Qorru Kyokaishi, 48, No. 9, 1975, p. 537 Loblems of hygiene maintenance for food coming into L,ntact with rubber and plastics products I Takahashi ffflsiated by E.A. Inglis SUMMARY GIVEN) .3**3 as*y. 1023 ene', 1 ed. tran970, ■ec974- , INTRODUCTION fttcently concern has arisen over food safety, and over M question of containers, packaging and utensils used in :ontact with food products in general. Investigations have ^een carried out to decide whether there is a health risk in jdditives, using the results of investigations to determine tnree (actors, i.e. the toxicity of additives, the amounts of migration of these additives, and the extent to which food products coming into contact with containers, utensils and packaging are consumed. To determine the tpxicity of ad­ ditives, three types of tests are employed, for acute, sub­ acute and chronic toxicity (1). Previously tests which determined life or death after a large amount of the ad­ ditive was given in a single dose, as in the acute toxicity tests, were regarded as important, but as amounts of materials migrating from packaging and utensils into the lood products are in any case extremely small, and because of the limited extent to which acute toxicity can be used as a screening test, more recently sub-acute toxicity has been used, with a certain amount of caution, i.e. observing an adequate number of symptoms, and since chronic toxicity is predictable.to a certain extent, a period of 90 days for sub-acute toxicity tests is now generally used in Europe. It has been reported that there may of course be a need to carry out chronic toxicity tests over a period of as long as 2 years if doubtful points arise. In the case of PVC and polyolefins, additives which are currently judged to be satisfactory, i.e. are drawn up on the positive list (PL), must meet five conditions. These conditions, which are strictly applied, are, in addition to the degree of confidence in the toxicity data, whether the substance in question is mentioned in positive lists abroad, whether there are cases of its use abroad, whether there are con­ siderable advantages derived from the use of the sub­ stance as an additive and which can be universally agreed to, and whether in addition the use of the substance is kept down to its lowest limit of significance. As regards migration of additives, it has become generally accepted that things which are highly toxic can­ not be used even if they do not migrate completely. It may be said in fact that there is no trouble about using an- ad­ ditive if its toxicity is comparatively low and not much migration takes place, in some cases, e.g. when a con­ tainer comes in contact with food products such as milk or frying oil, the actual food products may be used, but food products are not always quite so simple, but may contain highly complex materials, and since it is difficult to establish methods of analysis of migration, water, acetic acid, alcohol, n-heptane and similar solvents are used. A major concern is the Acceptable Daily Intake (ADI). This value represents data obtained by careful htorahmai Pnivmnr Science and Technology. Vol ' 3 No I. 1976 1975, abstract NG 75/09/537 examination of symptoms• occurring with agricultural chemicals. A level is found below which no symptoms areobserved in the most susceptible animals, and 1% of this is defined as the amount which is safe for human beings. With the exceptions of agricultural chemicals, carcinogenic materials and heavy metals, where the daily intake is less than 0.1 mg no hazard is presented. This value is known as the Frawley limiting value. Consideration of the car­ cinogenic nature of materials, of the foetal abnormalities caused by drugs containing thajidomide and of oc­ cupational cancer caused by materials such as aromatic amines, nitroso compounds and vinyl chloride monomer is also important in toxicity assessment. High-molecular materials such as rubber are generally considered to be harmless, but because of their method of production they contain additional low-molecular materials such as residual monomers, solvents, and polymeric chemicals which create a toxicity problem. The rubber in­ dustry has a rich history, and its experience goes back more than 50 years, and inthis respect and others differs from the plastics industry. Plastics are used a great deal in packaging and containers, whereas the rubber products in this field are few. mostly pertaining to containers. By con­ trast witb plastics containers and the like, where the area of contact with the medium is large and the time of contact is long, the majority of rubber products.used in packaging and containers have a small contact area and a long con­ tact time, such as packaging seals and crown top discs, or a large contact area and a short contact time, such as cups for milking apparatus and the like. Therefore it is not the case that tests can be carried out under the same con­ ditions as for plastics. However, test conditions are very strict for products such as teats for babies' bottles, teething rings and closures for drug containers. We shall now consider the problems of hygiene relating to rubber and plastics products, paying particular attention to rubber. 2. GENERAL CONCEPTS OF TOXICITY (refs. 2. 3 and 4) When we consider problems of hygiene relating to rubber and plastics, we use expressions such as 'toxic', but if these are to bp understood their meaning must be defined in advance. When a substance has a biological effect on a living organism, and this effect is unpleasant to the organism concerned, the effect is said to be toxic. There are also cases where the same biological effect is not necessarily considered to be toxic for our purposes, such as when this effect is the purpose of using the substance, i.e. in medical drugs. Generally, where a substance having a biological ef­ fect has been given to a living organism, the amount is classified as follows, on the basis of the reaction shown by the organism. BFG39196 7/9 3 V. r \< \ r \ r i ' ’ pt;ud frnm International Polymer Science and Technology. 