Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

No toxicity for reproduction was observed (OECD Guideline 416, Two-Generation Reproduction Toxicity Study; CATEGORY APPROACH)

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Reproduction toxicity

Justification for grouping of substances and read-Across

The Glycol ester category covers esters of an aliphatic diol (ethylene glycol (EG), propylene glycol (PG) or 1,3-butyleneglycol (1,3-BG)) and one or two carboxylic fatty acid chains. The fatty acid chains comprise carbon chain lengths ranging from C6 to C18, mainly saturated but also mono unsaturated C16 and C18, branched C18 and epoxidized C18.

 

The available data allows for an accurate hazard and risk assessment of the category and the category concept is applied for the assessment of environmental fate and environmental and human health hazards. Thus, where applicable, environmental and human health effects are predicted from adequate and reliable data for source substance(s) within the group by interpolation to the target substances in the group (read-across approach) applying the group concept in accordance with Annex XI, Item 1.5, of Regulation (EC) No 1907/2006. In particular, for each specific endpoint the source substance(s) structurally closest to the target substance is/are chosen for read-across, with due regard to the requirements of adequacy and reliability of the available data. Structural similarities and similarities in properties and/or activities of the source and target substance are the basis of read-across.

A detailed justification for the grouping of chemicals and read-across is provided in the technical dossier (see IUCLID Section 13).

 

Data Matrix

CAS #

Toxicity

627-83-8 (a)

RA: CAS 853947-59-8

68583-51-7

RA: CAS 853947-59-8

84988-75-0

RA: CAS 853947-59-8

624-03-3

RA: CAS 853947-59-8

91031-31-1(b)

RA: CAS 853947-59-8

853947-59-8

NOAEL:1000 mg/kg bw/day

 4219 -449 -2   

RA: CAS 853947-59-8

(a) Category members 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.

 

CAS 853947-59-8

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 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).

Based on the availability of a two-generation reproductive toxicity study performed in 2005, performance of an extended one-generation reproduction toxicity study is not considered as necessary to fulfil the standard data requirements according to Regulation (EC) No. 1907/2006, Annex X, 8.7.3 Column 2, which states that two-generation reproductive toxicity studies (OECD TG 416) initiated before 13 March 2015 shall be considered appropriate to address the standard information requirement.

For a detailed reference list please refer to the CSR or IUCLID section 13.


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

Effects on developmental toxicity

Description of key information
NOAEL oral (developmental): 1000 mg/kg bw/day (OECD 414, GLP)
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
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

The Glycol ester category covers esters of an aliphatic diol (ethylene glycol (EG), propylene glycol (PG) or 1,3-butyleneglycol (1,3-BG)) and one or two carboxylic fatty acid chains. The fatty acid chains comprise carbon chain lengths ranging from C6 to C18, mainly saturated but also mono unsaturated C16 and C18, branched C18 and epoxidized C18.

 

The available data allows for an accurate hazard and risk assessment of the category and the category concept is applied for the assessment of environmental fate and environmental and human health hazards. Thus, where applicable, environmental and human health effects are predicted from adequate and reliable data for source substance(s) within the group by interpolation to the target substances in the group (read-across approach) applying the group concept in accordance with Annex XI, Item 1.5, of Regulation (EC) No 1907/2006. In particular, for each specific endpoint the source substance(s) structurally closest to the target substance is/are chosen for read-across, with due regard to the requirements of adequacy and reliability of the available data. Structural similarities and similarities in properties and/or activities of the source and target substance are the basis of read-across.

A detailed justification for the grouping of chemicals and read-across is provided in the technical dossier (see IUCLID Section 13).

 

Data Matrix

CAS #

Developmental toxicity

627-83-8 (a)

RA: CAS 853947-59-8

RA: CAS 85883-73-4

RA: CAS 68583-51-7

RA: CAS 91031-31-1

68583-51-7

NOAEL: ≥1000 mg/kg bw/day

84988-75-0

RA: CAS 853947-59-8

RA: CAS 85883-73-4

RA: CAS 68583-51-7

RA: CAS 91031-31-1

624-03-3

RA: CAS 853947-59-8

RA: CAS 85883-73-4

RA: CAS 68583-51-7

RA: CAS 91031-31-1

91031-31-1 (b)

NOAEL:≥900 mg/kg bw/day

853947-59-8

NOAEL:≥1000 mg/kg bw/day

85883-73-4

NOAEL:≥1000 mg/kg bw/day

(a) Category members 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.

 

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.

CAS 91031-31-1

Fatty acids, C16-18, esters with ethylene glycol was tested in an oral prenatal developmental toxicity studies according to OECD 414 in compliance with GLP (Pittermann, 1997).

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

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.

CAS 853947-59-8

C8-10, 1,3-Butandiolester was tested in oral prenatal developmental toxicity study according to OECD 414 in compliance with GLP (Cicalese, 2007). 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.

 

CAS 85883-73-4

Fatty acids, C6-12, ester with propylene glycol was tested in an oral prenatal developmental toxicity studies according to OECD 414 in compliance with GLP (Bowman, 2007). 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

Four studies investigating the 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.

A waiver for the requirement to perform a prenatal developmental toxicity study in a 2nd species was included, as this requirement is considered not to add new information for hazard assessment and therefore is scientifically and, considering concerns regarding the use of vertebrate animals for experimental purposes, unjustified.

For a detailed reference list please refer to the CSR or IUCLID section 13.

Justification for classification or non-classification

According to Article 13 of Regulation (EC) No. 1907/2006 "General Requirements for Generation of Information on Intrinsic Properties of substances", information on intrinsic properties of substances may be generated by means other than tests e.g. from information from structurally related substances (grouping or read-across), provided that conditions set out in Annex XI are met. Annex XI, "General rules for adaptation of this standard testing regime set out in Annexes VII to X” states that “substances whose physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity may be considered as a group, or ‘category’ of substances. This avoids the need to test every substance for every endpoint". Since the group concept is applied to the members of the Glycol Ester Category, data will be generated from representative reference substance(s) within the category to avoid unnecessary animal testing. Additionally, once the group concept is applied, substances will be classified and labeled on this basis.

Therefore, based on the group concept, all 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.