Registration Dossier

NOAEL oral (fertility): 1000 mg/kg bw/day (OECD 416, GLP)

NOAEL oral (reproduction): 1000 mg/kg bw/day (OECD 422, GLP)

The hazard assessment is based on the data currently available. New studies with the registered substance and/or other member substances of the glycol esters category will be conducted in the future. The finalised studies will be included in the technical dossier as soon as they become available and the hazard assessment will be re-evaluated accordingly.

For further details, please refer to the category concept document attached to the category object (linked under IUCLID section 0.2) showing an overview of the strategy for all substances within the glycol esters category.

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.

Endpoint conclusion:

no study available

Endpoint conclusion:

no study available

The hazard assessment is based on the data currently available. New studies with the registered substance and/or other member substances of the glycol esters category will be conducted in the future. The finalised studies will be included in the technical dossier as soon as they become available and the hazard assessment will be re-evaluated accordingly.

For further details, please refer to the category concept document attached to the category object (linked under IUCLID section 0.2) showing an overview of the strategy for all substances within the glycol esters category.

Screening study

CAS 627-83-8

Ethylene distearate (octadecanoic acid, 1,2-ethanediyl ester; CAS No. 627-83-8, EC No. 211-014-3) was investigated for its reproductive and developmental toxicity in a combined repeated dose toxicity study with the reproduction / developmental toxicity screening test according to OECD guideline 422 under GLP conditions (Gotemba Laboratory, 2013). The test substance was administered orally by gavage to groups of Sprague-Dawley strain SPF rats (12 males and 12 females in mating groups and 10 females in non-mating groups (control and 1000 mg/kg groups only) at doses of 100, 300 and 1000 mg/kg bw/day in methylcellulose solution (0.5 w/v) as vehicle. Animals were treated as follows: Males were dosed for 14 days before mating, during the mating period until the day before necropsy (42 days in total). Females in the mating groups received the test substance for 14 days before mating, during the mating and gestation periods until day 4 of lactation (41 to 46 days in total) and females in the non-mating groups were treated for 42 days to examine the repeated dose toxicity and reproductive and developmental toxicity of the test substance. For 5 males in the mating group and 5 females in the non-mating group each in the control and 1000 mg/kg groups, a 14-day recovery period was provided to examine reversibility of the toxic changes.

To evaluate the reproductive toxicity of the test substance, parental animals were subjected to observation of oestrous cycle, mating, and delivery/lactation. Additional parameters related to repeated dose toxicity have also been assessed in the study and are reported in IUCLID section 7.5.

There were no toxicologically relevant treatment-related effects with respect to reproductive toxicity in parental animals. Based on the lack of relevant effects, the No-Observed-Adverse-Effect-Level (NOAEL) for toxicity to reproduction of ethylene distearate (CAS No. 627-83-8, EC No. 211-014-3) was established to be 1000 mg/kg bw/day.

Two-generation reproduction toxicity study

CAS 853947-59-8

Within the category of Glycol Esters, one study with Butylene glycol dicaprylate / dicaprate (CAS 853947-59-8) is available. The study of the category member was considered for assessment and read-across was conducted based on a category 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, 2005). Groups of 20 CD® / Crl:CD® rats per sex and dose were given 100, 300 and 1000 mg/kg bw/day of the test material by gavage. Males were given the test material daily for 10 weeks until mating and 2 weeks during mating. Females were treated with the test material 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 the body weight and the body weight gain of the male rats 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 was noted. In addition, no influence 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, as well. 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 and tissues of the parental animals. No changes in absolute and relative organ weights of the parental animals were observed, as well. 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. Furthermore, no effects on the physical development of the F1 offspring were noted in any treated group. 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).

References

Agency for Toxic Substances and Disease Registry (ATSDR) (1997): Toxicological Profile for Propylene Glycol. US Department of Health and Human Services. Atlanta, US.

Agency for Toxic Substances and Disease Registry (ATSDR) (2010): Toxicological Profile for Ethylene Glycol. US Department of Health and Human Services. Atlanta, US.

Gubicza, L., Kabiri-Badr, A., Keoves, E., Belafi-Bako, K. (2000): Large-scale enzymatic production of natural flavour esters in organic solvent with continuous water removal. Journal of Biotechnology 84(2): 193-196.

Heymann, E. (1980): Carboxylesterases and amidases. In: Jakoby, W.B., Bend, J.R. & Caldwell, J., eds., Enzymatic Basis of Detoxication, 2nd Ed., New York: Academic Press, pp. 291-323.Gubicza, L. et al. (2000). Large-scale enzymatic production of natural flavour esters in organic solvent with continuous water removal. Journal of Biotechnology 84(2): 193-196.