2, No. 9, No-effect Median level level toxic High Low ------------------------------- - ----- Level Medically effective level BFG39197 Figure 1 Lethal level Effects on living organisms No-effect dose: the amount which does not have any ef­ fect on the person; Effective dose: an amount which produces some effect; Medium toxicity: an amount which produces a severely unpleasant effect on tfie person concerned, without being lethal; Lethal dose: an amount which causes the death of the person. When a substance is given to a person and it produces a change in the work or functioning of that person it is said to have a biological effect. If we consider the case of medical drugs, which have a biological effect, the effects which an individual suffers vary according to the amount of the substance he is given. There are generally thought to be four dose levels; as shown in Fig. 1: the non-effect level, where the amount given is very small and no effect is observed; the medically effective level, where what ef­ fect there is is considered to be beneficiaLwith regard to certain ailments; the medium toxic level, where the dose is large and the recipient is considerably harmed; and the largest dose, the lethal level, sufficient to cause death. There are some substances which are harmful to health, and which can be ranked somewhere between harmless and toxic substances. In the present instance poisons are considered to be those substances which are frequently harmful to health, or in certain cases may bring about death by being inhaled, ingested or by infiltration through the skin. But neither true poisons nor substances which have a harmful effect on health have been clearly defined, and it is also difficult to classify hazardous materials. The reason for the difficulty in clearly defining hazardous and harmless substances is that some substances, such as table salt, are harmless and even necessary to life when taken in small doses but may be toxic when taken in larger doses. Another common example is sugar, which can be deadly to diabetics. Where food products have some biological activity because of some chemicals in them, these materials are considered to have a toxic effect for a toxic dose, and even when the effect is at the level thought to be effective for the purposes of medical drugs, this is generally con­ sidered to be toxic. In the case of drugs, where substances are consumed because they are effective in the treatment of particular illnesses and conditions, they may be shown to be effective in alleviating the symptoms of the person treated, but when the same dose is taken as a food, and is consumed by people who have no need of the medicai ef­ fect of the substance, then although its medical effect is not harmful over a short period, if substances whose ef­ fective level borders on the toxic level are consumed over a long period, i.e. if they are substances which may be presumed possibly to have a bad effect, not only is there no clear boundary between an effective dose and the no­ effect dose, but almost all chemicals which accord with the definition given above may be considered to be toxic. Food pollutants have been considered recently by the mass media, but because these were represented as existing levels in ppm or ppb, and because the emphasis was placed only on the fact that these levels exist, without any mention of the effect on human beings have accumulated amounts at this level, this has given to unnecessary anxiety. By contrast with medical drugs, which are used for effective treatment of certain illness, and food produ£ which are necessary to support life and maintain hea1 the additives in rubber and plastics used for packaging containers or utensils, where these come into contact' food products during their preparation, processing storage, and may be consumed along with the food, should have no effect on the human body. 3. METHODS OF EVALUATING TOXICITY and 3> <3$ The various types of toxicity tests are usually classified-* according to the length of the test period, but in order to ensure safety with regard to the use of the substances tested, their chemical properties and biological effect, We can classify the tests in terms of special toxicity as shown in Table 1. In addition to investigating toxicity phenomena from 'a wide variety of angles, in particular from the results of tests carried out on animals, toxicity tests are necessary as the sole means of estimating the harm which can afflict a human being. All kinds of improvements are observable in the techniques and methods of assessing toxicity, owing to the rapid progress which has been made in phar­ macology, toxicology and biochemistry, supplemented by examination of the real nature of toxicity, the substances causing it and the ways in which it can be represented. Table 2 shows the classifications of toxicity. 