Isooctadecyl isooctadecanoate

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

300 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

The available information comprises an adequate and reliable study (Klimisch score 2) from a reference substance 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 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 isooctadecyl isooctadecanoate (CAS 41669-30-1). 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 to avoid the need to test every substance for every endpoint.).

 

Overview of toxicity to reproduction

CAS	Chemical name	Molecular weight	Toxicity to reproduction – Fertility
41699-30-1	isooctadecyl isooctadecanoate	536.95	RA: CAS 59231-34-4
59231-34-4	Isodecyl oleate	422.73	Experimental result: NOAEL = 300 mg/kg bw/d

The above mentioned substances are considered to be similar to each other based on structurally similar properties and/or activities. Therefore, the available data on the source substance has been read-across to isooctadecyl isooctadecanoate (CAS 41669-30-1).

The target substance is characterized as an UVCB substance comprised of a branched C18 fatty acid esterified with an aliphatic, but branched C16 and C18 alcohol. The source substance is structurally very similar to the target substance. Isodecyl oleate (CAS 59231-34-4) is an UVCB substance consisting of oleic acid esterified with a branched alcohol (decanol). A detailed analogue approach justification is provided in the technical dossier (see IUCLID Section 13).

CAS 59231-34-4

A combined repeated dose toxicity and reproduction/developmental toxicity screening study (according to OECD 422 under GLP conditions) was performed with isodecyl oleate (Hansen, 2013). 10 rats/sex/dose were administered 100, 300 and 1000 mg/kg bw/day isodecyl oleate once daily for 36 days (males) and up to 54 days (females) via gavage. The application started two weeks before mating on test day one and ended on the day or one day before sacrifice. Day of sacrifice was on test Day 36 for the male rats and on lactation Day 4 or shortly thereafter for the female rats. The dose levels in the main study are based on the results of the dose range-finding study, in which 5 rats/sex/dose were administered 100, 300 and 1000 mg /kg bw/day isodecyl oleate for a period of 14 days. No mortality occurred in the parental generation and no clinical signs were observed during the study period. The body weight and food consumption was comparable between the control group and treatment groups in the low and medium dose groups, in the high dose group however, a reduction in body weight and food consumption was seen in female only, indicating maternal toxicity at a dose level of 1000 mg/kg bw/d. No substance-related findings were noted at necropsy, which also included the macroscopic examination of the appearance and size of the gonads, adrenal glands, uterus, and accessory reproductive organs. However, changes in reproduction parameters of the dam and in the development of pups were seen in the high dose females and their offspring, respectively. A statistically significant increase in post implantation loss was noted as well as a non-statistically significant decrease in the birth index. The observed elevated number of stillbirths led to a statistically significant reduction in the live birth index. No test item related influence was noted for the fertility index, the gestation index and the pre-implantation loss. The qualitative sperm staging revealed no test item related spermatogenic changes. Furthermore, a statistically significant decrease in the viability index of the pups of high dose dams was seen and a non-statistically significant decrease in mean litter weight of the pups and in total litter weight per dam. No visible gross abnormalities were detected in the pups. No test item related changes in any of the parameters assessed were seen in controls, low or mid dose groups. The NOAEL for reproduction and development was 300 mg/kg bw/day in this screening study, the NOAEL for systemic toxicity of the males was ≥ 1000 mg/kg bw/day, for the females however the NOAEL for systemic toxicity was 300 mg/kg bw/day because of maternal toxicity observed at the highest dose group (1000 mg/kg bw/d). Thus, the effects observed in the pups were not related to be adverse due to the maternal toxicity at the highest dose level.

Conclusions for reproductive toxicity 

Based on read-across data, sufficient evidence is available to conclude that the substance isooctadecyl isooctadecanoate(CAS 41669-30-1) has no toxic effects to reproduction.

Short description of key information:
Oral (OECD 422), rat: NOAEL (fertility) = 300 mg/kg bw/d
Oral (OECD 422), rat: NOAEL (systemic) = 300 mg/kg bw/d

Justification for selection of Effect on fertility via oral route:
Hazard assessment is conducted by means of read-across from a structural analogue. 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 (refer to the endpoint discussion for further details).

Effects on developmental toxicity

Description of key information

Oral (OECD 422), rat: NOEAL (developmental) = 300 mg/kg bw/d
Prenatal developmental toxicity study (OECD 414), rat, oral:
NOAEL teratogenicity (F1) ≥ 1000 mg/kg bw/day

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

300 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

The available information comprises adequate, reliable (Klimisch score 2 due to read-across) and consistent studies from reference substances with similar structure and intrinsic properties (refer to endpoint discussion for further details). The available studies are sufficient to fulfil the standard information requirements set out in Annex VIII-IX, 8.6, in accordance with Annex VIII, 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 data available on developmental toxicity of isooctadecyl isooctadecanoate (CAS 41669-30-1). 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 to avoid the need to test every substance for every endpoint).