International Programme on Chemical Safety (IPCS) (2001): Ethylene Glycol. Poisons Information Monograph. PIM 227.

Lilja, J. et al. (2005). Esterification of propanoic acid with ethanol, 1-propanol and butanol over a heterogeneous fiber catalyst. Chemical Engineering Journal, 115(1-2): 1-12.

Liu, Y. et al. (2006). A comparison of the esterification of acetic acid with methanol using heterogeneous versus homogeneous acid catalysis. Journal of Catalysis 242: 278-286.

Miller, O.N., Bazzano, G. (1965): Propanediol metabolism and its relation to lactic acid -metabolism. Annals of the New York Academy of Sciences 119, 957-973.

Radzi, S.M. et al. (2005). High performance enzymatic synthesis of oleyl oleate using immobilised lipase from Candida antartica. Electronic Journal of Biotechnology 8: 292-298.

Ritchie, A.D. (1927): Lactic acid in fish and crustacean muscle. Journal of Experimental Biology 4, 327-332.

Stryer, L. (1994): Biochemie. 2nd revised reprint, Heidelberg; Berlin; Oxford: Spektrum Akad. Verlag.

Tocher, D.R. (2003): Metabolism and Functions of Lipids and Fatty Acids in Teleost Fish. Reviews in Fisheries Science 11(2), 107-184.

WHO (2002): Ethylene Glycol: Human Health Aspects. Concise International Chemical Assessment Document 45.

Zhao, Z. (2000). Synthesis of butyl propionate using novel aluminophosphate molecular sieve as catalyst. Journal of Molecular Catalysis 154(1-2): 131-135.

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

NOAEL oral (development): 1000 mg/kg bw/day (OECD 422, GLP)

The hazard assessment is based on the data currently available. New studies with the registered substance and/or other member substances of the glycol esters category will be conducted in the future. The finalised studies will be included in the technical dossier as soon as they become available and the hazard assessment will be re-evaluated accordingly.

For further details, please refer to the category concept document attached to the category object (linked under IUCLID section 0.2) showing an overview of the strategy for all substances within the glycol esters category.

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.

Endpoint conclusion:

no study available

Endpoint conclusion:

no study available

The hazard assessment is based on the data currently available. New studies with the registered substance and/or other member substances of the glycol esters category will be conducted in the future. The finalised studies will be included in the technical dossier as soon as they become available and the hazard assessment will be re-evaluated accordingly.

For further details, please refer to the category concept document attached to the category object (linked under IUCLID section 0.2) showing an overview of the strategy for all substances within the glycol esters category.

Screening study

The reproductive and developmental toxicity / teratogenicity of ethylene distearate (CAS No. 627-83-8, EC No. 211-014-3) was investigated in a combined repeated dose toxicity study with the reproduction / developmental toxicity screening test according to OECD guideline 422 under GLP conditions (Gotemba Laboratory, 2013) as reported under ‘effects on fertility’. Here, only the parameters relevant for developmental toxicity / teratogenicity are summarised. For a full account of the study, please refer to IUCLID sections 7.5 and the description provided under ‘effects on fertility’.

Offspring were subjected to external observation at the time of birth, measurement of body weight for males and females at the time of birth and on day 4 after birth, macroscopic observation. In addition, sex ratio and viability index on day 4 after birth were calculated.

No toxicologically relevant effects related to treatment with the test substance were observed in any of the developmental parameters assessed. There were no indications of a teratogenic potential of the test substance in any of the dose groups. Based on the lack of relevant effects, the No-Observed-Adverse-Effect-Level (NOAEL) for developmental toxicity / teratogenicity of ethylene distearate (CAS No. 627-83-8, EC No. 211-014-3) was set at the high-dose level of 1000 mg/kg bw/day.

Prenatal developmental toxicity study

CAS 68583-51-7

One study with Decanoic acid, mixed diesters with octanoic acid and propylene glycol is available. The oral prenatal developmental toxicity study was conducted according to OECD 414 under GLP conditions (Pittermann, 1994).

Groups of 24 female Sprague Dawley rats per dose level were orally dosed with 100, 300 and 1000 mg/kg bw/day by gavage from Day 6-15 of gestation. A concurrent negative control group receiving the vehicle (arachis oil) only was included in the testing as well. No maternal mortality occurred and no substance-related clinical signs of toxicity were observed. In addition, maternal body weight profiles were similar in all groups. 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 group. Mean fetal placental and uterus weights and body weights of live fetus exhibited no significant differences between treatment and control groups. In addition, the fetal sex ratio was not affected by treatment. No treatment-related fetal abnormalities or malformations were found at necropsy. The figures of skeletal and visceral variations in the treatment and control groups were considered to be comparable. 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 identical and therefore not treatment-related.

