Isooctadecyl pivalate

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

Reproductive toxicity study, rat: NOAEL fertility = 6000 mg/kg bw/day (males and females) (read-across)

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

6 000 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

The available information comprises an adequate, reliable (Klimisch score 2) study from a reference substance with similar structure and intrinsic properties. Read-across is justified based on common precursors and breakdown products of hydrolysis and consistent trends in environmental fate, ecotoxicological and toxicological profile (refer to the endpoint discussion for further details).
The selected study is thus sufficient to fulfil the standard information requirements set out in Annex VIII-IX, 8.7, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006.

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

Justification for read-across

There are no data on the reproduction toxicity of Isooctadecyl pivalate (CAS 58958-60-4). The assessment was therefore based on studies conducted with analogue (source) substances as part of a read-across approach, which is in accordance with Regulation (EC) No. 1907/2006, Annex XI, 1.5. For each specific endpoint the source substance(s) structurally closest to the target substance is/are chosen for read-across, with due regard to the requirements of adequacy and reliability of the available data. Structural similarities and similarities in properties and/or activities of the source and target substance are the basis of read-across. A detailed justification for the analogue read-across approach is provided in the technical dossier (see IUCLID Section 13).

Toxicity to reproduction

CAS 123-95-5

A non-guideline reproduction/developmental toxicity study was performed with Butyl stearate (Smith, 1953). 20 Sprague-Dawley rats/sex were administered 6.25% butyl stearate in the diet (equivalent to approx. 6000 mg/kg bw/day) for a period of 10 weeks prior to mating. Control animals (12 males and 12 females) were fed with the concurrent diet. After 10 weeks animals were mated. The date of parturition and the number and sex of pups in each litter were recorded. Litters were weaned 21 days postpartum and the weights of the weanlings determined. From each of the control and treatment groups, 24 males and 24 females were chosen at random and fed the same 6.25% diet as had been ingested by their parents for 21 days. Diet intake and body weights were recorded daily; 21 days after weaning, the rats were sacrificed and necropsies were performed. No effects on the fertility index and other fertility parameters were noted. The results of the developmental parameters (litter size, viability index, sex ratio) were comparable between the control and treatment groups. The NOAEL for parental fertility was considered to be approximately 6000 mg/kg bw/day.

CAS 111-62-6

A 90-day oral feeding study (Bookstaff, 2004) was performed with Ethyl oleate according to the 1993 FDA draft "Redbook II" guidelines (Toxicological Principles for the Safety Assessment of Direct Food Additives and Color Additives Used in Food). The study was performed according to OECD guideline 408 (repeated dose 90-day oral toxicity in rodents) with additional assessment of oestrus cycle and sperm parameters. Ethyl oleate was administered at levels of 0, 3.3, 6.7 and 10% (equivalent to an average of 0, 1900, 3800 and 6000 mg/kg bw/day) via the diet to 20 rats/sex/dose. All diets were calorie- and fat-matched using high oleic safflower oil (HOSO) as the control fat. There were no toxicologically significant findings in any of the measured parameters (clinical observations, body weight gains, appearance of the faeces, ophthalmic examinations, haematology, clinical chemistry, urinalysis, organ weights and histopathology). The NOAEL systemic was approximately 5500 mg/kg bw/day in female and 6100 mg/kg bw/day in male rats.

The results of the examination of reproductive tissues/organs (histologic examinations of the epididymides, mammary gland, ovaries, prostate, seminal vesicles, testes, thyroid with parathyroid, uterus with uterine horns and vagina) and reproductive parameters assessed (oestrus cycle, and sperm motility, count and morphology) were comparable between the control and treatment groups. The NOAEL reproduction (fertility) was found to be approximately 5500 mg/kg bw/day in female and 6100 mg/kg bw/day in male rats.

Overall conclusion for effects on fertility

There are no available studies on the toxicity to reproduction and fertility of Isooctadecyl pivalate.