3.1 Methods of expressing toxicity The abbreviations generally used for expressions of toxicity are as follows: «• LD„'— Median Lethal Dose — dose giving 50% mortality it rate (mg/kg) LCm — Least Concentration — lowest concentration of ■ drugs resulting in 50% mortality (ppm) TLm — Median Tolerance Limit — concentration suf- c ficient to cause 50% mortality of fish after keeping for 96 j days (mg/I) TLV — Threshold Limit Value — permissible con­ centration (dose) (ppm) * TD — Tolerated Dose — dose of drug resulting in symp­ ? toms of illness in animals (mg/kg) TC — Tolerated Concentration — concentration of drug resulting in symptoms of illness in animals MNL — Maximum No-effect Level MLD — Minimum Lethal Dose MTD — Maximum Tolerated Dose MED — Minimum Effective Dose ADI (PADI) — Acceptable Daily Intake — dose which can be taken daily (mg/kg) (mg/person-days) Cvi (i) Unconditional intake zone (ii) Conditional intake zone Table 1 General Types of toxicity tests toxicity Acute toxicity Short-term chronic toxicity (sub-acute toxicity) Long-term chronic Special toxicity Local toxicity irritation Allergies Deformities Effect on Dependence fertility (habit-forming) Careinogenicity of toxicity Estimated lethal dose for human beings (1 mouthful) 4 cc (1 teaspoonful) 60 mg 30 g (1 oz.) about 250 g about 500 g >500 g Curve showing dose level vs. mortality Fig. 2 of toxicity on the basis of LO$q (dose administered per kg of body weight of rat) Less than 1 mg 1—50 mg 50-500 mg 0.5—5 g 5-15 g above 15 g J doses (mg/kg) -f of IHMi storing of toxins or danger- Subcut­ Oral feeding <30 Intrav­ aneous enous injection injection <20 <10 H»mt sub- M/y drugs classified according to the value of LDU when the drug is injected hypodermically into mice (see Tables 3 and 4). The LDm is found from sampling of results of tests and observations with all or non-response values measured in the organisms, and has the following properties: 1. it is the median value 2. Where the frequency distribution is symmetrical it coincides with the mean 3. Where the frequency distribution is asymmetric it coincides with the mode. 4. It is the value with the highest sensitivity. Accordingly, since the tests require a large number of animals, small, inexpensive animalSHJarticularly mice and rats, are most commonly used, though the use of rabbits, dogs and monkeys is also very common. In the case of mice and rats, where 50 to 100 are provided, they are divided into 4—8 groups, a group containing 10 animals (in the case or rabbits and dogs 2 to 3 form a group). All doses are given to each group, the dose being Table 5 Acute toxicity of ordinary substances rats, administered orally) <300 <200 <100 >300 >200 >100 Substance of chemical fox/city (ref. 5) doses are injected or fed into the stomach, tbdomen of mice, rats and rabbits, and when a itbt* it discovered which causes the death of 50% itett animals (ID,,) this shows the acute toxicity of IfliMeunce However, the L0W value of a material does fkt* whether there is any danger resulting from Mked migration, nor does it show whether the toxic l«Mtsed when, after a certain period of time a large or this substance is accumulated in the organism, does it show whether the substance may be carAcute toxicity tests have no importance in iing whether certain substances can cause toetai deformaties or mutations, or mental BFG39198 ft* V.0„ value represents the dose of substances roims etc) expressed in mg/kg or g/kg which under *'**®*,*h*d conditions results in a death rate of 50% of the *'*n"r* t«sted The drug is given gradually to a group of »nd the death rate (ordinate axis) is plotted trie uose given (abscissa axis), resulting in an Scurve The curve is symmetrical around the 50% point, where the change in the amount of toxic has the most marked effect on the death rate. !t'® LD..„ shows a greater sensitivity than LD1S or LD„. *1'* * ''equently used as a quantitative indication of the 11- 't of -■ drugs. To express the toxic strength of drugs ~ Japan we make use of the expressions normal strong drugs and poisonous drugs, which are ' r .Sf'ionr'o anH \/nl 3 Mn 1 1Q7F (on 3) Purity of substance ■given rn (a) LDS0 (%) 100% Acetic acid i (ref. 5.2 ml/’kg 10% aqueous Boric acid Calcium hydroxide Corn oil Ethanol solution 3.5 g/kg 100% 100% 100% 100% 5.14 g/kg 7.34 g/kg >100 ml/kg 21.3 g/kg (sic; Transl./Ed.) 50% aqueous Fuel oil Glycerol Lard Methanol Soap (Ivory snow) solution 13.6 g/kg 100% 100% 100% 100% 15.4 ml/kg >64 g/kg 12.9 g/kg 20% aqueous solution Table salt 10% aqueous Sorbic acid 10% aqueous Sugar 10% aqueous Sulphuric acid 50% aqueous solution solution solution solution Alcohol 27.5 g/kg f0 16 g/kg 4.54 kg/kg O O 10.9 g/kg o 35.4 g/kg 2.14 g/kg liquor (16% alcohol concentration) Notes: (*1 70.7 ml/kg the calculation is based on a standard of 100% purity; corresponds 100% 70.7 ml/kg for alcoholic liquor to 11.3 ml of ethanol W per kg V 95 Table 6 Toxicity of monomers 7 Toxicity Monomer Rubber thrombic phlebitis, fever Natural rubber (sulphur-cured products) ( Styrene TLV 100 ppm, skin irritant, loss of nerve functions after 1 day exposure to a vapour concentration of 375 ppm [ Butadiene at exposure of 8000 ppm, irritation to eyes, weakening of SBR eyesight, coughing, nose-bleeding, drowsiness, TLV 1000 ppm TLV 20 ppm Acrylonitrile NBR MLD 150 mg/kg at 20—45 min exposure to 16—100 ppm, dull headache, con­ striction of chest, irritation of mucous membranes in eye and nose, symptoms of discomfort and nervousness. Extreme itchiness and dermatitis. Jaundice, anaemia, lymphocytosis. The Federal Register of Nov. 1974 rec­ ommends amounts of less than 500 ppm n-dodecyl mercaptan and less than 11 ppm acrylonile monomer 2-Chloro-l,3-butadiene CR TLV 25 ppm ' depressant of central nervous system, also toxic effect (chloroprene) on liver. Also danger of absorption by skin, and of hair loss. Cancer of lung and skin with less than 1 ppm of monomer TLV 1 ppm Boron trifluoride IIR A highly toxic colourless gas, severely irritating to the respiratory system TLV 100 ppm Methyl chloride Anaesthetic, medium toxicity, causes damage to central *>. nervous system, liver, kidneys. 