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The German Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area has evaluated N,N-dimethyl-p-toluidine [99-97-8] considering all toxicological end points. N,N-Dimethyl-p-toluidine led to an increased incidence of liver adenomas and carcinomas in mice at 6 mg/kg body weight and day and in rats at 60 mg/kg body weight and day in a chronic gavage study. Additional tumours were observed in male rats in the transitional epithelium of the nose and in female rats in the lungs and the forestomach. On the basis of these effects, N,N-dimethyl-p-toluidine has been classified in Carcinogen Category 2. N,N-Dimethyl-p-toluidine induces mutagenic, aneugenic and clastogenic effects in vitro. In vivo, N,N-dimethyl-p-toluidine was found to cause DNA damage in the livers of rats and mice. As studies for germ cell mutagenicity are not available, N,N-dimethyl-p-toluidine has been classified in Germ Cell Mutagenicity Category 3^B. According to skin absorption models, percutaneous absorption is expected to contribute significantly to systemic toxicity. Therefore, N,N-dimethyl-p-toluidine has been designated with “H”. A sensitizing potential is not expected from the data available.

The German Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area has evaluated 2,2′-thiobis(4-methyl-6-tert-butylphenol) [90-66-4] considering all toxicological end points. 2,2′-Thiobis(4-methyl-6-tertbutylphenol) is neither irritating to the human skin in vitro nor irritating to the eyes of rabbits. In a gavage study carried out according to OECD Test Guideline 422, the incidence and severity (minimal to slight) of follicular hypertrophy in the thyroid glands of male rats were increased at 150 mg/kg body weight and day and above and slight changes in the colloid were observed at 500 mg/kg body weight and day. The Commission determined a NOAEL of 50 mg/kg body weight and day for this study. This dose has been scaled to a concentration of 10 mg/m3 I (inhalable fraction), a level of exposure protective against systemic effects. As 2,2′-thiobis(4-methyl-6-tert-butylphenol) is used diluted in metal-working fluids, the technically based limit value of 10 mg/m3 prevents toxicity if the dissolved solid is inhaled during this application. To prevent the induction of unspecific effects in the respiratory tract by the poorly soluble substance (

The German Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area has re-evaluated 2-mercaptobenzothiazole [149-30-4149-30-4] considering all toxicological end points. The critical effect in humans and animals is sensitization. Data for chronic inhalation exposure are not available. The most sensitive systemic end point observed in a 13-week gavage study in rats was an increase in relative liver weights. The female rat was found to be the most sensitive species. A LOAEL of 188 mg/kg body weight and day was derived, which corresponds to a concentration in the air of 27.5 mg/m3. No conclusions can be drawn for systemic toxicity from a 2-year gavage study in rats because of the high spontaneous incidence of different pathological effects observed in the control group. As there are no data for inhalation exposure to the poorly soluble substance, a particle effect in the lungs cannot be excluded. Additionally, epidemiological and animal data suggest a carcinogenic potential. As a result, the present maximum concentration at the workplace (MAK value) has been suspended. 2-Mercaptobenzothiazole is not mutagenic in bacteria. Mutagenic and clastogenic effects in mammalian cells are observed only at high, mostly cytotoxic concentrations. In vivo data do not provide evidence of genotoxic effects in soma cells or male germ cells, even at concentrations that cause systemic toxicity. Overall, the data from epidemiological studies are not sufficient to draw definite conclusions about whether 2-mercaptobenzothiazole is a human carcinogen. A carcinogenicity study with gavage administration in rats observed adenomas of the pancreas, preputial glands and pituitary gland as well as fibromas and phaeochromocytomas. However, the increased incidence of tumours is neither clear evidence for nor against a carcinogenic potential because of a number of uncertainties inherent in the study. Thus, 2-mercaptobenzothiazole remains classified in Carcinogen Category 3 for suspected carcinogens. Dermal absorption is not expected to contribute significantly to systemic toxicity. 2-Mercaptobenzothiaziole is a known contact allergen. Therefore, the “Sh” designation has been retained. There are no data for respiratory sensitization.