In a 13-week repeated dose toxicity study performed with the target substance, 10 rats/sex/dose were administered 0, 1.0, 2.0 and 4.0 mL/kg bw (equivalent to 0, 865, 1730 and 3460 mg/kg bw/day, based on a density of 0.865 g/mL) of the undiluted test substance, once daily via gavage for a period of 13 weeks. It was shown that the weight of the testes and uterus of the rats was comparable between the treatment and control animals, and no adverse effects were observed on the testes and uterus during the macroscopic and microscopic examination. The NOAEL reproduction (fertility) was found to be ≥ 3460 mg/kg bw/day in rats. Moreover, no hazard to reproduction was identified in a subchronic repeated dose toxicity study and a non-guideline reproduction toxicity study, both performed with analogue substances. Based on the available data and following the analogue approach, the target substance Isooctadecyl pivalate is not considered to affect fertility.

Effects on developmental toxicity

Description of key information

Prenatal developmental toxicity (OECD 414), rat: NOAEL development ≥ 1000 mg/kg bw/day
Prenatal developmental toxicity (OECD 414), rat: NOAEL systemic ≥ 1000 mg/kg bw/day

Link to relevant study records

Reference

Endpoint:

developmental toxicity

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reason / purpose for cross-reference:

read-across source

Key result

Dose descriptor:

NOAEL

Remarks:

maternal toxicity

Effect level:

1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

other: No adverse and treatment-related effects observed up to and including the highest tested dose level.

Key result

Dose descriptor:

NOAEL

Remarks:

teratogenicity

Effect level:

1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No adverse and treatment-related effects observed up to and including the highest tested dose level.

Key result

Developmental effects observed:

no

An additional study with CAS 91031480 was taken into account for the evaluation of the inauterine development. Since no adverse and treatment-related effects were observed, the NOAEL developmental and systemic are considered to be ≥ 1000 mg/kg bw/day, the highest tested dose level.

Conclusions:

No adverse effects on inauterine development were observed in the available studies with the source substances CAS 111937-03-2 and CAS 91031-48-0. Applying the read-across approach similar results are expected for the target substance CAS 58958-60-4.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

The available information comprises an adequate, reliable (Klimisch score 1) study from a reference substances with similar structure and intrinsic properties. Read-across is justified based on common precursors and breakdown products of hydrolysis and consistent trends in environmental fate, ecotoxicological and toxicological profile (refer to the endpoint discussion for further details).
The selected study is thus sufficient to fulfil the standard information requirements set out in Annex VIII-IX, 8.7, 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 read-across

There are no available data on the reproduction toxicity of Isooctadecyl pivalate (CAS 58958-60-4). The assessment was therefore based on studies conducted with analogue (source) substances as part of a read-across approach, which is in accordance with Regulation (EC) No. 1907/2006, Annex XI, 1.5. For each specific endpoint the source substance(s) structurally closest to the target substance is/are chosen for read-across, with due regard to the requirements of adequacy and reliability of the available data. Structural similarities and similarities in properties and/or activities of the source and target substance are the basis of read-across. A detailed justification for the analogue read-across approach is provided in the technical dossier (see IUCLID Section 13).

Developmental toxicity/teratogenicity

CAS 111937-03-2

The potential of Isononanoic acid, C16-18 alkyl esters (CAS 111937-03-2) to cause developmental toxicity was assessed in a prenatal developmental toxicity study performed using a study protocol similar to OECD guideline 414 under GLP conditions (Henkel, 1997). 23-24 pregnant female Sprague-Dawley rats/dose level were administered 0, 100, 300 and 1000 mg/kg bw/day of the test substance by gavage on gestation Day 6 to 15. No signs of systemic toxicity were observed in the P-females and no treatment-related effects were observed. One female in the high-dose group had blood in the uterine horn, but this is not considered to be treatment-related as no related effects were observed. One female in each of the control group and the low-dose group did not become pregnant, while all the pregnant females had viable foetuses. No treatment-related effects on the reproductive parameters (number of corpora lutea, implantation sites, pre-implantation loss, post-implantation loss, embryonic deaths, embryonic resorptions) were observed. Furthermore, the results of the developmental parameters (foetal resorptions, live foetuses, dead foetuses, body weight, placental weight, sex ratio) were comparable between the control and treatment groups. The external examination of the F1-foetuses did not reveal any treatment-related macroscopic findings. The skeletal examination showed a statistically significant increase in the number of foetuses with 6 ossified sternebrae in the mid-dose group (300 mg/kg bw/day). As there were no increases in ossification anywhere else and no overall increase in abnormal findings for this group, the result is considered to be incidental. The NOAEL developmental is considered to be ≥ 1000 mg/kg bw/day.

