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

Description of key information

Valid repeated dose toxicity studies with the test substance are available. In a 7 day oral range finding study (no guideline followed), 1000 mg/kg bw/d was given to SD-rats via gavage and established as LOAEL (rats, CIT 1986). In a follow up 28 day subacute oral gavage toxicity study conducted similar to OECD guideline 407 the NOAEL was 10 mg/kg bw/d (SD-rats, CIT 1986). In a 90 day subchronic oral gavage toxicity study conducted according to OECD guideline 408 the NOAEL was 2 mg/kg bw/d (SD-rats, CIT 1988). Based on the results of these studies the NOAEL of the test substance was established at 2 mg/kg bw/d. The NOAEL is based on hepatotoxic effects which are attributable to peroxisome proliferation and which are known to be a rodent specific phenomenon.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

2 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

Additional information

In a 7 day oral range finding study, 1000 mg/kg bw/d test article was administered daily via gavage to SD-rats (CIT 1986b). Mortality (1/10 animals), clinical signs, like piloerection and reduced activity, decreased bodyweight gain and a reduced food consumption compared to common values for animals of this age and strain were seen.

In a GLP-compliant subacute 28 day study conducted similar to OECD 407 doses of 10, 50, 200 and 1000 mg/kg bw/d were applied to SD-rats via gavage without recovery period (CIT 1986a). At 10 mg/kg bw/day a slight increase in absolute and relative male mean liver weight was the sole effect observed. No macroscopic or microscopic correlates were found. Therefore, 10 mg/kg bw/day was established as NOAEL. Due to increased absolute and relative liver weights as well as increased albumin level in both sexes, signs of liver necrosis in 1 animal and alopecia in females, the LOAEL was 50 mg/kg bw/day.

In the GLP-compliant oral subchronic 90 day toxicity study, conducted according to OECD guideline 408 (1981) with minor deviations doses of 2, 5, 10, and 50 mg/kg bw/d were administered by gavage to SD-rats (CIT 1988). Satellite groups of control and 10 mg/kg bw/d animals were allowed to recover for 4 weeks after the last treatment. Dose dependent hepatotropic effects were correlated with dose dependent enlargement of the liver (beginning at 5 mg/kg bw/day) and with hepatocyte hypertrophy at 50 mg/kg bw/day in males. In addition, some changes in plasma alkaline phosphatase activity and albumin and globulin concentrations were seen. Dose dependent and significant changes in liver weights were seen at 2, 5, 10 and 50 mg/kg bw/day (males and females, respectively).

Based on the results mentioned above the NOAEL of 2 mg/kg bw/d derived in the subchronic oral toxicity study was established as NOAEL for repeated dose oral toxicity.

However, several studies in rats are available, which confirm that the substance is a potent peroxisome proliferator in the liver after oral application (details see IUCLID-Chapter 7.9.3, specific investigations). The susceptibility to peroxisome proliferators is known to be a rodent specific phenomenon and therefore hepatotoxic effects seen in the repeated dose studies mentioned above are negligible to humans. Despite effects attributable to hepatotoxicity a slightly decreased body weight was seen in males (84-94% to control) at 50 mg/kg bw/d in the oral subchronic 90 day toxicity study solely.

No valid data for repeated dose toxicity after dermal or inhalative applications are available; no additional knowledge would be gained from such studies. The substance is a highly viscous liquid with a negligable vapour pressure, so vapour exposure is not relevant. Filling steps are performed in closed pipes at slightly elevated temperatures to improve the viscosity. The substance is added to coating formulation at concentrations in the range of 1 - 3% to obtain protection against UV light. Such formulations must be labelled as a skin sensitizer which requires personal protection.

Repeated dose toxicity: via oral route - systemic effects (target organ) digestive: liver

Justification for classification or non-classification

Based on the NOAEL of 2 mg/kg bw/d the substance would have been classified for repeated dose oral toxicity according to Directive 67/548/EEC and Directive EC/1272/2008. However, the NOAEL was based on hepatotoxic effects which are attributable to peroxisome proliferation. Since peroxisome proliferation is known to be a rodent specific phenomenon these effects were not considered relevant to humans. In consequence, the substance was not classified for repeated dose toxicity in Annex I of Directive 67/548/EEC (Index no. 607 -176 -00 -3).