Fatty acids, C16-18, 1,2-ethanediylbis(oxy-2,1-ethanediyl) esters

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: 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 substance with similar structure and intrinsic properties. Read-across is justified based on common functional group(s), common precursors and breakdown products and similarities in PC/ECO/TOX 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 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 reproduction toxicity of Fatty acids, C16-18, 1,2-ethanediylbis(oxy-2,1-ethanediyl) esters (3EO) (CAS 91031-45-7). 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 is 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
91031-45-7	C16-18, 1,2-ethanediylbis(oxy-2,1-ethanediyl) esters (3EO)	388.58 - 683.1	RA: CAS 853947-59-8
853947-59-8	Butylene glycol dicaprylate / dicaprate	342.52-398.63	NOAEL: 1000 mg/kg bw/day

 

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 Fatty acids, C16-18, 1,2-ethanediylbis(oxy-2,1-ethanediyl) esters (3EO) (CAS 91031-45-7).

A detailed analogue approach justification is provided in the technical dossier (see IUCLID Section 13).

Discussion

Since no studies are available investigating the toxicity to reproduction of Fatty acids, C16-18, 1,2-ethanediylbis(oxy-2,1-ethanediyl) esters (3EO) (CAS 91031-45-7), the available data for the structurally related analogue substanceButylene glycol dicaprylate / dicaprate (CAS 853947-59-8) was considered for assessment and read-across is conducted based on an analogue approach.

Butylene glycol dicaprylate / dicaprate was tested for toxicity to reproduction in a two-generation reproduction toxicity study according to OECD 416 in compliance with GLP (Cordts, 2005). Groups of 20 CD® / Crl:CD® rats per sex and dose were given 100, 300 and 1000 mg/kg bw/day by gavage. Males were given the test material daily for 10 weeks until mating and 2 weeks during mating. Females were treated in the same way and additionally approximately 3 weeks during pregnancy and 3 weeks during lactation. A concurrent negative control group receiving the vehicle corn oil only was included in the testing, as well. Examination of the parental animals revealed no clinical signs of toxicity or mortality in relation to the test substance. Furthermore, no influence was noted on body weight and body weight gain of the males during the pre-mating and mating period. Statistically significant differences in body weight gain in females were observed but were not considered to be test item-related. No influence on food consumption or food efficiency was noted in parental males during the premating period and in females during the premating, gestation and lactation period at any of the tested dose levels. In male animals of the parental F0 and F1 generation, examination showed no test-item related influence on the male fertility period, sperm number, viability and morphology within the treated groups. In female animals, no test item-related influence on female fertility indices and on the number or the length of the oestrous cycles was observed at any of the tested dose levels during the pre-mating and the mating period and no test item-related difference was noted for the number of abnormal cycles between the treated groups and the control group. However, in females of the high-dose group (F0) an increased but not dose-related post-implantation loss was observed. The value of post-implantation loss was slightly out of the range of the historical control data and was not considered to be of toxicological relevance. Furthermore, in the high-dose group a marginally and not dose-related increased prolonged gestation length was observed (21.8 days compared to 21.2 days of the control group). Post-implantation loss and gestation length in F1 females were not influenced as in the F0 females. No further effects on reproductive performance of F0 and F1 animals were observed and evaluation of the pre-coital time showed no test-item related influence in parental animals, either. Moreover, no deficiencies in maternal care of the parental animals were noted. The macroscopic examination at necropsy revealed no substance-related differences in the organs, absolute and relative organ weights and tissues of the parental animals. Histopathological examination revealed no morphological changes which were considered to be test item-related. Examinations of the F1 and F2 offspring showed no effects on the mean and total litter weight and no effects on the physical development of the F1 offspring were noted. The anogenital distance in the F2 pups was not influenced by the test substance. At necropsy, no substance-related differences were noted between control and treated animals in the organs or tissues of the selected animals. Furthermore, the absolute and relative organ weights of male and female F1 and F2 pups was not influenced. Functional tests showed no test item-related differences in the functional development of the F1 offspring.

