3,5,5-trimethylhexyl 3,5,5-trimethylhexanoate

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route

Endpoint conclusion:

no study available

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

A screening study for reproductive/developmental toxicity is not available.
Data on selected reproduction parameters are available in the 90-day oral repeated dose toxicity study, which has been performed according to OECD 408. To assess the possible effect on reproduction and fertility, additional parameters have been included (extensive gross necropsy and detailed histopathology of male and female reproductive organs and tissues, and sperm parameters), see section 7.5.1. No effects were reported.
Reliable data has been included to cover toxicity to reproduction, as set out in Column 2 of Annex VIII, Section 8.7.1, Regulation (EC) No 1907/2006. A pre-natal developmental toxicity study performed according to OECD 414 is available (Fabreguettes, 2000). No treatment-related effects were observed on any of the assessed reproductive and developmental parameters up to and including the highest dose level of 300 mg/kg bw/day. Thus, providing a screening study for reproductive/developmental toxicity is not necessary as the data requirements are met according to Column 2 of Annex VIII, Section 8.7.1, Regulation (EC) No 1907/2006.
Justification for selection of Effect on fertility via oral route:
No study required since data are available on reproductive parameters for males and female sin the 90-day oral repeated dose toxicity study. Furthermore, a pre-natal developmental toxicity study performed according to OECD guideline 414 is available. Referring to Column 2 of Annex VIII, Section 8.7.1, Regulation (EC) No 1907/2006, the required data is present and it is not necessary to provide a screening study for reproductive/developmental toxicity.

Effects on developmental toxicity

Description of key information

Oral: OECD 414, rat, NOAEL development ≥ 300 mg/kg bw/day
Oral: OECD 414, rat, NOAEL maternal systemic = 100 mg/kg bw/day

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

The available information comprises an adequate and reliable study, and is thus sufficient to fulfil the standard information requirements set out in Annex VIII-IX, 8.7, of Regulation (EC) No 1907/2006.

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

The potential of 3,5,5-trimethylhexyl 3,5,5-trimethylhexanoate to cause developmental toxicity was assessed in a prenatal developmental toxicity study performed according to OECD guideline 414 and under GLP conditions (Fabreguettes, 2000). 10 pregnant dams/dose were administered 30, 100 and 300 mg/kg bw/day in corn oil by gavage during gestation day 6 to 17. On day 20 of gestation the animals were euthanized and examined. No treatment-related systemic effects were observed in the P-females.

One female in the control group died, possibly due to a dosing error. In 1/10 dams in the high-dose group abdominal breathing and chromo rhinorrea were observed on gestation day 8 to 11, indicating poor health condition. The female that showed clinical signs of toxicity also had a body weight loss of approximately 10% from gestation day 6 to 12. For females in the high-dose group the body weight was significantly reduced on day 15 and 18. The body weight gain in the high-dose group was significantly reduced during gestation day 6 to 18, while total body weight gain was approximately 25% lower than in the control group. The food consumption was reduced in the high-dose group on gestation day 6-18, compared with the control group, although not statistically significant. In the female exhibiting clinical signs, a brownish content of the uterus and dilatation of the cervix was observed, but the toxicological relevance of this finding is unclear. No other treatment-related effects were noted. The NOAEL for systemic effects in the dams is considered to be 100 mg/kg bw/day.

There was no significant effect on the fertility index, corpora lutea, resorptions, pre-implantation loss, fetal viability (in utero), gravid uterus weight and number of fetuses. The slight, not significant, increase in resorptions and pre-implantation losses observed in the high-dose group is attributable to a single female that was in poor health (14/37 pre-implantation losses). All the results were within the historical data range. The slight changes observed are therefore not considered to be an adverse reproductive effect.

There were no significant differences between the control and treatment pups in the developmental parameters (post-implantation loss, embryo survival, body weight, sex ratio, viability). The slight, not significant, increase in post-implantation losses (7/12) observed in the high-dose group is attributable to a single female that was in poor health. This is considered to be a consequence of the poor maternal health condition and is not a reproductive effect. The incidence of malformations and variations in the offspring was comparable between the control and treatment groups. The NOAEL for developmental toxicity and teratogenicity was set at ≥ 300 mg/kg bw/day.

Based on the available data 3,5,5-trimethylhexyl 3,5,5-trimethylhexanoate is considered to be not toxic to development.

Justification for selection of Effect on developmental toxicity: via oral route:
The key GLP-compliant study performed similar to OECD guideline 414 was selected.

Justification for classification or non-classification

The available data on toxicity to reproduction does not meet the classification criteria according to Regulation (EC) 1272/2008 or Directive 67/548/EEC, and is therefore conclusive but not sufficient for classification.

An OECD Guideline 414 study will not provide evidence for definite claims of no fertility effects. However, since no adverse effects on reproduction and development was noted up to and including the highest dose level of 300 mg/kg bw/day, the conclusion of no classification (conclusive but not sufficient for classification) is considered to be justified.