Registration Dossier

Administrative data

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

Short description of key information:

Toxicity to reproduction – fertility: no study available. Data on selected reproduction parameters will be provided in the proposed 90-day oral repeated dose toxicity study, which will be performed according to OECD 408. To assess the possible effect on reproduction and fertility, additional parameters will be included (extensive gross necropsy and detailed histopathology of male and female reproductive organs and tissues, and sperm parameters).

Effects on developmental toxicity

Description of key information

NOAEL developmental toxicity (rat, m/f) ≥ 300 mg/kg bw/day (based on read-across from CAS 59219-71-5)

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 (Klimisch score 2) from a reference substances with similar structure and intrinsic properties. Read-across is justified based on common functional groups, common precursors/breakdown products and similarities in physicochemical and toxicological properties (refer to endpoint discussion for further details). The selected study is thus sufficient to fulfil the standard information requirements set out in Annex VIII, 8.5, in accordance with Annex XI, 1.5, 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

Justification for grouping of substances and read-across

There are no data available for the developmental toxicity of isononyl isononanoate. In order to fulfil the standard information requirements set out in Annex IX, 8.7, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006, read-across from structurally related substances was conducted.

In accordance with Article 13 (1) of Regulation (EC) No 1907/2006, "information on intrinsic properties of substances may be generated by means other than tests, provided that the conditions set out in Annex XI are met.” In particular for human toxicity, information shall be generated whenever possible by means other than vertebrate animal tests, which includes the use of information from structurally related substances (grouping or read-across).

Having regard to the general rules for grouping of substances and read-across approach laid down in Annex XI, Item 1.5, of Regulation (EC) No 1907/2006 whereby substances may be predicted as similar provided that their physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity.

Overview of toxicity to reproduction – developmental toxicity

CAS

Chemical name

Molecular weight

Toxicity to reproduction – Developmental Toxicity

(previously 42131-25-9) (a)

Isononyl isononanoate

ca. 285

RA: CAS 59219-71-5

59219-71-5 (b)

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

284.48

Experimental result:
NOAEL ≥300 mg/kg bw/day

(a) The substance subject to registration is indicated in bold font.

(b) Reference (read-across) substances are indicated in normal font. Lack of data for a given endpoint is indicated by “--“.

The above mentioned substances are considered to be similar on the basis of the structural similar properties and/or activities. The available endpoint information is used to predict the same endpoints for isononyl isononanoate. A detailed analogue approach justification is provided in the technical dossier (see IUCLID Section 13).

 

Discussion

Toxicity to reproduction – (pre-natal) development

CAS 59219-71-5

A prenatal developmental toxicity study was performed according to OECD guideline 414, 3,5,5-trimethylhexyl 3,5,5-trimethylhexanoate (CAS 59219-71-5) (Fabreguettes, 2000). 10 female Sprague-Dawley rats/dose were administered the test substance in corn oil at dose levels of 0, 30, 100 and 300 mg/kg bw/day by gavage during gestation days 6 to 17. On day 20 of gestation the animals were euthanized and examined for maternal and fetal effects. One female in the control group died on gestation day 7 of unknown causes. In 1/10 females in the high-dose group, piloerection, abdominal breathing and chromorhinorrea were observed on gestation day 8 to 11, indicating a poor health condition. This animal also had a body weight loss of approximately 10% from gestation day 6 to 12, and during the histopathological examination a brownish content in the uterus was reported. The toxicological relevance of these findings is unclear. The body weight in females in the high-dose group was significantly reduced on day 15 and 18, and the body weight gain was significantly reduced from gestation day 2-20, compared with the control group. The food consumption was reduced by 8-15% (varying per treatment period) in the high-dose group during the treatment, compared with the control group, although not statistically significant. During the post-treatment period (GD 18-20), the food consumption was comparable between the control and treatment groups, indicating that the treatment affected the intake. The systemic maternal NOAEL was set at 100 mg/kg bw/day.

No treatment-related effects were seen on the number of corpora lutea, implantation sites, pre-implantation loss, post-implantation loss, embryonic deaths, embryonic resorptions, fetal resorptions, and live foetuses. The slight, but not significant, increase in resorptions, pre-implantation loss and post-implantation loss observed in the high-dose group is attributable to a single female in poor health. The female in the high-dose group that exhibited clinical signs and body weight loss, had several resorptions and dead fetuses. This is considered to be a consequence of the poor maternal health condition and is not a reproductive effect. All results were within the historical data range. The litter weights in the high-dose group pups were slightly, but not significantly reduced (9%) compared with the control group. This is attributed to the reduced maternal body weight. The examination of foetus litter size, sex ratio and abnormalities (external, head, soft tissue and skeletal abnormalities) showed no differences between the control group and treatment groups and no indications of teratogenic effects. The NOAEL for developmental toxicity and teratogenicity in rats for 3,5,5-trimethylhexyl 3,5,5-trimethylhexanoate was considered to be ≥ 300 mg/kg bw/day.

Conclusions for toxicity to reproduction (development)

No developmental toxicity data is available for isononyl isononanoate. A prenatal developmental toxicity study was performed according to OECD guideline 414 with the analogue substance 3,5,5-trimethylhexyl 3,5,5-trimethylhexanoate (CAS 59219-71-5) (Fabreguettes, 2000). Based on the results of this study, the maternal systemic NOAEL was set at 100 mg/kg bw/day due to effects on body weight. No effects were noted on maternal fertility or reproduction and no effects were seen on developmental parameters (foetus litter size and weights, sex ratio and abnormalities). Therefore, the oral NOAEL developmental/teratogenicity was considered to be ≥ 300 mg/kg bw/day.

Overall, the available data provide evidence that the substance isononyl isononanoate has no toxic effects on intrauterine development.


Justification for selection of Effect on developmental toxicity: via oral route:
Hazard assessment is conducted by means of read-across from a structural surrogate. The selected study is the most adequate and reliable study based on the identified similarities in structure and intrinsic properties between source and target substance and overall assessment of quality, duration and dose descriptor level (refer to the endpoint discussion for further details).

Justification for classification or non-classification

Based on read-across from the structurally similar substances, the available data on toxicity to reproduction do not meet the classification criteria according to Regulation (EC) 1272/2008 or Directive 67/548/EEC, and are therefore conclusive but not sufficient for classification.

There are no data available on toxicity to reproduction (fertility).