30X mortality rate under severe exposure EPR Ethylene Should not exceed 1000 ppm in general atmosphere. Propylene Anaesthetic, but does not cause chronic illness. Death can occur on inhalation of high-concentration vapour. TLV not yet determined Tolylene diisocyanate, Polyure thane rubber Highly toxic sxibdtances, causing asthma and associated diphenylmethane allergies. diisocyarta te stipulated an exposure of 0.005 ppm 8 h/day, or 0.02 ppm TLV 0.02 ppm, causes mutations. NIOSH has for 20 min Table 7 Acute toxicity of crosslinking or vulcemising agents Acute toxicity BFG39199 Chemical name Test animals Method of administering LDso* mg/kg mice intraperitoneal mice mice intraperitoneal oral1y 225 4100,.15 g mice intraperitoneal 2400 mice intravenous mice oral 6. Di-tert.butyl peroxide (DTBP) mice intraperitoneal 1. Benzoyl peroxide 2. 2,4-Dichlorobenzoyl peroxide 3. Dicumyl peroxide 4. (BPO) (DCF) 2,S-Bis(tert. butyloxy)-2,5-dime thylhexane 5. Cyclohexylamine 250 200 710 >6000 7. Sulphur mice inhalation LC50 S2CI2 150 ppm 8. Zinc oxide mice inhalation LC50 2500 mg/cu.m 9. Calcium oxide mice inhalation TLV 5 mg/cu.m 10. Magnesium oxide mice inhalation TLV 10 mg/cu.m TLV 5 mg/cu.m In addition there are the moving average method, Weil's method, the Reed-Munch method and others. One example is shown in Fig. 2. • . > With the area method the calculation is easy. As shown in the Figure we plot the logarithm of the dose against the mortality rate. The dose L corresponding to a mortality rate of 50% gives the sought value, LD.,0. Ideally the mortality curve has a regular shape, and is symmetrical around the point M, but if the curve is irregular the area S enclosed by the curves OMP and OXnP is approximately equal to the rectangular area LXn x PXn. :> 0006 gradually increased. The examinations generally take 72 h, or in the case of slow-acting substances up to 1 week. Methods used for determining the LD50 are: 1. The Behrens-Karber method (mean lethal dose method or difference method) 2. The Van der Waerden method (the area method) 3. The Litchfield-Wilcoxon method (simplified version of the Miller-Tainter Probit method) 4. The up and down method (Dixon-Mood method, Brownlee's method) 5. The Gaddum method (the parabola equation method) cc re ra st cc le Ti In I Intravenous Subcutaneous 0.07 g/kg Intravenous 0.09 g/kg Subcutaneous 0.22—0.5 g/kg Lymph glands 0.8 mg/kg U)50 800 mg/kg 0.35 g/kg te>*n>**ible concentrations in air are as follows: Uadustrial Hygiene ItJ on) factories atmosphere 5 ppm, 6 mg/cu.m 1 mg/cu.m 0.035 mg/cu.m _ . the toxicity of formaldehyde, the LD5, for rats * to be 600—700 mg/kg, and we can infer a ^^♦Hct with 25 mg/day for a 50 kg adult. Akiyama el harmful effects on children who made regulai • (ebteware which came into contact with forbut after tightening up of regulations for for,n 1966 this decreased, ikiehyde resins give off formaldehyde mos^ leaching of formaldehyde from phenol and melamine-formaldehyde resins is less i "here there are surface cuts it is claimed tha o ormaidehyde is more noticeable). The reasor * **id to be that as urea resins have a lowe •rhperature than the two other resins, withou -Nation some separate formaldehyde rvtocA lh's can be readily determined by U\ Wrwig,.. ®no1 IS detectable in the anti-ager additivr Phenol a caustic effect on the skin, and when i iP* wNf|C?n,ac‘ w',h 25—50% °* the skin surface i: 'nhalecf it can damage the nervous system "centration in air is 8.8—12.2 mg/cu.m. Letha Science dnd Ter.hnninnxt \/r^l n 1 107C doses of phenol are as follows: Dogs Oral 0.5 g/kg Subcutaneous 0.027 g/kg Cats Subcutaneous 0.09 g/kg Rabbits Subcutaneous 0.6 g/kg Mice Subcutaneous 0.35—0.6 g/kg Frogs Subcutaneous 0.1—0.6 g/kg Human beings Oral 8.5—60 g/person (toxic) Permissible concentrations of Soviet phenol in air have been fixed at 5 mg/cu.m in production plants and at 0.01 mg/cu.m in the atmosphere generally, and for containers the concentration is 0.001 mg/litre. 3.3 Chronic toxicity (ref. 6) Tests are carried out involving the breeding and keeping of at least two types of animals for a period of at least two years. Rodents such as mice and rats should not be used, cats and dogs etc. being preferred. The substance being tested is fed to the animals over a period of at least three generations and with various numbers of stages of ad­ ministration, of which the maximum conditions show a toxic effect, and the minimum conditions must not show any toxicity. However, the main concern of these breeding tests is to investigate changes iojiody weight, body con­ dition, skin condition and composition of urine of the animals, and so every organ of the body is examined macroscopically or in sections microscopically. At the same time, the dose level which does not cause any abnormality in the test animal is found and expressed as mg of the substance per kg of the animal, and this value is called the ‘acceptable level'. A safety coefficient of 100 has to be introduced in order to apply these results to human beings. The reason tor this is that human beings are assumed to have ten times the sensitivity of the animals tested, and some people have a sensitivity which is ten times as great as that of the average human being. 