Isobutyl (S)-2-chloropropionate

Endpoint summary

Description of key information

oral
4 month, rat, diet: NOAEL = 70 mg/kg bw/day (due to severe neurological symptoms, morphological changes in the cerebellum and changed body weight gain in higher doses; GLP; OECD 407, FOB according to EPA-TSCA Fed. Reg. 50 (188); BASF 1992)

Additional information

oral

A GLP conform subchronic study was performed according to OECD guideline 407 and EPA-TSCA Test Guideline "Functional Observational Battery" with rats. The test substance (purity 99.7%) was initially administered in doses of 70, 210 and 700 mg/kg bw/day in the diet (actual ingested; corresponding nominal doses were 100, 300 and 1000 mg/kg bw/day) for 4 weeks. The main objective of the study was to investigate the neurotoxicologic potential of the test substance. However, during the first 4 weeks of the study most of the animals of test group 3 died or were killed in a moribund state, and in the mid dose test group only slight neurological symptoms were observed. Thus, the study was prolonged up to 4 months and the mid dose (300 mg/kg body weight) were elevated twice: after 70 days of treatment to 600 mg/kg body weight and after 105 days of treatment to 800 mg/kg body weight.

Feed consumption and body weight were determined once a week. The general state of health of the rats was checked at least daily and the animals were additionally thoroughly examined and palpated once a week. Twenty-eight days after the start of the study blood samples were taken from all survival animals for clinicochemical and hematological examinations. In addition to the clinical examinations, neurofunctional observations were carried out in all survival animals one day before the start of the study and thereafter on days 1, 7, 14, 29, 62, 73, 80, 87, 94, and 118 in male and female animals. An additional neurofunctional test was performed in the female rats 125 days after the beginning of the administration period. At the end of the study 9 male and 9 female animals were sacrificed by decapitation under carbon dioxide anesthesia and assessed by gross pathology. This was followed by a histopathological examination. Three animals per sex and dose, each from control and dose group 2, were deeply anaesthetised and sacrificed by perfusion fixation. The sacrificed animals were necropsied and the visible organs were assessed by gross pathology.

In high dosed animals, poor general state (both sexes), reduced feed consumption, body weight and body weight change (both sexes) and clinical signs of neurological symptoms (e.g. ataxia, waddling gait, tremor, hyperesthesia, oblique body posture, spasms, lateral position; both sexes) were observed. All animals died or were killed in a moribund state in the first three weeks (females) or six weeks (males) of the study. At necropsy, cachexia (both sexes), ulcer in the glandular stomach (both sexes), multifocal necrosis in the stratum granulosum of the cerebellum (both sexes) and focal degeneration of testes were detected.

In mid dosed animals, reduced feed consumption and body weight change (both sexes), clinical signs of neurological symptoms (e.g. slight ataxia, vocalization, staggering gait, spasms, tremor, or waddling gait; both sexes) were observed. At necropsy, multifocal necrosis in the stratum granulosum of the cerebellum (both sexes) was observed.

In the low dose treatment, no treatment related effects were observed at all.

Generally, in clinical chemistry and hematology there were no substance-related effects in any treatment. Therefore the "no adverse effect level" (NOAEL) for the repeated oral administration of the test substance can be fixed under the chosen test conditions at 70 mg/kg bw for male and female rats. The administration of higher doses (ca. 210 to 560 mg/kg bw and higher) led to severe neurological symptoms (e.g. ataxia), morphological changes in the cerebellum of male and female animals and changed body weight gain (BASF 1992).

Justification for classification or non-classification

According to the conditions of the test, there is no indication given for a classification of toxicity after repeated dosing of the test substance regarding 67/548/EEC and GHS requirements, respectively.