The German Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area has re-evaluated trichlorobenze isomers (1,2,3-trichlorobenzene [87-61-6], 1,2,4-trichlorobenzene [120-82-1] and 1,3,5-trichlorobenzene [108-70-3]) considering all toxicological end points. The critical effects of the trichlorobenzenes are adverse effects on the livers of mice and rats and on the kidneys of rats. These effects were more pronounced after exposure to 1,2,4-trichlorobenzene with the rat being the most sensitive species. However, as the isomers all have a similar primary toxicological mode of action and follow similar metabolic pathways, they have been evaluated together. After exposure to 1,2,4-trichlorobenzene, liver toxicity was manifest in rats and mice as increased liver weights and histological changes in the liver were preceded by an induction of metabolic enzymes. The most sensitive end point, a disruption of porphyrin biosynthesis, was observed in a 90-day inhalation study in rats with a NOAEC of 3 ml/m3. On this basis, the maximum concentration at the workplace (MAK value) has been set at 0.5 ml/m3. As the critical effect of the trichlorobenzenes is systemic, Peak Limitation Category II has been assigned with an excursion factor of 2. The trichlorobenzenes are not genotoxic. The neoplasms detected in rats and mice in carcinogenicity studies with 1,2,4-trichlorobenzene are considered to be of no human relevance. In rats, the NOAEC for developmental toxicity was 840 mg/m3 for 1,2,3-trichlorobenzene and 1,3,5-trichlorobenzene and 420 mg/m3 for 1,2,4-trichlorobenzene. The NOAEC for perinatal toxicity was 54 mg/m3 for 1,2,4-trichlorobenzene. As no teratogenicity was observed and the margins between the NOAECs and the MAK value are sufficiently large, the trichlorobenzenes have been assigned to Pregnancy Risk Group C. Data for skin sensitizing effects are limited to experiments performed with 1,2,3-trichlorobenzene that confirmed the induction of sensitizing effects. Therefore, only 1,2,3-trichlorobenzene has been designated with “Sh”. There are no data for sensitization of the respiratory tract. According to skin absorption models, 1,2,4-trichlorobenzene is expected to be taken up via the skin in toxicologically relevant amounts. Therefore, all trichlorobenzenes remain designated with “H”.

Zusammenfassung Das Internationale Krebsforschungszentrum IARC („International Agency for Research on Cancer“) der WHO hat im Rahmen seines Monographs-Programms im Dezember 2020 eine Bewertung von drei weiteren Stoffen vorgenommen, bei denen auch ein Vorkommen in bestimmten Lebensmitteln zu erwarten ist. Summary As part of its Monographs programme, the WHO’s International Agency for Research on Cancer (IARC) carried out an evaluation of three further substances in December 2020, which are also expected to be present in certain foods.

The German Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area has re-evaluated monomethylhydrazine [60-34-4] considering all toxicological end points. The acute toxicity of monomethylhydrazine is caused by depletion of gamma-aminobutyric acid leading to the effects on the central nervous system. Chronic and subchronic exposure induces haemolytic effects and adverse effects on the liver. In carcinogenicity studies, inhaled monomethylhydrazine caused tumours of the lungs, liver, blood vessels and olfactory epithelium in female mice and tumours of the nose and adrenal glands in male hamsters. Orally applied, it induced tumours of the lungs and liver in mice and tumours of the colon and small intestine in hamsters. Monomethylhydrazine therefore remains classified in Carcinogen Category 2 and no maximum concentration at the workplace (MAK value) can be derived. Monomethylhydrazine is genotoxic in vitro and in vivo and demonstrates a mutagenic potential in vitro. The substance forms methyl DNA adducts in vivo. On the basis of these effects and its structural similarity to 1,1-dimethylhydrazine and 1,2-dimethylhydrazine, which are genotoxic in germ cells, monomethylhydrazine has been classified in Germ Cell Mutagenicity Category 3 B. Monomethylhydrazine is irritating to the skin of dogs, guinea pigs and rabbits and to the eyes of rabbits. Although no valid studies considering dermal absorption are available, the ���H��� designation (for substances which can be taken up via the skin in toxicologically relevant amounts) has been retained because of the low dermal LD50 values in animals. Although no studies considering its sensitizing potential are available, the ���Sh��� designation (for substances which cause sensitization of the skin) has been retained because of its structural similarity to the known contact allergen hydrazine.