1/100 of the ‘acceptable concentration' is the value expressing (mg. pdf kg of body weight) the dose which is safe for long-term intake by human beings, and the amount which can be taken per day is called the 'acceptable daily intake' (AOI). If it is assumed that a normal person's body weight is 60 kg, 60 times the ADI is referred to as the PADI. This is the term used in Holland to express the acceptable daily intake of a substance for use in packaging, and shows the amount in mg which can be taken in daily by human beings without hazard, or the amount which can be contained in 1 kg of food, though it should be noted that the highest daily intake of such goods as are necessary to life should be 1 kgBecause of the knowledge which is already available concerning the hazards people are subjected to on coming into contact with these substances and their productequivalents. it is by no means always necessary to carry out tests costing several hundred thousand yen on every new substance. In many cases 90-day sub-acute tests on animals are satisfactory. The tolerated dose can be established by 3-month tests on a large number of one species, rats for instance, or on two species, such as rats and dogs, with more of the materials, and examining each organ of the animals concerned. Of course these tests do not give as much information as the 2-year tests. For this reason, when applying the results of these tests to human beings, a safety coefficient of 500—2000 is used here to calculate the ADI value. With the exception of agricultural chemicals, heavy metals and carcinogenic materials, a daily intake of less than 0.1 mg of any substance does not involve any toxicity hazard (the Frawley limiting value). Despite the substantial ) n n n rv .W *now the acute toxicity of common ^Vflomers use(j jn rubber (11), crosslinking * "^sation accelerators (3, 6), antioxidants C*t if 0 and 9*' heavy metals <10) and olb®r , ,o rubber (3. 6). w a m zinc oxide, zinc carbonate and dithi5***,ner zinc-containing. I.g. fatty acid, comtnct cadmium are detected as impurities lMd are - - —■ m The l ne JIS zinc oxides — - quality-i----actual products contain only very small " ol Pb and trace elements; No. 1 conand No. 3 0.13% of Pb and 0.05 of Cd. iir*' (ret 12) is detected in the structure of lairamme accelerator. ■s highly toxic in that it causes m solidifying of the protein in cellular «Tth which it has a strong chemical affinity. Mit the arrest and destruction of all cell funcaiation of formaldehyde, symptoms of acute . at irritation of the mucous membrane in the ***ition of the pharynx and oedema of the lung When taken internally, formaldehyde causes a oral cavity, oesophagus, stomach and small * large quantities causes vomiting of blood, 14 convulsions due to difficulties of respiration -**i*on. albuminuria, anuria and acidosis due to «t. rapid loss of consciousness and collapse m death In contact with the skin it causes rfitiammation. In terms of chronic toxicity, afi or tkm contact it gives rise tojnflammation of Whammation of the pharynx and larynx, and perp««titit Minimum lethal doses of formaldehyde safety coefficient, in Holland an even larger safety coef­ ficient is being sought, and a lower intake of the order of 0.05 mg is being discussed. Even where the daily intake for a human being is less than 0.05—0.1 mg, there are still many cases of considerable irritation to the skin and mucous membrane, and the same thing can be said of many chemicals used in rubber production. Tables 14—17 show the long-term tolerated doses of rubber chemicals and plasticisers. 3.4 Carcinogenicity (refs. 14, 15 and 16) The approach to the problem of carcinogenicity and some toxic reaction to their environments are illustrated in Tables 18-20. The anti-ageing additives phenyl-o-naphthylamine (PAN), phenyl-0-naphthylamine (PBN) and aldol-0napthylamine (AP) contain napthylamine as an impurity, aNaphthylamine has long been regarded as a hazardous Table 8 material which can cause cancer of the bladder. Pure naphthylamine is no longer used industrially, hence there _ no industrial hygiene experience or information availably concerning this material. However, its effect on animal has been tested, and no carcinogenic effect was o&-': served. Industrial «-naphthylamine contains as much as 4—5% of ft -naphthylamine, and is for this reason regarded as a hazardous substance, and precautionary measures' are imperative. The impurities shown in Table 22 are con­ tained in the anti-agers PAN, PBN and AP. It is clear from the literature and experience in industrial and en­ vironmental hygiene that even small amounts of pollution can result in irritation to groups of workers exposed to them. In Germany the anti-ager AP has been produced since 1926, and workers involved in its production have been examined recently. Despite the fact that these people have obviously been in contact with AP. there was no evidence of cancer of the bladder. Other carcinogenic substances are shown in Table 23. Acute toxicity of accelerators Acute toxicity Commercial Chemical name name Test Method of animals administering LD50 (mg/kg) a. Aldehyde-amines 1. H Hexamethylenetetramine >-• b. 2. Diphenylguanidine Diorthotolyl guanidine 3. Orthotolyldiguanide c. MLD 450 hypodermic MLD 200 marmots hypodermic MLD 300 cats hypodermic MLD 200 350,470 D, DPG mice intraperitoneal Vulkacit D rats oral 520 DT, DOTG marmots oral MLD 120 rabbits oral MLD 80 Vulkacit 1000 rats' oral about 800 HA—22 rats oral LUR rats intraperitoneal M wild rats Thioureas 1, Ethylenethiourea 2. Dilaurylthiourea d. hypodermic rats Guanidines 1. r~- mice v >100 >9000 Thiazoles 1. 2-Mercaptobenzothiazole 100 oral household e rats oral 5 00 mice oral 2000 mice intraperitoneal 437,733 Vulkacit 2. Dibenzothiakolyl disulphide 3. H,H-diethylthiocarbamyl-2- 4. Zinc salt of 2-mercaptobenzo- benzothiazolyl sulphide thiazole e. 1800 rats oral mice oral rats intraperi toneal Vulkacit DM rats oral >7000 64 rats oral 6000 Vulkacit ZM rats oral >5000 Vulkacit CZ ra ts oral >7500 Vulkacit AZ marmots rats oral >2000 oral 7500-10,000 rats oral 1980 Vulkacit DZ ra ts oral >1000 NS mice intraperitoneal Mercapto DM 7000 2600,3000 Sulphenamides 1. N-cyclohexyl-2-benzothiazolesulphenamide N,H-diethyl-2-benzothiazole- 3. H-oxydiethylene-2-benzo- 4. thiazole sulphenamide N-dicyclohexyl-2-benthiazole- sulphenamide sulphenamide f MSA 1 Vulkacit MOZ 0003 2. .' 