2-hydroxy-1-(4-(4-(2-hydroxy-2-methylpropionyl)benzyl)phenyl)-2-methylpropan-1-one

Endpoint summary

Description of key information

The test item was administered orally by gavage to male and female Wistar rats (F0 animals) at dose levels of 0, 10, 30 and 90 mg/kg bw/day (OECD 422). Treatment-related adverse local irritative effects in the stomach were observed in all test item-treated groups at incidences of 1, 2 and 2 animals at the dose levels 10, 30 and 90 mg/kg body weight/day, respectively. In addition, decreased body weight gain and lowered motor activity were observed. Treatment-related adverse local irritative effects in the stomach were observed in all test item-treated groups at incidences of 1, 2 and 2 animals at the dose levels 10, 30 and 90 mg/kg body weight/day, respectively. 

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

30 mg/kg bw/day

Study duration:

subacute

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

Procedure and observations

The test item was administered orally by gavage to groups of 10 male and 10 female Wistar rats (F0 animals) at dose levels of 0 mg/kg body weight/day (CMC as vehicle), 10 mg/kg bw/d, 30 mg/kg bw/d and 90 mg/kg bw/d. The duration of treatment covered a 2-week premating and a mating period in both sexes, approximately 1 week post-mating in males, and the entire gestation period as well as 4 days of lactation and 2 weeks thereafter in females. A detailed clinical observation was performed in all animals. Body weights and food consumption were determined in F0 animals. Clinicochemical and hematological examinations as well as urinalyses and FOB were performed in all animals towards the end of the administration period. All animals were assessed by gross pathology; weights of selected organs were recorded and a histopathological examination was performed.

At 90 mg/kg body weight/day, one male was killed for ethical reason, relationship to the treatment could not be excluded. Test item-related clinical signs, i.e. hunched posture, ruffled fur and discoloured feces, were observed of males and females of the high dose group. Food consumption and body weight gain in high dose males and females was found to be lower when compared to control. The animals showed also a slightly lower motor activity. Liver weights were increased in group 4 (90 mg/kg body weight/day). Additionally, thymus weights were decreased in females of the 90 mg/kg body weight/day group. Treatment-related adverse local irritative effects in the stomach were observed in all test item-treated groups at incidences of 1, 2 and 2 animals at the dose levels 10, 30 and 90 mg/kg body weight/day, respectively. Thymus atrophy and lowered thymus weight as well as liver cell hypertrophy was observed in (mid and) high dose animals.

Discussion

The reduced size in thymus in females, occurring in increased incidences, at ≥ 10 mg/kg body weight/day correlated histopathologically with athropy and reduced absolute and relative thymus weights only at the high dose levels. Although this is considered to be most likely to be stress related a test item-relationship cannot be excluded at the 90 mg/kg body weight/day dose level.

Treatment-related diffuse liver cell hypertrophy at 90 mg/kg body weight/day was considered to be adaptive. This hypertrophy was associated with follicular cell hypertrophy in thyroid glands in some males and females at 90 mg/kg body weight/day. Most probably the enhanced liver cell metabolism resulted in an acceleration of thyroid hormone breakdown with consequent thyroid follicular cell hypertrophy. This finding is commonly seen in rats after being exposed to xenobiotics.

The No-observed-effect-level for systemic toxicity is considered to be 30 mg/kg bw/day.

In addition to the above mentioned OECD 422 study, two range finding studies and a 28 day study were performed. In the course of the subacute study, 5, 50 and 160 mg/kg bw/day were administered by gavage to male and female wistar rats. Due to mortality in the high dose group an additional group was treated with 100 mg/kg bw/day. Similar to the findings of the OECD 422 study, gastric erosions were observed. Additionally, an adverse, nephrotoxic effect could be recorded in animals treated with 50, 100 and

160 mg/kg/day. The NOAEL was established at 5 mg/kg bw/day.

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

Justification for classification or non-classification

Dangerous Substance Directive (67/548/EEC)

The available studies are considered reliable and suitable for classification purposes under 67/548/EEC. As a result the substance is considered to be classified for repeated dose toxicity under Directive 67/548/EEC.

Classification, Labeling, and Packaging Regulation (EC) No. 1272/2008

The available experimental test data are reliable and suitable for classification purposes under Regulation 1272/2008. As a result the substance is considered to be classified for repeated dose toxicity under Regulation (EC) No. 1272/2008.