 

Overview of developmental toxicity/teratogenicity

 

 

CAS	Chemical name	Molecular weight	Developmental toxicity
41669-30-1	isooctadecyl isooctadecanoate	536.95	RA: CAS 868839-23-0 + CAS 59231-34-4
868839-23-0	Propylheptyl octanoate	284.48	Experimental result (OECD 408): NOAEL = ≥ 1000 mg/kg bw/d
59231-34-4	Isodecyl oleate	422.73	Experimental result (OECD 422): NOAEL = 300 mg/kg bw/d

 

The target substance and all source substances are considered to be similar on the basis of the structural similar properties and/or activities. The available endpoint information on the source substances is used to predict comparable results for the target substance isooctadecyl isooctadecanoate (CAS 41669-30-1).

The target substance is characterized as an UVCB substance comprised of a branched C18 fatty acid esterified with an aliphatic, but branched C16 and C18 alcohol. The source substances are structurally similar to the target substance. Isononanoic acid, C16-18 alkyl esters (CAS 111937-03-2) is a UVCB substance consisting of isononanoic acid esterified with C16-18 alcohol. Isodecyl oleate (CAS 59231-34-4) is an UVCB substance consisting of oleic acid esterified with a branched alcohol (decanol). A detailed analogue approach justification is provided in the technical dossier (see IUCLID Section 13).

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 (similar to OECD guideline 414) (Pitterman, 1997). 23-24 pregnant female Sprague-Dawley rats/dose level were administered 100, 300 and 1000 mg/kg bw/day of the test substance by gavage on gestation Days 6 to 15. On Day 20 the females were euthanized and examined.

No treatment-related systemic effects were observed in the P-females. 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, foetal resorptions, live foetuses, dead foetuses) 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 6 ossified sternebrae in the 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 for developmental toxicity and teratogenicity was set at ≥ 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.

 

 

CAS 59231-34-4

 

A combined repeated dose toxicity and reproduction/developmental toxicity screening study (according to OECD 422 under GLP conditions) was performed (Hansen, 2013). 10 rats/sex/dose were administered 100, 300 and 1000 mg/kg bw/day isodecyl oleate once daily for 28 day (males) and up to 54 days (females) via gavage. The application started two weeks before mating on test day one and ended on the day or one day before sacrifice. Day of sacrifice was on test Day 36 for the male rats and on lactation Day 4 or shortly thereafter for the female rats. The dose levels in the main study are based on the results of the dose range-finding study, in which 5 rats/sex/dose were administered 100, 300 and 1000 mg /kg bw/day isodecyl oleate for a period of 14 days. No mortality occurred in the parental generation and no clinical signs were observed during the study period. The body weight and food consumption was comparable between the control group and treatment groups in the low and medium dose groups, in the high dose group however, a reduction in body weight and food consumption was seen in female’s only, indicating maternal toxicity at a dose level of 1000 mg/kg bw/d.

No substance-related findings were noted at necropsy, which also included the macroscopic examination of the appearance and size of the gonads, adrenal glands, uterus, and accessory reproductive organs. However, changes in reproduction parameters of the dam and in the development of pups were seen in the high dose females and their offspring, respectively. A statistically significant increase in post implantation loss was noted as well as a non-statistically significant decrease in the birth index. The observed elevated number of stillbirths led to a statistically significant reduction in the live birth index. In detail, 5 pups of the control group died during the lactation period, 2 of the low dose group, none of the intermediate dose group and 30 of the high dose group, leading to a viability index of 71.3% (control group: 98.3%) The high number of dead pups in the high dose group was limited to 2 dams with no surviving pups on lactation day 4 (3 pups of one dam died early after birth, 10 pups were cannibalized on lactation day 4 and 11 pups of the other dam were found dead without milk on lactation day 2) Severe signs of maternal toxicity were seen in those two dams during the administration period of the test material. No visible gross abnormalities were detected in the pups. No test item related changes in any of the parameters assessed were seen in controls, low or mid dose groups. No test item related influence was noted for the fertility index, the gestation index and the preimplantation loss. Furthermore, a statistically significant decrease in the viability index of the pups of high dose dams was seen and a non-statistically significant decrease in mean litter weight of the pups and in total litter weight per dam. No visible gross abnormalities were detected in the pups. No test item related changes in any of the parameters assessed were seen in controls, low or mid dose groups. The NOAEL for reproduction and development was 300 mg/kg bw/day in this screening study, the NOAEL for systemic toxicity of the females was 300 mg/kg bw/day as well, because of maternal toxicity observed at the highest dose group (1000 mg/kg bw/day). Thus, the effects observed in the pups were not considered to be adverse due to the maternal toxicity at the highest dose level.

Conclusions for developmental toxicity 

Based on read-across data, sufficient evidence is available to conclude that the substance isooctadecyl isooctadecanoate(CAS 41669-30-1) 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 structural analogues. All available studies are adequate and reliable based on the identified similarities in structure and intrinsic properties between the source and target substances and overall quality assessment (refer to the endpoint discussion for further details). The study with the lowest dose descriptor was chosen for chemical safety assessment.

Justification for classification or non-classification

Based on read-across from 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.