The German Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area has evaluated Pigment Yellow 12 [6358-85-6], Pigment Yellow 13 [5102-83-0] and Pigment Yellow 83 [5567-15-7] considering all toxicological end points. Depending on their intended use, the pigments are produced in different sizes with a d50 ranging from 15 to 250 nm. In technical applications, particles smaller than 100 nm are called nanoparticles. By definition, pigments are not soluble in application media. Pigment Yellow 12, 13 and 83 were found to be insoluble in the body and in phagolysosomal solution in vitro, which simulates the lung environment. The carcinogenic 3,3′-dichlorobenzidine was not released. Systemic toxicity was not observed in oral studies in rats and mice with exposure periods of up to 2 years. Therefore, these three pigments are insoluble and not bioavailable. If inhaled, insoluble particles can accumulate in the lung. In two 5-day inhalation studies of Pigment Yellow 83 and two 21-day inhalation studies of Pigment Yellow 13 in rats, local effects in the lungs were observed, which were similar to those observed after exposure to granular biopersistent dusts. No long-term inhalation toxicity studies have been carried out with the pigments. Long-term exposure to pigment concentrations which exceed the lung clearance capacity is assumed to result in particle-induced carcinogenic effects in the lungs. Therefore, in analogy to granular biopersistent dusts, Pigment Yellow 12, 13 and 83 have been classified in Carcinogen Category 4. A maximum concentration at the workplace (MAK value) has been established in analogy to that for granular biopersistent dusts taking into account the lower agglomerate density of particles below 100 nm. This results in a MAK value of 0.3 mg/m × (mass density of the pigment × 0.5). In analogy to granular biopersistent dusts, the pigments have been assigned to Peak Limitation Category II with an excursion factor of 8. No developmental toxicity studies are available for Pigment Yellow 12, 13 and 83. In analogy to granular biopersistent dusts, and based on the findings of two developmental toxicity studies with orally applied nanoparticles, titan dioxide and amorphous silica, which did not induce any effects on the foetus, Pigment Yellow 12, 13 and 83 have been assigned to Pregnancy Risk Group C. As the pigments are not soluble or bioavailable, genotoxicity and mutagenicity were not observed. The pigments are not sensitizing to the skin or airways and do not penetrate the skin in toxicologically relevant amounts.

The German Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area has re-evaluated peracetic acid [79-21-0] considering all toxicological end points. Peracetic acid is commercially available only in aqueous solutions, in which it exists in equilibrium with hydrogen peroxide and acetic acid. Therefore, all three substances contribute to toxicity. No specific systemic effects were observed, which is plausible because peracetic acid immediately oxidizes the tissues at the point of contact and is thereby converted to acetic acid. Peracetic acid is a promotor of skin tumours in mice. Valid long-term carcinogenicity studies with peracetic acid, particularly studies using an inhalation route, are not available. The mechanisms by which peracetic acid may induce carcinogenic effects are, as has already been demonstrated for hydrogen peroxide, local cytotoxicity leading to tissue damage and genotoxicity; both are due to the strong oxidation potency. These mechanisms do not come into play unless the endogenous detoxification capacities are overloaded. Due to this mechanism of action, hydrogen peroxide was classified in Carcinogen Category 4. As the same mechanism is likewise plausible for peracetic acid, it has also been classified in Carcinogen Category 4. Peracetic acid is the strongest irritant of the substances in the equilibrium mixture. If sensory irritation is excluded, it is also ensured that the detoxifying enzymes are not overloaded and thus neither tissue-damaging nor genotoxic effects occur. Based on the RD for pure peracetic acid in mice of 4.6 ml/m, the maximum concentration at the workplace (MAK value) for peracetic acid is set at 0.1 ml/m. The available human data are not sufficient to derive a MAK value, but do not contradict it either. As the critical effect of peracetic acid is local, Peak Limitation Category I has been designated. By analogy with hydrogen peroxide and as the data for the human experience with peracetic acid are of only limited validity, an excursion factor of 1 has been set. The few positive results for genotoxicity in vitro obtained with peracetic acid occurred at cytotoxic concentrations or in the absence of detoxification systems. All valid in vivo genotoxicity tests were negative, but the significance of the negative test results is questionable since peracetic acid induces a rapid local reaction. Therefore, it can also be concluded that classification in a category for germ cell mutagens is not required. The NOAEL for developmental toxicity in rats is 30.4 mg/kg body weight and day, which corresponds to a concentration of 53 mg/m at the workplace. Therefore, damage to the embryo or foetus is unlikely when the MAK value is not exceeded and peracetic acid is assigned to Pregnancy Risk Group C. Skin contact is expected to contribute only slightly to systemic toxicity. With respect to skin sensitization, there are no positive findings in humans and no reliable positive findings in animals. The respiratory symptoms that occur in exposed workers are caused by irritation.

