SILATRIZOLE

Endpoint summary

Description of key information

In two reliable studies, NOAEL for systemic toxicity = 1000 mg/kg bw/day for male and female rats based on the absence of significant effects related to test item.

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

1 000 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

A GLP study conducted according to OECD Guideline 408 was available and of good quality (Klimisch score = 1). A GLP study conducted similarly to OECD Guideline 408 and in compliance with FDA guidelines was also available and of good quality.

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

In a GLP-compliant subchronic repeated dose oral toxicity study conducted according to the OECD Guideline 408 (RCC, 1996, Rel.1), Silatrizole (encoded "G4375") was administered by gavage to Sprague Dawley rats (10/sex/dose) at daily doses of 0, 100, 300 and 1000 mg/kg bw for 13 weeks. Additional 5 rats per group and sex at 0 and 1000 mg/kg bw were treated for at least 13 weeks and then allowed a 4 week treatment-free recovery period. There was no death, no treatment-related clinical signs, no effect on food consumption or body weight and no changes in ophthalmoscopic parameters which could be attributed to treatment. Further, hematology and urinalysis parameters were unaffected by treatment as well as organ weights. All morphologic findings recorded were within the normal range of background alterations. The only treatment-related changes in this study were confined to rats at 1000 mg/kg bw, affected few clinical biochemistry parameters, and were found to be reversed after the recovery period. They consisted of a lower glucose level in females, a higher cholesterol level in males, a higher creatine kinase activity in males, a higher sodium level in females and changes in some plasma protein fractions of the protein electrophoretic pattern. The differences from controls were of minor degree and suggest metabolic adaptations. Therefore, these findings are considered to be of no toxicological relevance. Based upon these results the No Observed Effect Level (NOEL) for Silatrizole in this study is considered to be 300 mg/kg bw/day and the No Observed Adverse Effect Level (NOAEL) is considered to be 1000 mg/kg bw/day.

 

In a repeated dose oral toxicity study (CIT, 2000, Rel.1), Silatrizole (encoded "G4375") was administered by gavage as a suspension in 4% aqueous methycellulose with 1 % Tween 80 to Wistar rats (12/sex/dose) at daily doses of 0, 100, 300 and 1000 mg/kg bw/day for approximately 26 weeks. Additional 8 rats per group and sex were used to obtain toxicokinetics data (group satellite 1). Additional 6 rats per group and sex were treated up to 13 weeks (group satellite 2). Further 6 rats per group and sex at 0 and 1000 mg/kg bw (group satellite 3) were treated for at least 26 weeks and then allowed a 4 weeks treatment-free recovery period. Plasma levels of the test substance showed that systemic exposure to the test substance was seen at all test treated dose-levels. There was no death and no clinical signs related to the treatment with the test substance. The body weight gain was similar in control and treated animals. The food consumption and the efficiency of food utilization were unaffected by treatment with the test substance. There was no abnormality in the ophthalmology investigations due to treatment with the test substance. There were no changes in hematology attributed to the treatment with the test substance. Slightly lower glucose levels were noted in females given 300 mg/kg/day and in males and females given 1000 mg/kg/day. Since there was no corresponding histopathological finding, these effects were considered to be toxicologically insignificant. There were considered to be of no toxicological significance. There were no test substance-related quantitative or qualitative changes of urine. There were no differences in organ weights attributed to the treatment with the test substance. No findings related to treatment with the test substance were found with macroscopic and microscopic examinations.

Based upon these results, the No Observed Adverse Effect Level (NOAEL) for Silatrizole in this study is considered to be 1000 mg/kg bw/day, confirming the results found in the RCC study

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Two studies were available (13 wks/26 wks). No study was selected since they were both of good quality (Klimisch score = 1) and since the conclusions and observations were the same.

Justification for classification or non-classification

Under the test conditions, the No Observed Adverse Effect Level (NOAEL) for systemic toxicity was considered to be the highest dose tested in rats (i.e. 1000 mg/kg bw/day which is >300 mg/kg bw/day); as the observed effects were considered not toxicologically relevant, therefore no target organ was identified. Thus, Silatrizole does not need to be classified for repeated dose toxicity according to the Regulation (EC) No. 1272-2008 (CLP).