Isodecyl pivalate

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

- 90 day feeding study: NOAEL (fertility) approximately 5500 mg/kg bw/day for male and female rats (based on read across from CAS 111 -62 -6 and CAS 123 -95 -5)

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

The available information comprises adequate and reliable (Klimisch score 2) studies from 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 studies are 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 grouping of substances and read-across

There are no data available on the toxicity to reproduction of isodecyl pivalate (CAS 60209-82-7). 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

CAS	Chemical name	Molecular weight	Toxicity to reproduction – Fertility	Toxicity to reproduction – Developmental Toxicity
60209-82-7 (a)	Isodecyl pivalate	ca. 242	WoE: RA: CAS 111-62-6 RA: CAS 123-95-5	WoE: RA: CAS 91031-48-0 RA: CAS 123-95-5
111-62-6 (b)	Ethyl oleate	310.52	Experimental result: NOAEL ≥5500 mg/kg bw/day	--
123-95-5	Butyl stearate	340.59	Experimental result: NOAEL 6000 mg/kg bw/day	Experimental result: NOAEL 6000 mg/kg bw/day
91031-48-0	Fatty acids, C16-18, 2-ethylhexyl esters	368.65; 396.70	--	Experimental result: NOAEL≥1000 mg/kg bw/day

(a) Substances subject to the REACh Phase-in registration deadline of 31 May 2013 are indicated in bold font.

(b) Substances that are either already registered under REACh or not subject to the REACh Phase-in registration deadline of 31 May 2013 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 isodecyl pivalate (CAS 60209-82-7). A detailed analogue approach justification is provided in the technical dossier (see IUCLID Section 13).

 

Discussion

Toxicity to reproduction - fertility

CAS 111-62-6

A 90-day oral feeding study (WoE, Bookstaff, 2004) was performed with ethyl oleate (CAS 111-62-6) 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 408 (repeated dose 90-day oral toxicity in rodents) with additional assessment of oestrus cycle and sperm parameters. The purpose of the study was to determine the safety of ethyl oleate in a 91-day feeding study in Sprague-Dawley rats. 20 rats/sex/dose were administered ethyl oleate via the feed at levels of 0, 3.3, 6.7, and 10% by weight (approximately 0, 2000, 3900 and 6100 mg/kg bw/day in females, and 0, 1800, 3600 and 5500 mg/kg bw/day in males). All diets were calorie- and fat-matched, using high oleic safflower oil (HOSO) as the control fat. 1/20 low-dose males and 2/20 mid-dose died during the study, due to causes unrelated to the treatment. EO in the diet was well tolerated and there were no toxicologically significant findings in any of the systemic toxicity parameters (clinical observations, body weight gains, appearance of the faeces, ophthalmic examinations, haematology, clinical chemistry, urinalysis, organ weights, histopathology, or male and female reproductive assessments). No abnormalities were noted in the histopathological evaluation of oestrus cycle in females, sperm characterization in males and histologic examinations or reproductive organs/tissues (incl. epididymides, mammary gland, ovaries, prostate, seminal vesicles, testes, thyroid with parathyroid, uterus with uterine horns and vagina). The 90-day oral NOAEL for fertility was determined to be ethyl oleate as ≥ 10% of the dietary intake, which corresponds to approximately 5500 mg/kg bw/day.

CAS 123-95-5

A non-guideline reproduction/developmental toxicity study was performed with butyl stearate (CAS 123-95-5) by Smith (WoE, 1953). 20 male and female Sprague-Dawley rats received butyl stearate at a concentration of 6.25% in the diet, corresponding to approx. 6000 mg/kg bw/day for a period of 10 weeks. Negative control animals (12 males and females) were fed with the concurrent basal 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 three groups of weanlings (those receiving the test material and the controls), 24 males and 24 females were chosen at random and for the next 21 days, these F1-pups were fed the same 6.25% diet as had been fed to the P-generation. Diet intake and body weights were recorded daily. 21 days after weaning, the F1-rats were sacrificed and necropsies were performed. No effects were noted in any of the reproduction and fertility parameters.

The NOAEL for parental fertility and reproduction was found to be approximately 6000 mg/kg bw/day.

Conclusions for toxicity to reproduction (fertility)

As there are no studies available on the reproduction toxicity of isodecyl pivalate (CAS 60209-82-7), data from two feeding studies performed with the analogue substances ethyl oleate (CAS 111-62-6) and butyl stearate (CAS 123-95-5) was read-across to cover this endpoint (WoE, Bookstaff, 2004; WoE, Smith, 1954). No effects on fertility and reproduction was observed up to and including the highest tested dose level in the studies, resulting in an overall oral NOAEL of approximately 5500 mg/kg bw/day (10% of the dietary intake) in males and females, respectively.

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

Effects on developmental toxicity

Description of key information

Prenatal developmental toxicity study (OECD 414), rat, oral:
NOAEL teratogenicity (F1) ≥ 1000 mg/kg bw/day based on read-across from CAS 91031 -48 -0 and CAS 123 -95 -5

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

The available information comprises adequate and reliable (Klimisch score 2) studies 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-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 grouping of substances and read-across

There are no data available the toxicity to reproduction of isodecyl pivalate (CAS 60209-82-7). 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.

