas

in female Han:NMRI mi c e by inhalation (Henschler et al.,
1980); and renal ade n o c a rcinomas in male Fischer 344 rats by
gavage

(NTP, 1982,

1986).

Evidence presented in EPA (1987)

m a r k e d l y s t rengthene d the B2 class i f i c a t io n by sho w i n g that
inhalation is a second exposure route that results in
carcin o g e n i c activit y in rats and mice, and by identifying
d i v e r s e tumor sites

(EPA, 1987).

EPA (1985) developed a quantitative cancer risk assessment
based on four sets of gavage bioassay data that show
h e p a t o c e l l u la r carcinomas in male and female mi c e
186

(NTP,

1982; NCI,

1976),

Th e NCI b i oassay involved exp o s u r e by

g a v a g e to B6C3F1 mice.

Alt h o u g h rats were also tested,

excessive mortality in all groups cast d oubt on the adequacy
of those results.

Mice were dosed in groups of 50 animals

per sex, 5 days/week for 78 weeks.

Surviving animals were

sacrificed at 90 weeks and subjected to com p l e t e n ecropsy
and h i s topathological examination.

The time-weighted-

average (TWA) doses for male mice w e r e 1,169 and 2,339
mg/kg,

and for the female mice th e y we r e 869 a nd 1,739

mg/kg.

The study included 20 matched vehi c l e control

animals of each sex.

It w as concluded that TCE induced a

s t a t i stically significant (p < 0.05)

increase in the

incidence of h epatoce l l u la r carcinoma in both m a l e and
female B6C3F1 mice.

A reduction in the t i m e-to-tumor

response was also reported among m a l e m i c e at the h i g h dose
level.

The p r e sence of the trace c o ntaminant

epich l o r o h y dr i n (0.09%)

in the test mat e r i a l for this

bioassay could be a c ause for concern.

However,

it has been

d e t e r m i n e d that any potential c o n t r ibution of
epic h l o r o h y dr i n to th e overall c a r c i n o g e n i c p o t e n c y of TCE
in the b i o assay was negligible

(EPA, 1985).

N T P (1982) conducted a carci n o g e n i ci t y bi o a s s a y on TCE in
B6C3F1 mice and F344/N rats.

The rats e x p e r i e n c e d reduced

survival when compared to controls, and the resu l t s were
therefore invalidated.

Male and female m i c e w e r e dosed by
187

gavage at 1,000 mg/kg,

5 days/week for 103 weeks. Survival

was significantly lower (p < 0.004)

in treated males whereas

survival in treated females was lower after 95 weeks,

but

the overall difference between vehicle controls and treated
females was not significant.

Male and female mi c e h ad a

s t a t istically significant increase in the incidence of
hepat o c e l l u la r carcinoma (p < 0.002)
adenoma

and h e p a t o c e l l u la r

(p < 0.05) over c o r responding vehicle controls. The

TCE test material for that bioassay was not c o n t a minated
with d e t e c t a b l e amounts of epichlorohydrin.

The potency of

TCE w i t h r egard to t he induction of hepat o c e l l u la r
carcinomas in mice has been d etermined to be ve r y similar in
the NTP (1982) bioas s a y and t he NCI

(1976) bio a s s a y

(EPA,

1985).

A d d i t i o n a l studies were rev i e w e d by E PA (1987)

identifying

p o s itive findings by inhalation exposure in rats and mice.
Maltoni et al.

(1986) c o n ducted bioassays of S p r a g ue-Dawley

rats e x posed to 0, 100, 300 and 600 p p m of TCE 7 hours/day,
5 d a y s / w e e k for 104 weeks.
animals.

Necropsy was p e r f o r m e d on all

Male rats d e m o nstrated increased incidences of

renal tubuli m egalonu c l e oc y t o s i s and renal adenocarcinomas,
and a slight increase in leukemias, particularly
immunoblastic lymphosarcomas.

Maltoni et al.

(1986)

c o n d ucted bioassays on Swiss mice and B6C3F1 m i c e
mice/strain/sex/group)

also

(90

exposed to 0, 100, 300, and 600 ppm
188

T C E for 78 weeks.

St a tistically s i gnificant increases in

hepatomas were noted among male Swiss mi c e at the high
concentration, and significant increases in p u l m o n a r y tumors
were observed among male Swiss mice at high and m e dium
exposures.

Among the B6C3F1 mice, there were increases in

hepatomas in males and females, p u l monary tumors in females,
and in the total number of tumors among females at all
concentrations.

Fukuda et al.,

(1983) r eported the results of bioassays with

female ICR mice and S p r a g ue-Dawley rats

(49-50 p e r group)

e x posed to airborne concentrations of 0, 50, 150, and 450
ppm of TCE for 7 hours/day,

5 d a y s /week for 107 weeks.

There were no statistically significant increases in tumors
among rats, however a statistically significant increase in
lung adenocarcinomas was found among the mice.

Using the mice liver tumor data sets from N T P (1982) and NCI
(1976), EPA (1985) calculated h u m a n slope e s t imates of 1.9
x l O - 2 , 8.0 x 10” 3 , 1.8 x 10"2 , and 5.8 x 10"3 p e r mg/kg/day.
Because the slope estimates from these four da t a sets were
found to be comparable, their g e o metric me a n was us e d to
d erive the recommende d slope factor of 1.1 x 10~2 /
(mg/k g / d a y ) . EPA (1987) also d e v eloped slope factors from
the inhalation studies of Maltoni et al.
et al.(1983).

(1986) a nd Fukuda

These slope factors were found to be
189

comparable to the
studies

d e v e loped earlier from the gavage

(EPA, 1987).

RAD = 1 x 1 0 ~ 5________________

= 9.091 x 10“ 4 mg/ k g / d

1.1 x 10“ 2 (mg/kg/d)"1

Drinking Water Sources:

HCV =

RAD x Wh_______ = 9.091 x 10~4 ma/ k a / d x 70 ka
WC + (FC x BAF)

= 0.028 mg/1

2 1/d + (0.015 kg/d x 18 1/kg*)

(rounded off to 0.03 m g / 1

(Tier 1))

N o n d r i n k i n g Water Sources:

HCV =

RAD

X

Wh________ = 9.091 x _1CT4 m q / k q / d

_

W C + (FC X BAF)

X

7Q_Jc_q_______

0.01 1/d + (0.015 kg/d

x 18 1/kg*)

= 0.227 mg/1

Where:

(rounded off to 0.2 mg/1

(Tier 1))

*BAF =» 18 Provided by EPA-Duluth and M i n n e s o t a PCA.

19 0

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192