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Administrative data

Description of key information

NOAEL (subacute, rat) = 100 mg/kg bw/day (males and females)

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
100 mg/kg bw/day
Study duration:
subacute
Species:
rat

Additional information

Oral

Subacute

Two consecutive 7-Day range-finding gavage studies were performed in Wistar rats to determine suitable doses for treatment with the test substance Y-15866 in a subacute toxicity study (Simon, 2011). Based on the results of these preliminary tests, doses of 100, 300 and 1000 mg/kg bw/day were selected for the assessment of subacute toxicity in rats.

In a subsequent 28-day oral toxicity study according to OECD guideline 407 and GLP, Y-15866 was administered undiluted once daily by gavage to 5 Wistar rats per sex and group at dose levels of 100, 300 and 1000 mg/kg bw/day, respectively (Simon, 2011). A control group of 5 male and 5 female animals received bidistilled water as control. Additional 5 rats per sex in the control group and 1000 mg/kg bw/day dose group were treated for 28 days and then allowed a 14-day treatment-free recovery period. All animals survived the scheduled treatment and recovery periods. No test substance-related clinical signs were noted at the daily observations and no findings were observed at the detailed behavioural observations. In males and females, slightly reduced food consumption was noted at 300 and 1000 mg/kg bw/day during the treatment period, which was considered to be test item-related. During recovery, food consumption increased again in all animals. The decline in food consumption during the study correlated with a decrease in body weight gain and mean body weights in both sexes at 300 and 1000 mg/kg/day and was considered to be of adverse nature. In haematology parameters, significantly decreased haematocrit was noted in males at 1000 mg/kg bw/day. The observed increase in mean corpuscular volume in females at this dose persisted up to the end of the recovery period. Several plasma clinical chemistry parameters were statistically significantly altered after treatment with 1000 mg/kg bw/day in males (increased triglyceride and alanine aminotransferase (ALAT), decreased calcium, protein, albumin and globulin levels) and females (decreased protein, globulin and urea levels, increased albumin / globulin ratio and chloride levels). At necropsy, no macroscopic findings related to treatment were observed. At 300 and 1000 mg/kg bw/day, reduced absolute and relative thymus weights in males and females, which were not fully reversible at the end of recovery, were observed. In females of all dose groups, reduced absolute and relative adrenal weights were seen. Although no clear dose-response was noted, this finding was considered to be test item-related, as the reduction in organ weights persisted up to the end of recovery and reached statistical significance at 1000 mg/kg/day. Histopathological examination revealed treatment-related adverse effects on urinary bladder as observed by transitional cell hyperplasia and inflammatory cell infiltration in all males treated with 300 and 1000 mg/kg bw/day as well as in one female at 300 mg/kg bw/day and four females at 1000 mg/kg bw/day. After recovery, these findings were found to be irreversible in male and female animals treated with 1000 mg/kg bw/day. The changes in haematology and clinical biochemistry parameters as well as effects on organ weights of thymus and adrenal glands showed no correlation with macroscopic or microscopic findings and were not considered to be adverse.

Based on the study results, the NOAEL for rats was established at 100 mg/kg bw/day.

Justification for classification or non-classification

The available data on subacute toxicity of Y-15866 meet the criteria for classification as STOT RE 2 (H373) according to Regulation (EC) 1272/2008.