Hexanedioic acid, di-C16-18 (even numbered) alkyl 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:

subchronic

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. Read-across is justified based on common functional group(s), common precursors/breakdown products, 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 toxicity to reproduction ofHexanedioic acid, di-C16-18 (even numbered)-alkyl esters (CAS 92969-90-9). 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.

Effects on fertility

CAS 103-23-1

The toxicity to reproduction of Bis(2-ethylhexyl) adipate (CAS 103-23-1) has been investigated in a one-generation reproduction toxicity study performed similar to OECD TG 415 and in compliance with GLP (key, 1988). Groups of 15 male and 30 female parental Alpk:APfSD (Wistar-derived) rats were exposed daily to the test substance at dietary concentrations of 300, 1800 or 12000 ppm, corresponding to mean achieved dose levels of 52, 178 and 2102 mg/kg bw/day for males and 61, 203 and 2399 mg/kg bw/day for females, respectively. A similar constituted group of animals received the plain diet and served as controls. After 10 weeks of treatment the parental (P) animals were mated to produce a single litter (F1), which was reared until Day 36 post partum. Male parental animals were killed after completion of mating and P-females were killed after weaning their litter. There was no indication of any clear adverse effect on bodyweight or food consumption during the premating phase of the study. However, a slight reduction in bodyweight gain (6%) for female rats in the 12000 ppm test group was observed, compared with the control females. This decrease in body weight gain continued through gestation in the female animals of the highest dose group. An increase in absolute and relative liver weight (18-20%) was observed in both male and female parents receiving dietary levels of 12000 ppm. No treatment-related findings were observed at gross pathology, except for accentuated lobular pattern in the liver of 2/30 female rats in the high-dose group. No histological changes were noted in the reproductive organs of those males and females which failed to breed and were thus suspected of being infertile.

There were no treatment-related effects on pre-coital interval, length of gestation, or on male and female fertility. The fertility of the parents was established by the success of each mating (production of a viable litter).

Based on the results of this study the NOAEL for systemic toxicity for P animals was considered to be 1800 ppm, equivalent to dose levels of 178 mg/kg bw/day in males and 203 mg/kg bw/day in females, respectively. The NOAEL for fertility was considered to be 12,000 ppm, equivalent to dose levels of 2399 mg/kg bw/day in females, and 2102 mg/kg bw/day in males, respectively.

 

CAS 105-99-7

An oral reproduction/developmental toxicity screening test with Dibutyl adipate (CAS 105-99-7) was performed in Sprague-Dawley rats according to OECD TG 421 and in compliance with GLP (supporting, 1996). Dilutions of the test substance in corn oil were administered once daily to groups of 13 animals per sex at dose levels of 100, 300 and 1000 mg/kg bw/day via oral gavage. A control group treated according to the same protocol received the vehicle only. Females were exposed for a total period of 42-53 days, including 14 days before mating and until Day 3 of lactation, whereas males were treated 14 days before mating and 28 days thereafter. After administration, clinical signs involved a dose-dependent increase in salivation in animals of both sexes. However, the increase in salivation was not regarded as neurological effect, but caused by stimulation by the administration of the test substance. A slight, but non-significant suppression of body weight gain was observed in males at 1000 mg/kg bw/day. The relative organ weight of kidney was statistically significantly increased in both sexes at 1000 mg/kg bw/day. In addition, an increase in the relative weight of spleen in males treated with 100 and 1000 mg/kg bw/day was observed, while the only change in spleen weight noted in females involved the increase in absolute weight at 100 mg/kg bw/day. No effects on reproductive function (sperm parameters and estrus cyclicity) and performance (copulation, fertility, gestation, implantation and delivery index) were observed after treatment compared to controls in any of the parental animals. Testis weight, epididymis weight, and histology of these organs did not reveal any substance-related effects in males. Effects on offspring included a slight, although statistically significant decrease (96.1%) in the pup viability on Day 4 of lactation at the 1000 mg/kg bw/day dose group compared with controls (100%). At the same dose, a slight decrease in pup weight was observed on Day 0 and Day 4 of lactation, without reaching statistical significance. Based on the results of this study, the NOAEL for reproductive toxicity in parental animals was established at ≥1000 mg/kg bw/day, while the NOAEL for systemic toxicity in parental animals was set at 300 mg/kg bw/day.

 

Conclusion for toxicity to reproduction

In summary, an one-generation reproduction toxicity study is available with the source substance Bis(2-ethylhexyl) adipate (CAS 103-23-1) and a reproduction/developmental toxicity screening test is available with the source substance Dibutyl adipate (CAS 105-99-7). The data for the source substance showed that no adverse effects on fertility were observed via the oral route up to the limit dose recommended in the relevant guideline. Thus, as the available data did not identify any hazard for toxicity to reproduction, Hexanedioic acid, di-C16-18 (even numbered)-alkyl ester is not expected to be hazardous following oral exposure.

Effects on developmental toxicity

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

There are no data available on developmental toxicity ofHexanedioic acid, di-C16-18 (even numbered)-alkyl esters (CAS 92969-90-9). 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.

 

CAS 103-23-1

The toxicity to reproduction of Bis(2-ethylhexyl) adipate (CAS 103-23-1) has been investigated in a one-generation reproduction toxicity study performed similar to OECD TG 415 and in compliance with GLP (key, 1988). Groups of 15 male and 30 female parental Alpk:APfSD (Wistar-derived) rats were exposed daily to the test substance at dietary concentrations of 300, 1800 or 12000 ppm, corresponding to mean achieved dose levels of 52, 178 and 2102 mg/kg bw/day for males and 61, 203 and 2399 mg/kg bw/day for females, respectively. After 10 weeks of treatment the parental (P) animals were mated to produce a single litter (F1), which was reared until Day 36 postpartum. In the F1-offspring, body weight gain and total litter weight in the 12000 ppm test group were significantly reduced compared with the control group. The litter size in the high-dose group was slightly reduced (non-significant), compared with the control group. No effect on the number of live-born pups or on their survival at any dose level was observed, compared with the control group. In the F1-offspring, adverse effects were only noted at the dose level causing maternal toxicity. The NOAEL for systemic toxicity in the P was considered to be 1800 ppm, equivalent to dose levels of 178 mg/kg bw/day in P-males and 203 mg/kg bw/day in P-females, respectively. Based on the results of this study the NOAEL for developmental toxicity was considered to be 1800 ppm, equivalent to 178 mg/kg bw/day in P-males and 203 mg/kg bw/day in P-females, respectively.

 

Conclusion for toxicity to reproduction

In summary, an one-generation reproduction toxicity study is available with the source substances Bis(2-ethylhexyl) adipate (CAS 103-23-1). The data for the source substance showed that adverse effects on developmental toxicity were observed via the oral route only at the dose level causing maternal toxicity. Thus, the available data did not identify any hazard for developmental toxicity, Hexanedioic acid, di-C16-18 (even numbered)-alkyl ester is not expected to be hazardous following oral exposure.

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 analogue concept is applied to Hexanedioic acid, di-C16-18 (even numbered)alkyl esters, data will be generated from information on reference source substance(s) to avoid unnecessary animal testing. Additionally, once the analogue read-across concept is applied, substances will be classified and labelled on this basis.

 

Therefore, based on the analogue read-across approach, the available data on toxicity to reproduction do not meet the classification criteria according to Regulation (EC) 1272/2008, and are therefore conclusive but not sufficient for classification.