Registration Dossier

Administrative data

Description of key information

- Subchronic repeated dose toxicity study on analogue substance (OECD 408, GLP, K, rel.1): NOAEL(analogue)= 1000 mg/kg bw/day ; NOAEL(registered substance, corrected by MM) = 1781.45 mg/kg bw/day

- Subacute repeated dose toxicity study (OECD 407, pre-GLP, S, rel.2): NOAEL = 1000 mg/kg bw/day

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
1 781.45 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
The key study performed on an analogue substance is GLP-compliant and of high quality (Klimisch score = 1). The study performed on the registered substance supports the results of the key study.

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

OECD 408:

A Key study was identified (Braun, 2008). In a repeated dose toxicity study performed in accordance with OECD test guideline No. 408 and in compliance with GLP, an analogue substance was administered daily by oral gavage to SPF-bred Wistar rats of both sexes at dose levels of 100, 300 and 1000 mg/kg bw/day for a period of at least 90 days. A control group was treated similarly with the vehicle, bidistilled water, only. The groups comprised 12 animals per sex which were sacrificed after 91/92 days of treatment. Additional 6 rats per sex and group were used at 0 and 1000 mg/kg bw/day. These animals were treated as those described above and then allowed a 28-day treatment-free recovery period after which they were sacrificed. During the study, clinical condition, detailed physical and arena observations, grip strength, motor activity, body weight, food consumption, ophthalmoscopy, hematology, blood chemistry, urinalysis, organ weight, sperm analysis, estrus, macropathology and histopathology investigations were undertaken.

 

The following parameters were considered to be unaffected by the test item: mortality, food consumption, body weights, weekly observations (weeks 1-12, 14-16), functional observational battery (including grip strength and locomotor activity at weeks 13 and 17), ophthalmoscopy, mean testicular sperm count and mean epididymal sperm count, duration of estrus, organ weights and ratios, macroscopical and microscopical evaluations.

 

Test item-related changes were restricted to:

Clinical Signs: Soft feces was noted in males and females treated with 300 and 1000 mg/kg bw/day. This finding was considered to be test item-related but was reversible during the recovery period.

Hematology: In males and females treated with 1000 mg/kg bw/day, the mean relative thromboplastin time was elevated when compared with the controls, and the differences exceeded the ranges of the historical control data.

Clinical Biochemistry: Although most remained within the historical control ranges, the differences noted in some parameters (sodium in all test item-treated females; protein in females at 1000 mg/kg bw/day and 300 mg/kg bw/day, globulin in females at 1000 mg/kg bw/day), exceeded the upper ranges, and were considered likely to represent functional effects of the test item.

Urinalysis: At 300 and 1000 mg/kg bw/day, the pH of the urine was slightly acidic in males and females at the end of the treatment period, and considered to be test item-related. This finding was not seen after recovery.

 

Under these test conditions, the NOAEL for test substance was considered to be 1000 mg/kg bw/day in rats.

Based on the molecular weight and the purity of the test and registered substance, the NOAEL for registered substance was considered to be 1781.45 mg/kg bw/day in rats.

OECD 407:

In a subacute repeated dose toxicity study, the registered substance was administered to groups of Cpb:WU Wistar rats (10/sex/dose) in the diets at the dose-levels of 0 (vehicle), 400, 2000 and 10000 ppm for a period of 4 weeks. Examinations during the study included: clinical condition, bodyweight, food/water consumption, haematology, organ weight, gross pathology and histopathology. 

 

General condition, behaviour, survival and haematology were not adversely affected in any of the groups. Growth and food intake were slightly decreased in the 10000 ppm group in males while food efficiency was unfavourably affected in this group in both sexes. Water intake was slightly diminished in the 10000 ppm group in males only. The relative weights of the liver and kidneys were increased in the 10000 ppm group in females only. Gross examination at autopsy did not reveal any changes that could be ascribed to the ingestion of the test substance. Microscopic examination of the kidneys revealed an increased incidence of tubular nephrosis in male rats of the 10000 ppm group, as compared to controls.

 

The increase in the relative weight of the kidneys in females at 10000 ppm and the increased incidence of tubular nephrosis in the kidneys of males in this group suggests aslightnephrotoxic action of the test substance. The increase in the relative weight of the liver in females at 10000 ppm was not accompanied by treatment-related hepatic lesions. Therefore, the liver enlargement may be considered the expression of an adaptive phenomenon rather than of a toxic action of the test substance.

 

No toxicity effects were observed at 400 and 2000 ppm in both sexes.

 

Under the test conditions, the NOAEL for test substance is 10000 ppm in the diet of rats for 4 weeks. This level is approximately equivalent to a nominal intake of 1000 mg/kg bw/day.

This study supports the results of the subchronic study performed on the read-across substance as the NOAEL is higher than 1000 mg/kg bw/day.

CONCLUSION: NOAEL(subchronic) = 1781.45 mg/kg bw/day

Justification for classification or non-classification

Harmonized classification:

The substance has no harmonized classification according to the Regulation (EC) No 1272/2008.

Self-classification:

Based on the available data, no additional classification is proposed for the target substance regarding specific target organ toxicity after oral dose-repeated exposure. Indeed, adverse effects were not observed at the dose level of 1000 mg/kg bw/day, i.e. above the treshold for Category 1 or 2 classification for a study duration of 13 weeks.