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Administrative data

Description of key information

Several feeding studies with rodents and non-rodents were available. The chronic study with dogs was chosen as key study showing no substance related effects in male and female Beagle dogs. A NO(A)EL of 286.5 mg/kg bw/d was determined.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
286.5 mg/kg bw/day
Study duration:
chronic
Species:
dog

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Key study: 1-year Dog feeding study (American Cyanamid Company, IZ-427-002, 1987)

A one-year toxicity study was conducted equivalent or similar to OECD guideline 452, to determine the potential adverse effects, if any, of the test substance when added to the diet of four (4) groups of six (6) male and six (6) female Beagle dogs each, at levels of 0 (control), 1000 (low-dose), 5000 (mid-dose), or 10000 (high-dose) parts per million (ppm). The dose levels correspond to 30, 140 and 286 mg/kg bw/d for the low, mid and high dose, respectively.

Body weights were determined prior to treatment, at the start of the study and weekly thereafter; feed consumption was measured daily. Blood biochemical and haematological parameters and urine analyses were determined prior to dosing, at 6 weeks and at 3, 6 and 12 months. Ophthalmological examinations were performed during the pre-test period and at 6 and 12 months. All animals were necropsied for a complete gross and histopathological evaluation and determination of absolute and relative organ weights.

No clinical signs of toxicity were observed that could be attributed to the test chemical and all animals survived to the terminal necropsy. Ophthalmological examinations revealed no abnormalities considered to be related to the test chemical. Body weight and feed consumption as well as clinical chemistry, haematological and urinalysis parameters were similar in control and compound-treated males and females at all dose levels used in this study; statistically significant differences observed occasionally were considered to be random occurrences unrelated to test chemical or changes not considered toxicologically significant. There were no statistically significant differences in mean absolute organ weights or organ-to-body weight or organ-to-brain weight ratios. Tissue lesions observed grossly at terminal necropsy were findings commonly seen in dogs in chronic toxicity studies and were distributed similarly between control and compound-treated animals. Microscopic examination of tissues revealed no findings attributable to the test chemical; all lesions appeared in equal incidence in control and compound-treated males and females, and were seen predominantly in control and mid-dose animals or were seen only in an occasional animal in one or more groups.

Results, therefore, demonstrated no effects attributable to the test chemical and the highest dose level (10000 ppm) used in this one-year study is considered to be a "no-effect" level corresponding to 286 mg/kg bw/d.

Supporting study: 13-week Rat Feeding Study (American Cyanamid Company, IZ-425-001, 1984)

In a subchronic toxicity study equivalent or similar to OECD guideline 408, the test substance was administered to thirty 4 week old Sprague Dawley rats/sex/dose in diet at dose levels of 0, 1000, 5000 and 10000 ppm (0, 88.6, 438.6 and 879.1 mg/kg bw/d) for 13 consecutive weeks. The rats were observed twice daily for signs of overt toxicity, morbidity, and mortality. Detailed observations, individual body weights and individual food consumptions were recorded weekly. Hematological, biochemical and urinalysis tests were performed on 10 rats/sex/group at 44-45 days and at termination of the study.

There were no overt signs of toxicity observed at any treatment level during the course of the study. One control female rat was found dead during week 3 of the study. Total weight gains were somewhat decreased though not significantly (P<0.05) in both sexes at the 5000 and 10000 ppm dose levels. Total gains for both sexes at the 1000 ppm dosage level were comparable to those of the untreated controls. Food intakes for both sexes at the 1000, 5000 and 10000 ppm dosage levels were comparable to those of the untreated control group. Hematological, clinical chemistry, and urinalysis parameters were generally unaffected by ingestion of the test substance. Relative kidney weights were significantly (P<0.05) increased in female rats at the 10000 ppm dose level. Subsequent histopathological examination failed to reveal any cause for this change, therefore, the change was considered to be fortuitous. No other significant organ weight changes were observed in either sex at the 10000 ppm level. Absolute and relative organ weights for both sexes at the 1000 and 5000 ppm levels were unaffected by ingestion of the test substance. No test substance related gross or microscopic changes were observed at any treatment level.

It was concluded that the 13-week maximum demonstrated no effect level (NOEL) in the rat is 10000 ppm which was equivalent to an average intake of 879.1 mg/kg of body weight/day.

Supporting study: 13-week Rat Feeding Study (American Cyanamid Company, IZ-425-002, 1992)

In a subchronic toxicity study according to EPA guideline OPP 82-1, the test substance was administered to ten 4.5 week old Sprague Dawley rats/sex/dose in diet at dose levels of 0, 15000 and 20000 ppm (0, 1336 and 1740 mg/kg bw/d) for 13 consecutive weeks. The rats were observed daily for signs of overt toxicity, morbidity, and mortality. Ophthalmological examinations were conducted prior to the study and at termination. Detailed clinical observations, individual body weights and individual food consumptions were recorded weekly. Haematological, clinical chemistry and urinalysis determinations were performed on all surviving animals at termination of the study. At termination, all surviving animals were subjected to a gross necropsy and selected organs were weighed. Samples of selected tissues were submitted for histopathological evaluation from all test animals.

No overt clinical signs of toxicity or mortality were observed during the study period that could be attributed to administration of the test material. Food consumption for both male and female rats at all dosage levels was generally comparable to or excessive to the control group at most measurement intervals. Body weights were increased (not statistically significant) during the 13-week study period for both sexes at all treatment levels in comparison to those of the control rats. Total body weight gains for male and female rats which received test substance tended to be increased (2.5 - 6.5 %) over those of the control group. Haematology, clinical chemistry, and urinalysis parameters were unaffected by treatment with the test substance. No changes were observed in absolute or relative (to body weight) organ weights which could be attributed to administration of the test material. There were no gross or microscopic pathology observations which were attributable to the test substance, in any of the tissues evaluated.

The data for this study support a No-Observable-Effect Level (NOEL) for the test substance in the rat of greater than 20000 ppm which was equivalent to an average daily intake of greater than 1740 mg/kg of body weight/day.

Conclusions

Several feeding studies with rodents and non rodents were available. No significant adverse effects was observed in all feeding studies.

Justification for classification or non-classification

The available experimental test data are reliable and suitable for classification purposes under Regulation 1272/2008. As a result the substance does not need to be classified and labelled for repeated dose toxicity under Regulation (EC) No 1272/2008, as amended for the ninth time in Regulation EC No 2016/1179.