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Toxicological information

Carcinogenicity

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Description of key information

oral: non genotoxic carcinogen in pancreas with a NOEL of 190 mg/kg bw in rats, (CIBA 1990e), OECD 453
dermal: not photocarcinogenic upon skin painting of mice, (SCHPP 1974 and 1976)

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion
Dose descriptor:
NOAEL
190 mg/kg bw/day

Justification for classification or non-classification

Dangerous Substance Directive (67/548/EEC)

The available studies are considered reliable and suitable for classification purposes under 67/548/EEC. As a result the substance is not considered to be classified for carcinogenicity under Directive 67/548/EEC, as amended for the 28th time in Directive 2001/59/EC.

 

Classification, Labelling, and Packaging Regulation (EC) No. 1272/2008

The available experimental test data are reliable and suitable for classification purposes under Regulation 1272/2008. As a result the substance is not considered to be classified for carcinogenicity under Regulation (EC) No. 1272/2008.

Additional information

Oral:

In a combined chronic / carcinogenicity study (OECD 453, CIBA 1990e), the test substance, 89.8% a.i. was administered to 80 albino rats /sex /dose in diet at dose levels of 500, 5000 and 50000 ppm for 24 months.A 5% dietary inclusion level (50000 ppm) of the test substance was well tolerated and without effect on survival, behaviour or appearance. An increased food intake for rats of group 4 (50000 ppm) may reflect some dietary compensation for the level of inclusion of the test substance although this increase failed to maintain bodyweight, for which a 10% decrease was recorded compared with control values. A dose related increase in water intake occurred in groups 3 and 4 (5000 and 50000 ppm), possibly compensating for the increased salinity of the diet (the test item contained approximately 7.0% sodium chloride), and was associated with increased urine output in group 4. Hematology and blood chemistry profiles for treated rats were not disturbed by treatment apart from a tendency towards higher platelet counts in some females of group 4 (50000 ppm). Treatment at a dietary level of 5% (50000 ppm) induced hyperplasia in males and females, and in males adenomas and two carcinomas of the exocrine pancreas. Based on the above findings, the dietary level of the test substance producing no findings of toxicological relevance can be defined as 5000 ppm, equivalent to an average daily intake of 190 mg/kg bodyweight for males and 226 mg/kg bodyweight for females. It is considered that the hyperplastic and adenomatous lesions found in the rat pancreas are the consequence of an adaptive process to compensate, with increased secretion, for inefficient digestion and absorption caused by long-term dietary administration of 5% of indigestible test substance. Inefficient digestion was probably the cause of the increased food consumption ratio that was observed at this dose level. It is most unlikely that these pancreatic findings are of any human relevance, since they were obtained at an extremely high dietary level only (50000 ppm) and involved an animal species known to be particularly sensitive to various dietary-induced pancreatotrophic processes. The test substance is clearly devoid of in vivo mutagenic potential. The lesions induced in the carcinogenicity study appear to be specific to the rat and there is strong evidence that they occur by non-genotoxic mechanisms that do not operate in other animal species, nor in man. Details on follow-up investigations are discussed in the section of the specific investigations.

Photocarcinogenicity:

A further study was done in order to investigate wheter the test substance has a carcinogenic effect onto skin under light exposure (SCHPP 1974 and 1976).

This study investigating the appearance of skin tumors after several ultraviolet light exposures after dermal exposure to the test substance. Photocarcinogenesis testing involved pretreating hairless mouse skin with the test compounds, 8 -methoxypsoralen (8 -MOP; known phototoxic agent), or solvent only before each daily exposure to simulated solar ultraviolet light. In terms of tumor yield and tumor development time, photocarcinogenesis was enhanced by 8 -MOP, but not by test substances.

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