Fatty acids, C18-unsatd., dimers, hydrogenated, 2-ethylhexyl esters

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Study duration:

subacute

Species:

rat

Quality of whole database:

The available information comprises an adequate and reliable (Klimisch score 2) study from a reference substance with similar structure and intrinsic properties. Read-across is justified based on structural similarity between the source and target substances, the source substance being a product of the hydrolysis of the target substance.

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 only limited data available on toxicity to reproduction of Fatty acids, C18-unsatd., dimers, hydrogenated, 2-ethylhexyl esters (CAS 68440-06-2). In order to fulfil the standard information requirements set out in Annex VIII, 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 [g/mol]	Toxicity to reproduction	Developmental toxicity / teratogenicity
68440-06-2 (a)	Fatty acids, C18-unsatd., dimers, hydrogenated, 2-ethylhexyl esters	789	RA: CAS 61788-89-4	RA: CAS 104-76-7
61788-89-4 (b)	Fatty acids, C18-unsaturated, dimers	564	Experimental result: NOAEL (P) ≥ 1450/1692 (males/females) mg/kg bw/day; NOAEL (developmental toxicity) ≥ 1692 (males/females) mg/kg bw/day (rat)	--
104-76-7 (b)	2-ethylhexanol	130	--	Experimental result: NOAEL (maternal/developmental) = 191 (females/males) mg/kg bw/day (mouse)

(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 the possible hydrolysis products of Fatty acids, C18-unsatd., dimers, hydrogenated, 2-ethylhexyl esters. The available endpoint information is used to predict the same endpoints for Fatty acids, C18-unsatd., dimers, hydrogenated, 2-ethylhexyl esters (CAS 68440-06-2). A detailed analogue approach justification is provided in the technical dossier (see IUCLID Section 13).

Discussion

Effects on fertility

No data on toxicity to reproduction is available with Fatty acids, C18-unsatd., dimers, hydrogenated, 2-ethylhexyl esters (CAS 68440-06-2). Therefore, read across from the possible theoretically hydrolysis products 2-ethylhexanol (CAS 104-76-7) and Fatty acids, C18-unsaturated, dimers (CAS61788-89-4) was applied.

CAS 61788-89-4

A key reproduction/developmental toxicity screening test performed according to OECD TG 421 and in compliance with GLP with Fatty acids, C18-unsaturated, dimers (CAS 61788-89-4) is available (Clubb and Sutherland, 2004). Groups of 10 Sprague-Dawley rats of each sex per dose were administered doses of 200, 2000 and 20000 ppm with the diet corresponding to a test substance intake of 14.5, 147 and 1450 mg/kg bw/day and 16.5, 166 and 1692 mg/kg bw/day for males and females, respectively. Males were treated for at least 4 weeks, starting from 2 weeks prior to mating; females were treated for 2 weeks prior to mating, during mating and gestation until at least day 4 of lactation. The animals were monitored for clinical signs, body weight, food consumption, mating and litter performance. All animals were submitted to necropsy, which included weighing of testes and epididymides. Histopathology was conducted on male and female reproductive organs of the control and high dose group. The observed effects were limited to the 20000 ppm males and included slightly decreased body weight gain during the first week of treatment and an increased incidence of piloerection. However, weight gain for males at 20000 ppm was essentially similar to control animals for the rest of the study on weeks 2-4 and the incidence of piloerection lacked any dose-relationship. There were no effects on testes, epididymides and ovaries and on reproductive performance between control and test animals. The fertility index was 100% for males and females in all dose groups. A NOAEL (reproductive toxicity/fertility) of ≥ 1450 mg/kg bw/day and ≥ 1692 mg/kg bw/day for males and females, respectively, was determined based on no toxicologically significant effects at the highest dose tested. Moreover, a NOAEL (developmental toxicity) of ≥ 1692 mg/kg bw/day for both sexes was determined. The molecular weight ratio of Fatty acids, C18-unsaturated, dimers (MW 564.93 g/mol) and Fatty acids, C18-unsatd., dimers, hydrogenated, 2-ethylhexyl esters (MW 677.14 g/mol) is 1.12 (677.14/564.93). Thus, based on this molecular ratio factor the NAEL for Fatty acids, C18-unsatd., dimers, hydrogenated, 2-ethylhexyl esters (CAS 68440-06-2) was calculated to be 1624 and 1895 mg/kg bw/day for males and females, respectively (1450 mg/kg bw/day x 1.12; 1692 mg/kg bw/day x 1.12).

Short description of key information:
Reproduction/Developmental Toxicity Screening (OECD 421), rat NOAEL (parental) ≥ 1450/1692 mg/kg bw/day (males/females); NOAEL (developmental) ≥ 1692 mg/kg bw/day (males/females) (RA CAS 61788-89-4), corresponding NAEL (parental) = 2030/2368.8 mg/kg bw/day (males/females); NAEL (developmental) ≥ 2368.8 mg/kg bw/day (males/females) for Fatty acids, C18-unsatd., dimers, hydrogenated, 2-ethylhexyl esters

Justification for selection of Effect on fertility via oral route:
Hazard assessment is conducted by means of read-across from structural analogues/surrogates. The selected study is the most adequate and reliable study based on the identified similarities in structure and intrinsic properties between source and target substances and overall assessment of quality, duration and dose descriptor level.