In summary, under the conditions of the study, the substance had no effect on reproductive performance and the NOAEL for reproduction toxicity of the parental and the F1 and F2 generations is considered to be above 1000 mg/kg bw/day (m, f).

Conclusion for toxicity to reproduction

One study with Butylene glycol dicaprylate / dicaprate (CAS 853947-59-8) is available. The substance had no effect on reproductive performance and the NOAEL for reproduction toxicity of the parental and the F1 and F2 generations was considered to be above 1000 mg/kg bw/day (m, f).

A detailed reference list is provided in the technical dossier (see IUCLID, section 13) and within CSR.

Short description of key information:
NOAEL oral (fertility): ≥ 1000 mg/kg bw/day (OECD 416, GLP)

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 and overall assessment of quality, duration and dose descriptor level (refer to the endpoint discussion for further details).

Effects on developmental toxicity

Description of key information

NOAEL oral (developmental): ≥ 900 mg/kg bw/day (OECD 414, GLP)

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

The available information comprises adequate, reliable (Klimisch score 2) studies from reference substances with similar structure and intrinsic properties. Read-across is justified based on common origin, common precursors and breakdown products of hydrolysis and consistent trends in environmental fate, ecotoxicological and toxicological profile (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 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 on the developmental toxicity of Fatty acids, C16-18, 1,2-ethanediylbis(oxy-2,1-ethanediyl) esters (3EO) (CAS 91031-45-7). 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 is 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 developmental toxicity

CAS #	Chemical name	Molecular weight	Developmental toxicity
91031-45-7	C16-18, 1,2-ethanediylbis(oxy-2,1-ethanediyl) esters (3EO)	388.58 - 683.1	WoE: RA: CAS 853947-59-8 RA: CAS 85883-73-4 RA: CAS 68583-51-7 RA: CAS 91031-31-1
68583-51-7	Decanoic acid, mixed diesters with octanoic acid and propylene glycol	328.49 - 384.59	NOAEL: ≥ 1000 mg/kg bw/day
91031-31-1	Fatty acids, C16-18, esters with ethylene glycol	300.48 – 563.00	NOAEL: ≥ 900 mg/kg bw/day
853947-59-8	Butylene glycol dicaprylate / dicaprate	342.52 – 398.63	NOAEL: ≥ 1000 mg/kg bw/day
85883-73-4	Fatty acids, C6-12, esters with propylene glycol	202.29 – 440.71	NOAEL: ≥ 2500 mg/kg bw/day

 

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 Fatty acids, C16-18, 1,2-ethanediylbis(oxy-2,1-ethanediyl) esters (3EO) (CAS 91031-45-7).

A detailed analogue approach justification is provided in the technical dossier (see IUCLID Section 13).

Discussion

Since no studies are available investigating the developmental toxicity of Fatty acids, C16-18, 1,2-ethanediylbis(oxy-2,1-ethanediyl) esters (3EO) (CAS No 91031-45-7), to the available data for the structurally related analogue substances Fatty acids, C16-18, esters with ethylene glycol (CAS No 91031-31-1), Decanoic acid, mixed diesters with octanoic acid and propylene (CAS No 68583-51-7), Fatty acids, C6-12, ester with propylene glycol (CAS 85883-73-4) andButylene glycol dicaprylate / dicaprate (CAS No 853947-59-8) was considered for assessment and read-across is conducted based on an analogue and weight of evidence approach.

The four prenatal developmental toxicity studies were conducted according to OECD 414 in compliance with GLP (Pittermann, 1997, 1994; Cicalese, 2007; Bowman, 2007).