Therefore, due to the lack of adverse effects in this study, the NOAEL for maternal toxicity and developmental toxicity for rats was considered to be 1000 mg/kg bw/day.

Altogether, four studies investigating the developmental toxicity are available within the Glycol Ester category in addition to the screening study according to OECD guideline 422 with the registration substance ethylene distearate (CAS No. 627-83-8, EC No. 211-014-3). The studies from the category members 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), C8-10, 1,3-Butandiolester (CAS 853947-59-8) and Fatty acids, C6-12, ester with propylene glycol (CAS 85883-73-4) were considered for assessment and read-across was conducted based on a category and weight of evidence approach.

The results of the study with Decanoic acid, mixed diesters with octanoic acid and propylene are already described above.

Fatty acids, C16-18, esters with ethylene glycol, C8-10, 1,3-Butandiolester and Fatty acids, C6-12, ester with propylene glycol were tested in oral prenatal developmental toxicity studies according to OECD 414 in compliance with GLP (Pittermann, 1997; Cicalese, 2007; Bowman, 2007).

Groups of 24 or 25 female rats per dose were dosed with the respective test compound via gavage from Day 6-15, Day 6-17 or Day 6-19 post mating. Concurrent negative control groups receiving the vehicle alone were included in all testings.

Animals were dosed via gavage with 100, 300 and 900 mg/kg bw/day of Fatty acids, C16-18, esters with ethylene glycol. No mortalities in maternal animals and no compound-related symptoms were observed in the treatment groups. In addition, body weight and body weight gains were within the expected ranges. No compound-related differences were noted between the mean reproduction data of the test groups in comparison to the control group. At scheduled necropsy no macroscopic changes were noted in the dams of the treatment groups. Furthermore, pre-implantation loss, post-implantation loss, mean number of resorptions, embryonic deaths and total fetuses were not affected by treatment with the test substance. In addition, mean fetal placental and uterus weights were not affected. The fetal sex ratio was comparable in all groups and no treatment-related fetal abnormalities were found at necropsy. The examined fetuses showed no treatment-related malformations and the figures of visceral variations in the test groups were considered to be similar to the control group. 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.

Based on the lack of adverse effects in this study, the NOAEL for maternal toxicity and developmental toxicity for rats was considered to be above 900 mg/kg bw/day.

In the study with C8-10, 1,3-Butandiolester, animals were dosed with the limit dose of 1000 mg/kg bw/day. No mortality or treatment-related signs of toxicity in maternal animals occurred during the study period. Body weight, body weight gain and food consumption were unaffected by treatment. No treatment-related effects in uterus weight or macroscopic changes were detected in treated females. No compound-related differences were observed in pre-and post-implantation loss, embryonic deaths and mean numbers of resorptions of the test groups in comparison to the control group. In fetuses of the treatment group, a slight but statistically significant lower mean fetal weight was observed when compared to the control group but within the historical control data for this rat strain. This slight difference was attributed to the higher presence of fetuses in the treated group compared to controls in which mean fetal weight was also unusually higher when compared to the internal historical control data of the laboratory. 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.

Thus, based on the lack of adverse effects in this study, the NOAEL for maternal toxicity and developmental toxicity for rats was considered to be 1000 mg/kg bw/day.

Fatty acids, C6-12, ester with propylene glycol was administered to groups of female rats at dose levels of 500, 1500 and 2500 mg/kg bw/day. No mortality occurred in maternal animals during the study period. In the mid- and high-dose group, test article-related salivation was noted in 8 and 6 females, respectively. Further findings noted in the treated groups included hair loss, scabbing and red material on various body surfaces as well as rales and soft stool. These findings occurred infrequently and were not dose-related. Mean maternal body weights, body weight gains, net body weights, net body weight gains and gravid uterine weights were unaffected by test article administration. A slightly lower food consumption in the high-dose group was not considered to be adverse based on the lack of an effect on mean body weights. Post-implantation loss, live litter size, mean fetal body weights, fetal sex ratios, mean numbers of corpora lutea and implantation sites and the mean litter proportions of pre-implantation loss were similar across all groups. There were no external developmental variations for any fetuses and no visceral and no skeletal malformations were noted for fetuses in this study which were considered to be test substance-related. 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.

Thus, no adverse effects in the maternal animals and the offspring were observed and a NOAEL of 1000 mg/kg bw/day for maternal and developmental toxicity was considered.

Conclusion for developmental toxicity

One screening study and four studies investigating the prenatal developmental toxicity are available within the Glycol Ester category. The studies from the category members 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), C8-10, 1,3-Butandiolester (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.