5. N-tert.butyl-2-benzothiazolesulphenamide 5000-7000 continued on next pagf/L International Polymer Science and Technology, Vol 3. No. I. 1976 BFG39201 T/i I -jatitfd Acute toxicity of accelerators Acute toxicity Chemical name Test Method of animals administering mice mice peritoneum MLD 1 name LD50 (mg/kg) -thylthiuram monosulTS Vulkacit MS 800 intraperi toneal rats peri toneum MLD 5 marmots stomach MLD 10 rabbits stomach MLD 100 dogs stomach MLD 100 rats oral 1150 f^itjbucyl Chiuram monosulfhiie fetramethyl thi uram disulphide >5000 mice intraperi toneal rabbits oral 210 rats 865 mice oral intraperitoneal rats oral 1250 mice intraperitoneal rabbits oral TBT mice intraperitoneal >5000 Vulkacit J rats oral >5000 TRA mice intraperitoneaX_ >3200 PZ rabbi ts oral rats oral 1400*99 1400 TT 333 Vulkacit Thiuram TET £ fatramethyl thiuram disulphide fatrabucyl thi uram disulphide 967 2050 H*ethyIdiphenyl thiuram iitu tphide t, pipentamcthylenethiuram lotrasulphide j/ltiocarbamates t. tinc dimethyldiothiocarbamate >, line dicthyldiothiocarbamate 400 Vulkacit L rats oral EZ rabbits mice oral i n tra peri toneal Vulkacit LDA rats oral >2500 BZ mice intraperitoneal >2500 ZP mice intraperi toneal 260 PX mice intraperitoneal 533 400 142 f. tine di -n-butyldi thiocarbami(r . 4 tine pen tame thy1 enedi thiocar- bamate ♦. line ethylphenyldi thiocarbamate tibylene thiourea (HA-22)has been banned from use in connection with food products in the Federal . • 19, So. IBS, Sept. 23rd, 1974 Acute toxicity of anti-agers Acute toxicity Commercial name Chemical name Test Method of animals administering LD50 (mg/kg) M**tic araine derivatives tti rrhanylcnediamine derivatives !• *,*' -di-2-naphthyl-p-phenylenedlaazne rats rats oral oral 4500 MLD >710,000 rats oral rats rabbits oral 1620 720 oral MLD >7500 rats oral >3500 Flexzone 6H ra ts oral 2000 Flexzone 5L human beings skin Sensitiser rats rabbits rats oral hypodermic inhalation LDS0 30 ppm marmots inhalation £,D50 37.5 ppm rats oral Agerite white /• *•*' ~dpheny 1 -p~phenylenediamine Agerite DPPD i, ».■< topropyl-N‘-phenyl-p-phenylene- JZF Flexzone 3C, Santoflex 4010 NA *• *-cvci< lohexyl-s'-phenyl-p-phenylene,:<=:ne *• 7500 rats rats rats oral oral 1700-1970 8000 oral 1700 Hauga White rats oral rats oral 32700 at 158,500 4. Alkylated phenols Wingstay S Agerite Spar Wingstay T fats oral Hevastain A S. Alkyl-aralkyl phenol . Nevastain B KSH TSP rats rats rats rats rats oral oral oral oral oral idant 7 03 rats oral 1030 Tecquinol rabbits cats 200 2; 2,5—Diamylhydroquinone Santovar A rats rabbits oral oral oral oral 3. Hydroquinone-monobenzyl ether 4. Pyrocatechol(1,2-dihydroxybenzene) Agerite Alba mice dogs Elastozone 33 lenediamine 1600 9. N,N'-diakyl-butyl-p-phenylenediamine (sic; Transl..Ed.) (2)Key tone-amine condensates (quinolines) 1. 2,2,4-Trimethyl—1,2-dihydroquinoline polymers Flectol H 2. 6-Ethoxy-2,2,4-trimethyl-1,2-dihydro­ quinoline 3. 6-Dodecyl-2,2,4-trimethyl-l,2-dihydroquinoline (3) Naphthylamines 1. Phenyl-6-naphthyl amine 2. Phenyl-1000 >1000 (4) Diphenylamine derivatives 1. p-Isopropoxydiphenylamine Agerite Stalite Agerite Stalite S DDA 2. Alkylated diphenylamine blends * 3. Styrenated diphenylamine 15 ml/kg Phenolic derivatives (1) Monophenols 1. 2,6-Di-tert.butyl-4-methylphenol BHT (butylated hydroxy toluene) KB 2. 2,2'-Methylene-bis(4-methyl-6-nonyl- phenol), (alkylated bisphenol) 3. Styrenated phenols DS Ethyl Antiox­ 6. 2,6-Di-tert .butyl- (a-dimethylamino) p-cresol (2) Polyphenols 1. Hydroquinone impedes growth at 158,500 impedes growth 1700 20000 2500 2500 >2500 80 2000 2000 >600 130 cats rabbits marmots intraperitoneal oral oral oral oral Antioxidant 2246 BKF mice rats oral oral >5000 >2500 ZKF rats ■ oral >2500 Antioxidant 425 rats oral >15000 Santowhite Powder rats oral MLD 17000 100 200 160 (3) Bisphenols 1. 2,2-Methylenebis(4-methyl-6-butylphenol ) 2. 2,2'-Methylenebis(4-methy1-6-cyclohex­ 3. yl phenol) 2,2' -Methylenebis (4-ethyl-6-butyl- phenol ) 4. 4,41 -Bu ty 1 idenebis ( 3-toe thyl -6-bu tyi phenol) continued on next BFG39203 ^ Nn 1 1976 Ni (V r C> o tinned Acute toxicity af anti-agers Acute toxicity S' Commercial name Chemical name i-'i Test Method of animals administering £*>50 (mg/kg) es*1 . , y.pritnethyl-2,4,6-tris (3,5•#* 1 * ’ £y; -4-hydroxylbenzyl) benzene Antioxidant 330 rats oral 1500 #. AMl*eed bispheno1 comPosition Cyanox LF rats oral 2470 rats rabbits percutaneous absorption percutaneous Agerite Superlite rats oral MTD 7500 ppm NKF rats oral >2500 Santowhite rats oral 2345 Crystals rabbits oral 3200 rats oral 6340 rats rats oral >50000 absorption . .aiuMj tylated bisphenol ► J* ^Jared bisphenol (bis (3-t-butyl-SJh \fttyi-2-oxyphenyl (isobutane) >12600 (sic; ttansl./Ed.) m tatobitpbenols ^ 4 4- .fhiobis (3-methyl-6-butylphenol) I* 4ti‘-Thiobis(2-methyl-6-butylphenol) », fttiobis(diamylphenol) 4 *.#ucy! -m-cresol SC12 condensate Ethyl Antiox­ idant 736 Santowhite L Santowhlte MK rabbits oral percutaneous MLD >20000 17500 MLD >10000 - E*£^,nic chioacid (salts, esters) 17000 i, tickel dibutyldithiocarbamate NBC rats oral fito*phorous acid esters f.Hvtphorous tri (nonylphenyl) ester Polygard rats oral 19500 MB rats oral 1000 taliUtoles and thiazoles |. line 2-Mercaptobenzimidazole*“ 4) mi*c*l ianeous l, panto (u ran derivatives AFT rats oral >2500 l. Composition unclear(anti-ozonants) AFD rats oral >2500 l. Composition unclear (anti-ozonants) Produkt DS) rats oral >650 iO Acute toxicity of plasticisers Plasticiser Animals used Method of £*>50 administering (9/ltg) OlMJiaiic ester) mice intraperitoneal 1.38 (0.98-1.99) Diethyl phthalate (DEP) mice intraperitoneal 2.83 (2.24-3.29) Dlbutyl phthalate (DBP) mice rats intraperitoneal 4.00 (2.94-5.45) oral mice intraperi toneal 4.50 (3.36-6.02) Dimethyl phthalate (DMP) Di-isobutyl phthalate Di-2-ethylhexyl