Groups of 24 or 25 female Sprague Dawley rats per treatment group were orally dosed with the respective test compound via gavage at doses from 100 – 2500 mg/kg bw/day from Day 6-15, Day 6-17 or Day 6-19 post mating. The highest applied dose of Fatty acids, C16-18, esters with ethylene glycol was 900 mg/kg bw/day. Concurrent negative control groups receiving the vehicle only were included in all tests.

In all studies, no maternal mortality occurred and no substance-related clinical signs of toxicity were observed. Body weight and body weight gains and gravid uterine weights were unaffected. Furthermore, at scheduled necropsy no macroscopic changes were noted in maternal animals. No compound-related differences were observed in pre-and post-implantation loss, embryonic deaths, mean numbers of resorptions and total fetuses of the test groups in comparison to the control groups with the four test materials. The fetal sex ratio was not affected by treatment and no treatment-related fetal abnormalities or malformations, skeletal and visceral variations were found at necropsies.

In the study with Decanoic acid, mixed diesters with octanoic acid and propylene, mean fetal placental and body weights of live fetus exhibited no significant differences between treatment and control group. Skeletal ossification showed in the low- and high-dose treatment groups one fetus each with incomplete ossified skull bones and additionally one fetus in the high-dose group with non-ossified skull bones. In the control group, 12 fetuses showed incomplete ossified skull bones and 6 fetuses showed non-ossified skull bones as well. Thus, the number of incomplete- and non-ossified skull bones was decreased in the treatment groups in comparison to the control group and the findings were considered to be incidental and therefore not treatment-related.

In the study with Fatty acids, C16-18, esters with ethylene glycol, the mean weight of live male and female fetuses in the mid-dose group was significantly increased, whereas the weights of live fetuses of the other treatment groups exhibited no significant differences. The figures of skeletal ossifications and variations showed no treatment-related deviations; thus various findings, all without dose-relationship, were considered to be incidental.

In the limit test with Butylene glycol dicaprylate / dicaprate, fetuses of the treatment group showed a slight but statistically significant lower mean fetal weight when compared to the control group but being within the historical control data for this rat strain. Three small fetuses were observed in the control and treatment group and one control fetus and one fetus of the treated group showed multiple anomalies. These changes were considered incidental. Furthermore, spontaneous changes at skeletal examination of the fetuses were noted between the treated and the control group. Visceral examination of fetuses showed unilateral cryptorchidism in two fetuses from two different litters of the treated group. The identification of the same stock male being mated with these two females gave rise to the hypothesis that the male parent could genetically transmit the finding. In addition, considering also the high presence of displaced testes in the control group, the findings described were considered evidence of spontaneous pathology, often seen in this species under the experimental conditions.

Animals dosed with Fatty acids, C6-12, ester with propylene glycol showed a slightly lower food consumption in the high-dose group (2500 mg/kg bw/day). This finding was not considered to be adverse based on the lack of an effect on mean body weights. Fetal malformations and developmental variations, when observed in treatment groups, occurred infrequently or at a frequency similar to that in the control group and did not occur in a dose-related manner or were within the historical control data ranges.

Conclusion for developmental toxicity

Four studies investigating the developmental toxicity are available from structurally related analogue substances. The studies from Fatty acids, C16-18, esters with ethylene glycol (CAS 91031-31-1), Decanoic acid, mixed diesters with octanoic acid and propylene (CAS 68583-51-7), Butylene glycol dicaprylate / dicaprate (CAS 853947-59-8) and Fatty acids, C6-12, ester with propylene glycol (CAS 85883-73-4) did not show treatment-related effects up to the highest tested dose level. Thus, no hazard for developmental toxicity was identified and a NOAEL for developmental toxicity is considered to be above the highest dose level (≥ 900 mg/kg bw/day (m, f)).

A detailed reference list is provided in the technical dossier (see IUCLID, section 13) and within CSR.

Justification for selection of Effect on developmental toxicity: via oral route:
Hazard assessment is based on the weight of evidence from all available studies.

Justification for classification or non-classification

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