A mixture of: α-3-(3-(2H-benzotriazol-2-yl)-5-tert-butyl-4-hydroxyphenyl)propionyl-ω-hydroxypoly(oxyethylene); α-3-(3-(2H-benzotriazol-2-yl)-5-tert-butyl-4-hydroxyphenyl)propionyl-ω-3-(3-(2H-benzotriazol-2-yl)-5-tert-butyl-4-hydroxyphenyl)propionyloxypoly(oxyethylene)

Endpoint summary

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Guideline study, GLP compliance

Qualifier:

according to guideline

Guideline:

other: 87/302/EEC p.8 (See comments)

GLP compliance:

yes

Species:

rat

Route of administration:

oral: unspecified

Details on oral exposure:

Method of administration:
Gavage

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

Test duration: 90 days

No. of animals per sex per dose:

Male: 16 animals at 0 mg/kg bw/day
Male: 10 animals at 2 mg/kg bw/day
Male: 10 animals at 5 mg/kg bw/day
Male: 10 animals at 50 mg/kg bw/day
Male: 20 animals at 10 mg/kg bw/day
Female: 16 animals at 0 mg/kg bw/day
Female: 10 animals at 2 mg/kg bw/day
Female: 10 animals at 5 mg/kg bw/day
Female: 10 animals at 50 mg/kg bw/day
Female: 20 animals at 10 mg/kg bw/day

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

There were no specific treatment-related clinical signs.

Mortality:

mortality observed, treatment-related

Description (incidence):

There were no specific treatment-related clinical signs.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Bodyweight gain was reduced by 8% in top dose males only /statistically significant, P<0.01) and was considered treatment-related. (Non-significant effects on bodyweight gain were also seen in other groups).

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

Food consumption was unaddected.

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

effects observed, treatment-related

Description (incidence and severity):

There were no opthalmologic effects.

Haematological findings:

effects observed, treatment-related

Description (incidence and severity):

platelet counts were increased (statistically significant) in all male groups. The increases were dose-related and resolved during the recovery period. There were no other treatment-related haematological effects.

Clinical biochemistry findings:

effects observed, treatment-related

Urinalysis findings:

not specified

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Details on results:

Clinical observations:
SIGNS OF TOXICITY:
Deaths: 4/16 males, 1/16 females (0 mg/kg/day); 1/10 females (2 mg/kg/day); 1/10 males (5 mg/kg/day). No deaths were considered treatment-related: two were due to gavage errors. No cause was established for the others.

There were no specific treatment-related clinical signs.

Bodyweight gain was reduced by 8% in top dose males only /statistically significant, P<0.01) and was considered treatment-related. (Non-significant effects on bodyweight gain were also seen in other groups). Food consumption was unaddected.

There were no opthalmologic effects.

Haematology: platelet counts were increased (statistically significant) in all male groups. The increases were dose-related and resolved during the recovery period. There were no other treatment-related haematological effects.

Clinical chemistry: Alkaline phosphatase activity was increased (statistically significant) in males in the 10 (1.5 times) and 50 mg/kg/day (2.9 times) goups and in females in the group (1.4 times). It was normal in both sexes in the recovery groups. Albumin concentrations were increased in males and females from the 10 and 50 mg/kg/day groups and globulins were decreased in these groups. All plasma protein concentrations were normal in recovery group animals except beta-globulin which was still decreased. Plasma glucose was increased in top dose group males. Aminotransferases were reduced in activity in all test groups but activity was generally within the rang of that of that of the control animals, and was the same as control levels in the recovery groups.

Effects in organs:
Fross adrenal weights were decreased and relative kidney and testes weights increased in males of the top dose group. Liver weights (gross) were increased in all rats in the 5, 10 and 50 mg/kg/day groups /by 85% in males, 46% in femals in the top dose group) and relative liver weights were also increased in males in the 2 mg/kg/day group. The livers of many male rats were visibly enlarged. There were no significant differences in organ weights in the recovery group animals. The only microscopic changes seen which could be related to treatment were minimal to slight hepatic cell hypertrophy in 3/10 top dose group male animals. Chronic necrosis was seen in the liver of 1/10 of the same group.

Dose descriptor:

NOAEL

Effect level:

5 mg/kg bw/day (nominal)

Basis for effect level:

other: original NCD unit is mg/kg/day

Critical effects observed:

not specified

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

5 mg/kg bw/day

Study duration:

subchronic

Species:

rat

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