phthalate ^ (DOP) 8.0 30.6 rats oral Dicapryl phthalate mice intraperitoneal butyl phthalyl butyl glycollate mice oral 14.19 (11.21-15.87) 12.567 boxy lie acid esters) ’7-ethylhexyl adipate Di-tsodecyl adipate - Dibutyl sebacate (DOA) (DBS) marmots oral rats oral rats oral rats oral 7.0 rats oral 7.0 22.5 20-5 16.32 (lethal dose) *f»tric esters) Triethyl citrate —. ft:ethyl acetyl citrate o o H' ***** Plasticisers) — Spoxidised soya bean oil rats oral Clycidyl oleate rats oral 3.52 *‘10'EDoxuan,i stearate rats oral 1.41 * c'b9lhexyl diphenyl phosphate rabbits oral 0.218-0.272 »t. tol ul phosphate rabbits hypodermic 40 7 When a report was published at the end of January 1974 linking contact with vinyl chloride monomer (VCM) with the occurrence of a very rare disease of the liver (liver angiosarcoma) in employees of B.F. Goodrich Co., the Table 12 Acute toxicity of other rubber ingredients Acute toxicity Commercial Chemical name name Test Method of animals administering LDS o (mg/kg) a. Scorch-retarders b. 1. Diphenylnitrosamine Vulkalent A rats oral about 2500 2. Phthalic anhydride Vulkalent B rats oral >2500 3. Benzoic acid GV rats oral 1700 Renacit TV rats oral >2000 Renacit rats oral >2500 Peptisers 1. Zinc salt of pentachlorothiophenol 2. Zinc salt of pentachlorothiophenol + hemoporphorazine c. Blowing agents 1. Benzene sulphonhydrazide Porofor BSH 100* 2. Dimitroso pen tame thy1 enetetramine Porofor DNO/F t Porofor ADC 3. Azodicarbonamide rats oral <50 rats oral >2900 rats oral >6800 rats ■' oral >5000 rats oral d. Organic fillers 1. Phenol-formaldehyde resins Vulkadur A V e. Plasticiser 1. Alkylsulphate ester of phenol Table 13 Harmful metals Measamoll Toxicity of heavy metals Acute toxicity, LD50 mg/kg rabbits and rats, oral 2000 (ZnSOy) mice, oral 57 Zinc >80 ml/kg Toxicity above 700 ppm vomiting MLD 15 mg/cu.m nausea, diarrhoea, vomiting, abdominal pain and fever, and paralysis of digestive organs and mucous membrane Lead • rats, oral 100 rabbits, oral 125 MLD 0.5 mg/cu.m nausea, vomiting, convulsions, changes in blood and gums, neuritis (lead palsy), abdominal pain, distruction of central nervous system and tooth and jaw ducts chickens oral 450 (lead arsenate) human beings, oral Cadmi urn (v; 50 g/person (lead acetate) W human beings, oral 40—50 g/person (lead carbonate) O rabbits, oral, 70—150 MLD 0.1 mg/cu.m nausea, vomiting, convulsions, irritating effect on eyes, hepatitis, jaundice, prevention of tooth growth, (CdCl2) osteomyelitis, and anaemia Arsenic rats, oral 138 dogs, marmots, oral 30—70 oral 20—39 rabbits chickens, oral 14—30 oral 60—150 human beings, oral lethal dose 100—300 mg/person, acute constriction of throat and oesophagus, stomach pains, nausea, diarrhoea, bloody faeces, spasms due to lack of oxygen, vascular poisoning, paralysis of heart muscles 5—50 mg/person International Polymer Science and Technology, Vol 3, No. 1. 1976 BFG39205 r/102 e 13a r* jf£ dus: (2) the' prote? sftecf y 10.". mentiq" :tion‘" aisterjg a,e,y$u Offcingjffi ppm otiSi 'ths till USP he 1st 'of If Zinc oxide for industrial * Zinc oxide, Special No. >99.5 >99.5 <0.005 * lead, use according 1410 French zinc oxide k No. 1 2 No. 3 >98.5 >99.0 <0.3 <0.3 <0.1 <0.1 <0.03 Cadmium, % American zinc oxide No. Zinc oxide, Lead, 1 No. >98.5 * <0.8 ■ <0.2 <0.3 JIS K 5102 Zinc oxide Consti tuents, No. % 1 (cosmetics) No. >99.5 Zinc oxide >98.0 <0.3 % Cadmium, * No. 2 3 >98.5 >99.0 <0.3 <0.3 <0.03 Lead 2 January 1975. The proposed European standard tor working environments is 20—50 ppm averaged over 8 h and where it is less than 25 ppm there is claimed to be very little possibility of any disorder of the liver. In the USA the Society of the Plastics Industry (SPI) rebutted the idea of introducing the level at 1 ppm, and the lawcourts ordered the standard to be left as it was at 50 ppm for the moment, but the President of the lawcourts shocked the SPI and the industry in general by introducing as a judicial precedent the new level of 1 ppm, to apply on and after the 1st of April 1975. In Japan, following an increase in the number of people suffering from high blood pressure in the hepatic portal system, which is a pre-symptom of an angiosarcoma, a committee of technical experts met to devise coun­ termeasures against occupational cancer risks, and produced a report recommending a level of 2 ppm for workers coming into contact with VCM. The toxicity of VCM is shown in Table 23. 3.5 Skin sensitisation (ref. 6) Acrolein—aromatic base condensates, tricrotonylidenetetramine. cyclohexylamine, hexamethylenetetramine and sulphur chloride have a strong corrosive and sensitising ef­ fect on the epidermis. Certain people are particularly »9/kg) 2S00 o o Table 14 Results of long-term exposure tests (ref.6) o HNL Commercial name Chemical name o 2 years (ppm) 0 o 0 ADI PADI (mg/kg) (mg/person/day) 1. Benzoic acid 5-10 (WHO) 2. Benzoyl peroxide 0-40 3. Saccharin OS (UC) 5-15 (C) 4. 5. L-sodium glutamate 0-120 40-75 1 'kg Tetramethyl thiuram disuphide (TT) Vulkacit Thiurhm 6. Zinc dimethyldithiocarbamate (PZ) 7. 2-mercaptobenzothiazole (M) 8. 2,6-Di-tert.butyl-4-methylphenol (BTH) 9. Alkyl-aralkylphenol ffotes: (1) : C : 250 Vulkacit L Vulkacit Mercapto KB TSP* 2 120 1000 250 (C) (UC) 0-0.025 0-0.125 0.075*1 (WHO) (WHO) 0-0.5 (WHO) 0.04*1 7 7 (WHO) (WHO) 4.5*1 30*1 2. S*1 (WHO): 90 day feeding test value formulated by the World Health Organisation; (using a safety factor of 500); VC : underconditional : special assessment; (sic; Transl./Ed.); conditional C/I W H* :ver, vane o o id -uct- icts Table 15 BFG39206 Acceptable daily intake for human beings (mg/kg of body weight) Uncon­ Condit­ ditional ional 0-2.5 2.5-5.0 Di-2-ethylhexyl phthalate 0-1 .0 0-1.0 1.0-2.0 1.0-2.0 Di-isobutyl adipate Epoxidised soya bean oil 0-2.5 0-12.5 12.5-25.0 Acetyl 0—10.0 10.0—20.0 0—30.0 30.0-60.0 0—1.0 1.0—2.0 30.0—60.0 Name of substance Ethyl phthalyl ethyl glycollate n wth, p-tert.butyl phenyl salicylate tributyl citrate Dibutyl sebacate Dibutyl phthalate Butyl stearate TV 102 . This ADI value is unsuitable for children under 1 year old, except for the fraction contained naturally in foods; *2 48 300-600*1 (VC) Table 16 No-effect level of DEHP(?, OOP; Ed.) Test animals 0—30.0 2.5-5.0 intvmatinnxl Pnlvmer Science and Technology. Vol 3. No. 1. 