CAS 91031-48-0

A prenatal developmental toxicity study was performed with Fatty acids, C16-18, 2-ethylhexyl esters using a study protocol similar to OECD guideline 414 under GLP conditions (Henkel, 1994). 24 pregnant female Sprague-Dawley rats/dose level were administered 0, 100, 300 and 1000 mg/kg bw/day of the test substance by gavage on gestation Day 6 to 15. No signs of systemic toxicity were observed in the P-females and no treatment-related effects were observed. One female in the high-dose group did not become pregnant, which is considered to be an incidental occurrence. No treatment-related effects on the reproductive parameters (number of corpora lutea, implantation sites, pre-implantation loss, post-implantation loss, embryonic deaths, embryonic resorptions) were observed. Furthermore, the results of the developmental parameters (foetal resorptions, live foetuses, dead foetuses, body weight, placental weight, sex ratio) were comparable between the control and treatment groups. The external examination of the F1-foetuses did not reveal any treatment-related macroscopic findings. The increase in the number of offspring with single, non-ossified sternebrae was significant in the low-, and high-dose groups, while the increase in the number of offspring with two non-ossified sternebrae was significant in the high-dose groups. However, the incidence of these retardations was within the range of variation for this strain. The NOAEL developmental is considered to be ≥ 1000 mg/kg bw/day.

The most recent version of OECD guideline 414, adopted in January 2001, stipulates that the dams should be dosed from implantation (gestation Day 0) to the day prior to scheduled caesarean section (around gestation day 19 for rats). The study was performed according to the previous version of OECD guideline 414, adopted in May 1981, which recommended exposure during organogenesis; gestation Day 6-15 for rats. The available data on repeated dose toxicity and developmental toxicity is of high quality and does not show treatment-related adverse effects at dose levels up to and including the highest dose of 1000 mg/kg bw/day, indicating that adverse effects are unlikely to occur in the period prior to Day 6 of gestation (Pitterman, 1993, 1997). Based on the available it is not considered necessary to perform an additional, dedicated, developmental toxicity study.

 

Overall conclusion fordevelopmental toxicity/teratogenicity

There are no available studies on the developmental toxicity and teratogenicity of Isooctadecyl pivalate. Therefore analogue read-across from two source substances was applied. The NOAEL values for developmental toxicity/teratogenicity were at the currently applied limit dose value of 1000 mg/kg bw/day. Therefore, no hazard to development was identified. Based on the available data and following the analogue approach, the target substance Isooctadecyl pivalate is not expected to cause adverse effects on intrauterine development.

Justification for classification or non-classification

According to Article 13 of Regulation (EC) No. 1907/2006 "General Requirements for Generation of Information on Intrinsic Properties of substances", information on intrinsic properties of substances may be generated by means other than tests e.g. from information from structurally related substances (grouping or read-across), provided that conditions set out in Annex XI are met. Annex XI, "General rules for adaptation of this standard testing regime set out in Annexes VII to X” states that “substances whose physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity may be considered as a group, or ‘category’ of substances. This avoids the need to test every substance for every endpoint". Since the analogue concept is applied to Isooctadecyl pivalate (CAS 58958-60-4), data will be generated from data for reference source substance(s) to avoid unnecessary animal testing. Additionally, once the analogue read-across concept is applied, substances will be classified and labelled on this basis.

Based on the analogue read-across approach, the available data on toxicity to reproduction does not meet the classification criteria according to Regulation (EC) 1272/2008 and is therefore conclusive but not sufficient for classification.