The German Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area has re-evaluated methyl chloride [74-87-3], considering all toxicological end points. Critical effects are neurotoxicity and reduced fertility. The NOAEC for adverse effects on fertility in male rats after 3-month exposure was 150 ml/m. A NAEC of 100 ml/mfor reduced fertility in male rats was estimated from a 2-year study.The NOAEC for degenerations of the cerebellar granular layer is 150 ml/m in mice. Slight behavioural toxic effects were observed in humans at a concentration of 200 ml/m; neurotoxic effects developed at much higher concentrations. On the basis of neurotoxic effects in humans and reduced fertility and severe neurotoxic effects in animals, the maximum concentration at the workplace (MAK value) for methyl chloride has been lowered to 10 ml/m. As the critical effect of methyl chloride is systemic, Peak Limitation Category II is retained. The initial half-live in humans is below one hour, so an excursion factor of 1 is determined. Methyl chloride is genotoxic in vitro only at very high concentrations of 8000 ml/m and above. DNA adducts were not observed even with very high concentrations of methyl chloride. From in-vivo- and metabolism-studies it can be concluded that cytotoxic and secondary genotoxic effects are of prime importance. Thus, methyl chloride is not regarded as a germ cell mutagen. The observed kidney tumours occurred only in one species and sex (male mouse) and can be explained with a mechanism, that is of no relevance in humans. In comparison with methyl bromide and methyl iodide, carcinogenic effects of methyl chloride due to alkylating effects are not to be expected. However, a possible formation of DNA adducts cannot be completely excluded. If at all, these are only formed at concentrations far exceeding the MAK value and even then only to a very small extent, so that it is of no significance for the situation at the workplace. Methyl chloride is therefore not classified in a Carcinogen Category. There are no data on developmental neurotoxicity, therefore methyl chloride is assigned to Pregnancy Risk Group D. Skin contact is not expected to contribute significantly to systemic toxicity. There are no data on sensitization.

The German Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area has re-evaluated 1,2-dimethylhydrazine [540-73-8] considering all toxicological end points. Chronic and subchronic exposure induced adverse effects on the liver, heart and kidneys of mice and the liver and bile ducts of mini-pigs and guinea pigs. In dogs, 1,2-dimethylhydrazine caused adverse effects on the liver. The critical effect of 1,2-dimethylhydrazine is its carcinogenic potential. In carcinogenicity studies, 1,2-dimethylhydrazine induced various intestinal and vascular tumours such as haemangiosarcomas in addition to lung tumours in rodents after oral and intraperitoneal application. Particularly noteworthy is the high incidence of colon carcinoma in rats, which was observed both after acute and chronic application. Additionally, tumours of the digestive system were observed in hamsters and monkeys after subcutaneous or intramuscular injection. On the basis of the carcinogenic effects induced in several animal species, 1,2-dimethylhydrazine remains classified in Carcinogen Category 2. It is not possible to derive a maximum concentration at the workplace (MAK value). Enzymatic activation of 1,2-dimethylhydrazine leads to highly reactive metabolites, such as the well-known procarcinogen methylazoxymethanol, which are able to methylate DNA. The substance is clastogenic and mutagenic in somatic cells in vitro and in vivo. Additionally, in mouse testes, 1,2-dimethylhydrazine was found to inhibit DNA synthesis after oral application and to methylate DNA after subcutaneous application. Therefore, the substance has been classified in Germ Cell Mutagenicity Category 3 A. Although no valid studies considering the dermal absorption of 1,2-dimethylhydrazine are available, the ���H��� designation has been retained because of the low dermal LD 50 values in animals and the potential for genotoxic effects after dermal application. Although no studies considering the sensitizing potential of 1,2-dimethylhydrazine are available, the ���Sh��� designation has been retained because of its structural similarity with the known contact allergen hydrazine.

A new type of fibrous glass showing a low durability in the body was injected intraperitoneally into rats. In the range of the doses applied (up to 10 high 9 of a thinner product and up to 0.24 x 10 high 9 of a thicker product) a carcinogenicity was not detected; in contrast, durable glass fibres induced tumours. It is recommended to use mineral fibres with low durability as far as possible.