1976 w Feeding period No effect dose (days) (mg/kg/day) 4 00 Rats 365 Rats 730 80 Dogs 98 36 5 100 200 100 >60, <200 Guinea-pigs 36 5 about 60 Dogs 365 about 60 Rats 90 Dogs 98 Rats 7/102 Table 17 No-effect level of C6-C9 PAE acid ester) (? phthalic Table 20 Actions of organic toxins in the presen envi ronmen t ' S Dihexyl Di-2-ethylhexyl Dialkyl Diisononyl (m g /k g / rats 90 0.5 300 dogs 90 1.0 rats 730 0.4 200 200 dogs 90 79 rats 90 rats 90 (c) L.B. 60 0.125 60 Anaemia Polycylic hydrocarbons 0.125 L.N. Aromatic amines N.B. Epoxy compounds L.N.B. N-nitroso com­ 150 25-50 (? 150175)*) pounds •Carcinogenic Causes mutations N Organic perox­ ides increase in the weight of the liver of Affects nerves Biphenyl poly­ males only Affects liver chlorides Table 18 Estimated Carcinogens ml/kg/day (? 0.5) Note *): Toxicity Causes mutations 150 90 substance Benzene 0.06 mg/kg/daydogs loc­ ation Name of day) (* o f fo o d ) (d a y s ) animals F e e d in g Test PAE p e r io d No effect level Questions in connection with carcinogen­ [a] L - atmosphere; N ” food products; B = at work icity What is the amount which when used will give the least effect? Table 21 Impurities in anti-agers Name of What is the mechanism of assimilation? impurity What are the products of assimilation? Is the substance accumulated in the Jx>dy? a-Naphthyl- Methods of expulsion of the substance? How does it enter the body? Max 0.002% analysis [c] N.T.B. Estimated Ver... , ified Carcinogenic e n v ir o n m e n t ation Tendency Toxicity r e g a r d in g t h e hoc- L.N.B. l Affects blood t Affects nerves Causes mutations N.B. Test subjects t pressure Carcinogenic [a! natural product; Human Rats Dogs a-Naphthylamine Neg c C Benzidine C C c? m-Tolylenediamine Methylene bis (O-chloroanilone) C - Neg C C — Neg-6 yr - ? ? Neg Neg Name of beings substance V Phenyl-B-naphthylamine carcinogenic Affects kidneys High blood lb) > • 1' Ethylene thiourea Cadmium Not found by analysis Table 22 Types of carcinogenic substances (a) Lead [a] 0.2-0.3% :>■ Actions of inorganic toxins in the pres­ Name of substance Table 23 Toxicity of vinyl chloride monomer Monomer Time of (ppm) exposure 400 12—20 sec 200 100 18—55 min 120—300 min 50 300 min Delay in sensory perception 10 480 min Has no narcotic effect Result (using marmots) [b] refined product; [c] L = atmosphere; N = food products; water; Not found by 0-Naphthyl- Not found by ent-day environment Arsenic 0.5% analysis amine Table 19 PBN amine •* I ig AP PAN T = drinking B = at work Death Death Marked delay in sensory BFG39207 perception susceptible to the effect of some of these compounds, though this is rare and may be due to some hereditary fac­ tor. These cases are called allergic reactions (mono- or polyallergies) and can be predicted by certain methods. Care should be taken to see that the skin of such people does not come into contact with particular chemicals. There are also cases of people being hypersensitive to various natural products such as grass seed and primroses, or to foods such as strawberries or fish. If a ban were placed on the use of all chemicals connected with some observed allergy, probably very few would remain in use. One could quote, for example the derivatives tetramethylInternational Polymer Science and Technology. Vol. 3, No. 1. 1976 thiuram disulphide, zinc dimethyldithiocarbamate, 2-mercaptobenzothiazole, diphenylguanidine, di-o-tolylguanidine (sic; Ed./Transl.), hexamethylenetetramine, phenyl-0-naph- ' thylamine, p-phenylenediamine. Where this type of allergic, skin eruption is observed either the person's place of work should be changed or the actual materials should be replaced by others which are equally effective For examf/104 jeS are ctuoted in the literature where N-(1,3-dim. >|i MhAnuI.rLnhanulAnaHiAmine USOd jpiLN’-phcny'-p-phcnylcncdiaminc was Kl !_nknnnl ^ U A MI i IA ■ ""/N./sopfOpyl-N1 '-phenyl-p-phenylenediamine, though niitisiog effect of isopropyl compounds such as this •* am a ^ woOab|y been eXa"erated KW* p ^jOGRAPHY food Preserves Hygiene Council Report No. 8. 1969. p. I f food and ■u> p toxicity', Japanese Food Hygiene Society, 13 Toxicology of plastics additives, Food Preserves * #ne Council Reports No. 3, 1974, p. 135 ** food preserves Hygiene Council Reports No. 6, 1969, p. food Preserves Hygiene Council Reports No. 22, 1973, t; 6. W, Hofmann, Ned. Rubberind., 33, 1972, p. 20- SGF No 39, 1972. p. 1 7. Food Preserves Hygiene Council Reports No. 28, 1974, P- 1 8. Environment and Technology (Kankyo Gijutsu), 3. No. 9 1974 9. Food Preserves Hygiene Council Reports Nos. 13 and 14. 1971 10. Food Preserves Hygiene Council Reports No. 4, 1968, p. 2; No. 5, 1968, p. 11 11. W.E. McCormick, Rubb. Chem. Technol., 44, No. 2, 1971. p. 512; Gijutsu Shiryo, No. 2, 1973 12. Industrial Materials (Kogyo Zairyo), 21, No. 12, 1971, p. 10 13. W. Hofmann, Rubber 73 (1973) 12 (1974) 14. P.R. Johnson, Rubb. J., 155, No. 4, 1973, p. 37 15. Ned. Rubber Ind., No. 22, 1970, p. 1 16. 0. Henschler, Angew. Chem., 85. No. 8, 1973, p. 317 ■ st I ffuau' b«i«i omer aszmtM) I N5 (71 rnsory M- o o xsxcaptiott 'feet C? ate 2- of allergic ace of wort should be For examT/itf BFG39208 'He:rnational Polymer Science and Technology. Vol. 3 No. 1. 1976 m