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EC number: 212-133-3
CAS number: 764-99-8
A study according OECD 422/GLP was performed. The test item was administered at 80, 250 or 800 mg/kg bw/day to Hannover Wistar rats for 28 days in males and 50-55 days in females. Based on the results of this study, the following NOAELs were considered:
The NOAEL for systemic toxicity of the parental generation was 80 mg/kg bw/day for males based on clinical signs, body weight gain and food consumption effects on the high dose group and on kidney findings in male rats at the mid and high dose group.
The NOAEL for systemic toxicity was 250 mg/kg bw/day for females based on clinical signs, body weight gain and food consumption effects.
The NOAEL for reproductive effects of the parental generation was 800 mg/kg bw/day based on no findings. The NOAEL for pups’ (F1 generation) development and survival was 800 mg/kg bw/day based on no specific findings that were not attributed to maternal toxicity.
A study according OECD 422/GLP was performed. The test item was administered at 80, 250 or 800 mg/kg bw/day to Hannover Wistar rats for 28 days in males and 50-55 days in females. The dose levels were selected based on the results of a Dose Range Finding (DRF) study.
Parameters measured during the study included twice a day mortality checking, daily routine and weekly detailed observation of clinical signs, weekly body weight and food consumption measurements and clinical pathology evaluation (including haematology, coagulation, clinical chemistry and urinalysis). Neurological assessment (Functional Observation Battery (FOB) including measurements of the landing foot splay, grip strength, Irwin test as well as locomotor activity measurement) was performed during the last week of the treatment for each sex. In addition, the reproductive performance, pregnancy, parturition and postpartum/lactation period were monitored in the adult animals, and viability, clinical signs and development were evaluated in their F1 offspring until PND13. At termination (Day 28 for males, PPD (Post-partum Day) 14 for females), necropsy with macroscopic examination was performed. Weights of selected organs were recorded, and representative tissues/organs were sampled and preserved in appropriate fixatives from the adult animals or F1 animals. T4 and TSH levels in the PND (Post-natal Day) 13 pups and parental males were also determined. For the adult animals, a detailed histological examination was performed on the selected list of retained organs of 5 animals/sex in the Control and High dose groups, reproductive organs of all animals of Control and High dose groups, all those male / females mating pairs where no liveborn pups were achieved. Dosing formulations were analyzed for concentration and/or homogeneity on three occasions during the study. Overall, the formulations were considered adequate for the study.
Decreased activity, ataxia, increased salivation, piloerection, recumbency, red discharge and coloured urine were observed in some High dose male or female animals, increased salivation for all the animals and were considered as test item related effects. Slightly reduced growth of adult High dose males (D0-27) and females (D0-14), and female weights in the lactation phase were considered to be treatment related. Test item related adverse effect on food consumption was observed in the first two weeks of the treatment in the High dose group of both sexes, correlating with the body weight data. There were no changes in animal behaviour, general physical condition or in the reactions to different type of stimuli related to test item treatment when compared to control. There were no adverse test item related changes in the haematology parameters in the male and female dosed group. Test item related increase in the alkaline phosphatase activity and alanine aminotransferase activity and possibly increased plasma calcium, was observed in the High dose female group and increased urea in the High dose male group. No test item effect on oestrus cycle of parental females was noted. No test item related changes were noted in the reproductive parameters during mating and gestation, delivery and post-partum/lactation period until PPD14. There were no adverse effects on the F1 offspring viability, clinical signs, physical or sexual development. No test item related macroscopic finding was recorded for F1 pups at necropsy. The High dose pups were slightly smaller and had slightly lower growth rates than controls, but this was most probably related to maternal toxicity and was not attributed to a direct effect on the pups. Histological kidney changes in the High dose males were characterised by tubular basophilia, tubular dilatation and presence of crystals in the tubular lumen. It is considered that either the test item or its metabolites are excreted through the kidney which contribute to the partial blockage of the tubule and contributes to other spectrum of changes which was collectively diagnosed as retrograde nephropathy. The tubular basophilia and dilatation without the presence of crystals in the tubules were recorded as independent terminologies, even though they are considered as part of the spectrum of changes contributing to retrograde nephropathy. The microscopic changes observed in the male kidneys correlated with organ weight changes and macroscopic observations. Immunohistochemical staining for alpha 2 u globulin revealed comparable incidences between Control and High dose male kidneys. Therefore, although the accumulation of proteinaceous droplets in the kidney tubules appears to be specific for male rats, the mechanism differs from the classic mechanism involving alpha 2 u globulin. However, these changes are considered potentially as adverse since the relevance for humans cannot be completely ruled out. Non-glandular gastric squamous cell hyperplasia (minimal to mild) was observed in both sexes at the High dose. Kidney findings were also present in males of the Mid dose group, but to a lesser extent.
Under the experimental conditions of this study and based on the results of thyroid hormone measurement, thyroid weights, nipple retention, anogenital distance and external reproductive organs analysis, histopathology and reproductive performance, there was no evidence for any endocrine effects.
Based on the results of this study, the following NOAELs were considered:
The NOAEL for systemic toxicity of the parental generation: 80 mg/kg bw/day for males based on clinical signs, body weight gain and food consumption effects on the High dose group and on kidney findings in male rats at the Mid and high dose group.
The NOAEL for systemic toxicity was 250 mg/kg bw/day for females (based on clinical signs, body weight gain and food consumption effects).
The NOAEL for reproductive effects of the parental generation: 800 mg/kg bw/day (based on no findings). The NOAEL for pups’ (F1 generation) development and survival: 800 mg/kg bw/day (based on no specific findings that were not attributed to maternal toxicity).
A testing proposal for a developmental toxicity study in rats (OECD TG 414) was submitted to ECHA for evaluation. As soon as the TPE is finalized the study will be conducted and the dossier will be updated after finalization of the report.
Classification, Labelling, and Packaging Regulation (EC) No 1272/2008 The available experimental test data are reliable and suitable for classification purposes under Regulation (EC) No 1272/2008. Based on available data the test item is not classified and labelled for reproduction/developmental toxicity according to Regulation (EC) No 1272/2008 (CLP), as amended for the eighteenth time in Regulation (EU) 2022/692.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
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