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Carcinogenicity

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Description of key information

Not carcinogenic. Toxicity NOAEL = 121 mg/kg bw/day (male); 112 mg/kg bw/day (female), 18 month (mice), OECD 451, EPA OPP 83-2, Gerspach 2000a
Not carcinogenic. Toxicity NOAEL = 82.6 mg/kg bw/day (male); 23.7 mg/kg bw/day (female), 24 month (rat), OECD 453, EPA OPP 83-5, Gerspach 2000b

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
23.7 mg/kg bw/day
Study duration:
chronic
Species:
rat
Quality of whole database:
Two chronic studies are available for assessing the carcinogenic potential of the test material. Both studies were performed in line with GLP and accepted standardised guidelines with a high standard of reporting. Both studies were assigned a reliability score of 1 in accordance with the criteria for assessing data quality as outlined in Klimisch (1997) and were considered suitable for assessment as an accurate reflection of the test material. The overall quality of the database is therefore high.

Carcinogenicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Carcinogenicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

In accordance with the criteria for classification as defined in Annex I Point 3.6, Regulation 1272/2008, the test material does not require classification for carcinogenicity based on the available data.

In accordance with criteria for classification as defined by Directive 2001/59/EC, Annex VI, Point 4.2.1, the test material does not require classification for carcinogenicity based on the available data.

Additional information

The carcinogenic potential of the test material was determined in accordance with standardised guidelines OECD 451 and EPA OPP 83 -2. During the study test material was administered to mice, at dietary concentrations of 0, 50, 200, 1000 and 7000 ppm, for 18 months, 60 males and 60 females per dose group. Fifty animals per sex and group were utilised for evaluation of carcinogenic potential and ten animals per sex and group were utilised for hematological evaluation. Clinical signs, body weight, food consumption, water consumption, and mortality were monitored throughout the study for all animals. Hematological investigations were performed at 12 and 18 months. At sacrifice, animals were examined macroscopically and organ weights were recorded. Organs and tissues were collected and prepared for histopathological evaluation. Organs and tissues from all animals in the carcinogenicity group were examined microscopically.

Analytical determinations confirmed that the test material was homogeneously distributed and stable in diet for the duration of use at the targeted dietary concentrations. the calculated average daily doses of test material, corrected for actual amount of test material were 5.91, 24.5, 121 and 854 mg/kg body weight for males and 5.76 , 24.1, 112 and 818 mg/kg body weight for females fed 50, 200, 1000 and 7000 ppm, respectively.

Overall, treatment with test material was well tolerated, and the survival rate was comparable to that of the respective control group. Treatment-related effects were restricted to reduced food consumption of females leading to slightly decreased body weight gain (-21 % at 3 months, -16 % after 18 months compared to the control group) in high dose females. High dose males consumed more water through the first 3 months of treatment compared to the control animals and at the end of the treatment period only, slightly lower values for the erythrocyte parameters were measured. There were no macroscopic or microscopic findings related to the treatment. There was no evidence of treatment-related carcinogenicity during the study.

Based on the findings, the NOEL after 18 months of treatment was 1000 ppm, equivalent to an average daily intake of 121 or 112 mg/kg bodyweight for males and females, respectively.

 

In a further study, conducted in accordance with standardised guidelines OECD 453 and EPA OPP 83 -5, the test material was administered to rats at dietary concentrations of 0, 50, 500, 2000 and 10000 ppm, for 24 months, 80 males and 80 females per dose group. Fifty animals per sex and group were utilised for evaluation of carcinogenic potential (group 1), twenty animals per sex and group were utilised for hematological investigations (group 2), of which 10 animals per sex and dose group were utilised for investigation of blood chemistry and urine parameters (group 3). Additionally, 10 animals per sex and group were used for interim sacrifice at 12 months (group 4). Clinical signs, body weight, food consumption, water consumption, and mortality were monitored throughout the study for all animals. Eye examinations were conducted in animals of group 1 at 6 month intervals during the study. At scheduled sacrifices, all animals were examined macroscopically, organ weights were recorded, and organs and tissues were collected and prepared for histologic evaluation. Organs and tissues from all animals in the carcinogenicity and interim sacrifice group were examined microscopically.

Overall, oral treatment with the test material admixed in the diet over a period of 2 years was well tolerated without occurrence of overt toxicity. There was no adverse effect of treatment on the mortality rate and the animal's behaviour was normal. A significant decrease in body weight gain occurred in high dose group animals of both sexes indicating that the maximum tolerated dose had been met or exceeded at 10000 ppm. Treatment-related toxicity was mainly noted at this dose group and effects most often related to the decreased weight gain. These included marginal effects on hematology parameters and several increased organ weight to body weight ratios without laboratory or pathology correlates. Histopathologic evaluation showed a non-dose responsive increase in the incidence of kidney tubular atrophy in females dosed at 2000 and 10000 ppm. This common finding, greater than 25 % in controls, was seen at greater than 60% at the two top doses, but with a severity grade of only minimal to slight. There were no data from other measured parameters to support the kidney as the target organ. In males, there was an increase in the incidence of Leydig cell hyperplasia at the high dose only. The grades were mostly minimal to slight with no differences in severity among the groups. This group of animals may have been particularly susceptible to this lesion, as the control group (and the other treated groups) had an unusually high incidence (22 %). In the historical control database of 11 studies, only one study had a control incidence higher (24 %) than this study. Another control group had an incidence of 16 %, but all other control incidences were less than 10 %. At the same dose level, the mean testes to body weight ratios were increased. There were no treatment-related increases in neoplastic lesions in this study.

Under the conditions of the study, decreased body weight gain indicated that the maximum tolerated dose level was met or exceeded at 10000 ppm. Consumption of 10000 ppm test material in the diet resulted in a number of high-dose effects including increased incidences of kidney tubular atrophy in females and Leydig cell hyperplasia in males. A non-dose responsive increase in tubular atrophy was also noted in 2000 ppm females. Based on this kidney effect, the overall no observable effect level was 500 ppm, and corresponded to 23.7 mg/kg body weight/day. The no observable effect level for males was at 2000 ppm and corresponded to 82.6 mg/kg body weight. There was no evidence during the study for a carcinogenic effect in rats.


Justification for selection of carcinogenicity via oral route endpoint:
Findings from two studies, an 18 month carcinogenicity study in mice and a 24 month carcinogenicity and chronic toxicity study in rats, were considered in a weight of evidence approach.

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