The read-across is based on the metabolism of isodecyl pivalate, in particular on the fact that the substance undergoes enzymatic ester hydrolysis resulting in the formation of isodecyl alcohol and pivalic acid. A detailed analogue approach justification is provided in the technical dossier (see IUCLID Section 13).

Overview of toxicity to reproduction

CAS	Chemical name	Molecular weight	Toxicity to reproduction – Fertility	Toxicity to reproduction – Developmental Toxicity
60209-82-7 (a)	Isodecyl pivalate	ca. 242	WoE: RA: CAS 111-62-6 RA: CAS 123-95-5	WoE: RA: CAS 91031-48-0 RA: CAS 123-95-5
111-62-6 (b)	Ethyl oleate	310.52	Experimental result: NOAEL ≥5500 mg/kg bw/day	--
123-95-5	Butyl stearate	340.59	Experimental result: NOAEL 6000 mg/kg bw/day	Experimental result: NOAEL 6000 mg/kg bw/day
91031-48-0	Fatty acids, C16-18, 2-ethylhexyl esters	368.65; 396.70	--	Experimental result: NOAEL≥1000 mg/kg bw/day

(a) Substances subject to the REACh Phase-in registration deadline of 31 May 2013 are indicated in bold font.

(b) Substances that are either already registered under REACh or not subject to the REACh Phase-in registration deadline of 31 May 2013 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 isodecyl pivalate (CAS 60209-82-7). A detailed analogue approach justification is provided in the technical dossier (see IUCLID Section 13).

 

Discussion

Toxicity to reproduction – (pre-natal) development

CAS 123-95-5

A non-guideline reproduction/developmental toxicity study was performed with butyl stearate (CAS 123-95-5) by Smith (WoE, 1953). 20 male and female Sprague-Dawley rats received butyl stearate at a concentration of 6.25% in the diet, corresponding to approx. 6000 mg/kg bw/day for a period of 10 weeks. Negative control animals (12 males and females) were fed with the concurrent basal 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 group and treatment group of weanlings 24 males and 24 females were chosen at random. For the next 21 days, these F1-pups were fed the same 6.25% diet as had been fed to the P-generation. Diet intake and body weights were recorded daily. 21 days after weaning, the F1-rats were sacrificed and necropsies were performed. No effects were noted on survival, no gross pathologic changes were observed in the F1-pups. The body weight was significantly reduced in the treatment group, however the absolute reduction in body weight was < 15% for males and females at weaning and <10% at termination of the study. Furthermore the standard deviation was large and no individual data was given. It is unclear whether the effect is toxicologically relevant. The LOAEL for developmental toxicity was found to be approximately 6000 mg/kg bw/day.

CAS 91031-48-0

The potential of Fatty acids, C16-18, 2-ethylhexyl esters (CAS 91031-48-0) to cause developmental toxicity was assessed in a study performed using a study protocol similar to OECD guideline 414 (WoE, BASF, 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 have viable foetuses, but this 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, fetal resorptions, live fetuses, dead foetuses, placental weight, uterus weight) were observed. 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 one non- ossified sternebrum in the low- and high-dose group. 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 results for the remaining offspring parameters (body weight, placental weight, sex ratio) were comparable between the control and treatment groups. 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 from analogue substances 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 (Bookstaff, 2004; Smith, 1954). Based on the available and expected data it is not considered necessary to perform an additional, dedicated, developmental toxicity study.

Conclusions for toxicity to reproduction (development)

As there were no available studies on the reproduction toxicity of isodecyl pivalate (CAS 60209-82-7), data from two studies performed with structurally related substances was used to cover this endpoint.

Ethyl oleate (CAS 123-95-5) was administered to female rats in the diet at 6.25% (approximately 6000 mg/kg bw/day) from 10 weeks before mating until weaning of the pups, while the pups received the same dose level for 21 days after weaning. No effects were noted on survival, no gross pathologic changes were observed in the F1-pups. The body weight was significantly reduced in the treated pups compared with control pups, although the absolute reduction in body weight was < 15% for males and females at weaning and <10% at termination of the study. The LOAEL for developmental toxicity was found to be approximately 6000 mg/kg bw/day. In a developmental toxicity study performed with Fatty acids, C16-18, 2-ethylhexyl esters (CAS 91031-48-0), using a protocol similar to OECD guideline 414, pregnant rats were administered the test substance from gestation day 6-15 (WoE, BASF, 1997). No effects on development (survival, body weight, sex ratio, external appearance, skeletal development) in the P1-pups were observed up to and including the highest dose level of 1000 mg/kg bw/day.

The overall NOAEL developmental is considered to be ≥ 1000 mg/kg bw/day. Therefore, no toxic effects on intrauterine development are expected to occur after exposure to isononyl isononanoate.

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, and are therefore conclusive but not sufficient for classification.