Effects on developmental toxicity

Description of key information

Developmental toxicity (OECD 414), mouse NOAEL (maternal/developmental) = 191 mg/kg bw/day (RA CAS 104-76-7), corresponding NAEL = 1157.46 mg/kg bw/day for Fatty acids, C18-unsatd., dimers, hydrogenated, 2-ethylhexyl esters

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

191 mg/kg bw/day

Study duration:

subacute

Species:

mouse

Quality of whole database:

The available information comprises an adequate and reliable (Klimisch score 2) study from a reference substance with similar structure and intrinsic properties. Read-across is justified based on structural similarity between the source and target substances, the source substance being a product of the hydrolysis of the target substance.

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 only limited data available on toxicity to reproduction of Fatty acids, C18-unsatd., dimers, hydrogenated, 2-ethylhexyl esters (CAS 68440-06-2). In order to fulfil the standard information requirements set out in Annex VIII, 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	Developmental toxicity / teratogenicity
68440-06-2 (a)	Fatty acids, C18-unsatd., dimers, hydrogenated, 2-ethylhexyl esters	789	RA: CAS 61788-89-4	RA: CAS 104-76-7
61788-89-4 (b)	Fatty acids, C18-unsaturated, dimers	564	Experimental result: NOAEL (P) ≥ 1450/1692 (females/males) mg/kg bw/day; NOAEL (developmental toxicity) ≥ 1692 (females/males) mg/kg bw/day (rat)	--
104-76-7 (b)	2-ethylhexanol	130	--	Experimental result: NOAEL (maternal/developmental) = 191 (females/males) mg/kg bw/day (mouse)

(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 forFatty acids, C18-unsatd., dimers, hydrogenated, 2-ethylhexyl esters (CAS 68440-06-2). A detailed analogue approach justification is provided in the technical dossier (see IUCLID Section 13).

Discussion

Effects on developmental toxicity

No data on toxicity to reproduction is available with Fatty acids, C18-unsatd., dimers, hydrogenated, 2-ethylhexyl esters (CAS 68440-06-2). Therefore, read across from the possible theoretical hydrolysis product 2-ethylhexanol (CAS 104-76-7) and Fatty acids, C18-unsaturated, dimers (CAS61788-89-4) was applied.

CAS 104-76-7

A reliable key developmental toxicity study performed equivalent or similar to OECD TG 414 with 2-ethylhexanol (CAS 104-76-7) is available (Tyl, 1991). Groups of 28 CD-1 mice were treated with modified corn starch microcapsules in the diet continuously from 0 to day 17 of gestation with 0.009, 0.03 or 0.09% in feed corresponding to 17, 59 and 191 mg/kg/day of the test substance. No females died, delivered early or were removed from the study. Pregnancy rates were high and equivalent across all groups (93-96%), maternal weight change for the gestational (and treatment) period, gestation day 0-17, was unaffected, as was weight change corrected for gravid uterine weight and maternal organ weights and food consumption were also unaffected. There were no effects of exposure on the number of ovarian corpora lutea, or of uterine implantation sites (resorptions, dead fetuses or live fetuses) per litter. Live litter size and fetal body weight per litter (all fetuses, males or females) were equivalent across all groups. There were also no effects of treatment on the incidence of malformations (external, visceral, skeletal or total) or variations, whether expressed as number or percentage of fetuses per litter or of litters with one or more affected fetuses. Examination of individual fetal findings also indicated no specific malformations or variations with a dose-related incidence. In conclusion, the test material administered in the diet during gestation days 0-17 in CD1 mice at concentrations of 17, 59 and 191 mg/kg bw/day resulted in no maternal or developmental toxicity. Therefore, the NOAEL for developmental toxicity was considered to be 191 mg/kg bw/day. The molecular weight ratio of 2-ethylhexanol (MW 130.23 g/mol) and Fatty acids, C18-unsatd., dimers, hydrogenated, 2-ethylhexyl esters (MW 677.14 g/mol) is 5.19 (677.14/130.23). Thus, based on this molecular ratio factor the NAEL for Fatty acids, C18-unsatd., dimers, hydrogenated, 2-ethylhexyl esters (CAS 68440-06-2) was calculated to be 991.29 mg/kg bw/day (191 mg/kg bw/day x 5.19).

Justification for selection of Effect on developmental toxicity: via oral route:
Hazard assessment is conducted by means of read-across from structural analogues/surrogates. The selected study is the most adequate and reliable study based on the identified similarities in structure and intrinsic properties between source and target substances and overall assessment of quality, duration and dose descriptor level.

Justification for classification or non-classification

The available data on reproductive/developmental toxicity of Fatty acids, C18-unsatd., dimers, hydrogenated, 2-ethylhexyl esters do not meet the criteria for classification according to Regulation (EC) 1272/2008 and are therefore conclusive but not sufficient for classification.