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Administrative data

Description of key information

In a subchronic repeated dose oral toxicity study with rats, according to OECD 408, a NOAEL was determined to be 80 mg/kg bw/day.

 

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
80 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
The study is GLP-compliant and was conducted according to OECD TG 408.

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

- Repeated dose toxicity, oral, subchronic:

A valid OECD 408 compliant study on repeated dose toxicity via oral route was conducted. Once daily oral gavage administration of test item to male and female Sprague-Dawley rats at dose levels of 20, 80 and 300 mg/kg bw/day for at least 13 weeks resulted in mortality at the high dose in a single animal after roughly 1 month of dosing. Salient test item-related effects were noted primarily in the liver and kidney and included hepatocellular hypertrophy (related to microsomal enzyme induction at all dose levels), hepatocellular vacuolation/necrosis at the high dose with increased serum liver enzymes, renal tubular degeneration/necrosis, casts, and inflammation (males) with increased urine volume and serum analyte changes in recovery males. The liver changes demonstrated complete or partial reversibility, while the kidney changes in males were not reversed within the 28-day observation period. The hyaline droplet (α2μ-globulin) nephropathy observed in males was considered to represent an adverse change for the rat only and to have limited relevance for other species including man.

Based on the results of this study and the observations of non-reversible microscopic kidney changes of minimal to marked severity in males at all dose levels, including up to moderate severity in low dose Main males, it was not possible to determine a No Observed Adverse Effect Level (NOAEL) for daily oral administration of test item in Sprague-Dawley rats for 13 weeks.Therefore a LOAEL for male rats was determined to be 20 mg/kg bw/d. In female rats, however, all test item-related effects were reversible at all dose levels, and since the liver changes were more severe at the high dose, and given that the mortality of one high dose animal was likely test item-related, the NOAEL was considered the mid dose of 80 mg/kg bw/day. Effects observed in male rats are most likely caused by alpha2 -microglobin-associated nephropathy and are therefore considedered to be sex and species specific for male rats and not of relevance for humans. Therefore, these effects were not taken into account for risk assessment (DNEL derivation) and classification and labelling.

- Repeated dose toxicity, oral, subacute:

A reliable study was conducted according to OECD TG 422, EPA OPPTS 870.3650 and GLP in rats (Dettwiler 2013) using 28 -day oral administration (gavage) at dose levels of 0, 40, 125 and 400 mg/kg bw/day of 3,5,5-trimethylhexyl acetate. The NOAEL for repeated dose toxicity of 3,5,5-trimethylhexyl acetate was 40 mg/kg bw/day, based on high maternal mortality at 125 and 400 mg/kg bw/day doses. In male rats no adverse effects could be observed even at the highest dose. Although, lethal effects occurring at a dose of 125 mg/kg bw/day are considered as expression of substance-related toxicity, the symptoms are not explicit for justifying a classification with STOT RE Category 2 according to CLP guidance. No specific organ toxicity could be identified and the mortality was shown only in pregnant rats. The cause of the deaths could not be identified. Male animals did not show any adverse effects in all dose groups.

Justification for classification or non-classification

Classification, Labelling, and Packaging Regulation (EC) No 1272/2008
The available experimental test data are reliable and suitable for classification purposes under Regulation (EC) No 1272/2008.

- Repeated dose toxicity, oral:
Available data on repeated dose toxicity via oral route imply species and sex specifc effects on kidneys of male rats, which were not considered to be of relevance for humans. All other effects observed were reversible within 28 days. Thus, the test item is not classified as STOT-RE according to Regulation (EC) No 1272/2008 (CLP), as amended for the eighth time in Regulation (EU) No 2016/918.

-Repeated dose toxicity, dermal:

As no data on the specific target organ toxicity potential after repeated dermal exposure of the test item is available a classification is not possible according to CLP (Regulation (EC) No 1272/2008 of the European Parliament and of the Council) as implementation of UN-GHS in the EU.

 

-Repeated dose toxicity, inhalation:

As no data on the specific target organ toxicity potential after repeated dermal exposure of test item is available a classification is not possible according to CLP (Regulation (EC) No 1272/2008 of the European Parliament and of the Council) as implementation of UN-GHS in the EU.