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Key value for chemical safety assessment

Effects on fertility

Description of key information

Oral (OECD TG 422, Combined repeated dose toxicity study with the reproduction / developmental toxicity screening test, rat): NOAEL (systemic / reproduction) ≥ 1000 mg/kg bw/day

Read-across from source substance 1,2,3-Propanetriol, homopolymer, diisooctadecanoate (CAS 63705-03-3)

Oral (OECD TG 415, One-generation reproductive toxicity study): NOAEL (systemic / fertility) ≥ 1000 mg/kg bw/day

Read-across from source substance Hexanedioic acid, mixed esters with decanoic acid, 12-hydroxyoctadecanoic acid, isostearic acid, octanoic acid, 3,3'-oxybis[1,2-propanediol] and stearic acid (CAS 130905-60-1)

Link to relevant study records
Reference
Endpoint:
screening for reproductive / developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Remarks:
Summary of available data used for the endpoint assessment of the target substance
Adequacy of study:
weight of evidence
Justification for type of information:
Please refer to the Analogue Approach Justification provided in Section 13.
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across source
Dose descriptor:
NOAEL
Remarks:
systemic
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Remarks on result:
other: Source: CAS 63705-03-3, BASF, 2013a
Dose descriptor:
NOEL
Remarks:
fertility
Effect level:
300 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Remarks on result:
other: Source: CAS 63705-03-3, BASF, 2013a
Critical effects observed:
no
Dose descriptor:
NOAEL
Remarks:
development
Generation:
F1
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Remarks on result:
other: Source: CAS 63705-03-3, BASF, 2013a
Critical effects observed:
no
Reproductive effects observed:
no

Additional study considered in the Weight-of-Evidence approach:

CAS 130905-60-1, Sasol, 1996b: NOAEL systemic, fertility, development (rat, m/f) > 1000 mg/kg bw/day (one-generation study)

Conclusions:
In a combined repeated dose and reproduction / developmental screening study and in a one-generation reproductive toxicity study, the test substances were administered to rats orally by gavage. Doses of up to 1000 mg/kg bw/day did not result in any toxicologically relevant changes with respect to systemic parental toxicity, fertility and development of offspring.
Executive summary:

The reproductive toxicity of the target substance is estimated based on adequate and reliable investigations of structural analogue source substances. In a combined repeated dose and reproduction / developmental screening study and in a one-generation reproductive toxicity study, the test substances were administered to rats orally by gavage. Doses of up to 1000 mg/kg bw/day did not result in any toxicologically relevant changes with respect to systemic parental toxicity, fertility and development of offspring. Based on these findings, the No-Observed-Adverse-Effect-Level (NOAEL) for reproductive and developmental toxicity was established at 1000 mg/kg bw/day, the highest dose tested, in both studies. Therefore, a NOAEL of 1000 mg/kg bw/day is also considered for the target substance. As explained in the analogue justification, the differences in molecular structure between the target and the source substances are unlikely to lead to differences with respect to toxicity to reproduction.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
The available information comprises adequate and reliable studies (Klimisch score 1) from analogue substances with similar structure and intrinsic properties. Read-across is justified based on common precursors and breakdown products of hydrolysis and consistent trends in environmental fate, ecotoxicological and toxicological profile. The selected studies are thus sufficient 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 (REACH).
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 read-across

The read-across from structural analogue source substances approach comprises aliphatic esters of the poly-functional alcohols di- and triglycerol. The fatty acid rests of the esters exhibit carbon chain lengths in the range C5 - C20. They are either linear and saturated in nature but also unsaturated C16 and C18 and branched C6 and C18 moieties are present. Since the alcohols employed provide 4 - 5 reactive hydroxyl functions, the esterification degree found in source and target substances ranges from mono- to penta-esters.

The available data allows for an accurate hazard and risk assessment of the target substance and the read-across 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 substances by interpolation to the target substance applying the read-across concept in accordance with Annex XI, Item 1.5, of Regulation (EC) No. 1907/2006 (REACH). In particular, for each specific endpoint the source substances structurally closest to the target substance 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 substances 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).

Discussion

No data on toxicity to reproduction are available for the target substance Isooctadecanoic acid, mixed esters with oxybis[propanediol]. Therefore, read-across from the source substances 1,2,3-Propanetriol, homopolymer, diisooctadecanoate (CAS 63705-03-3) and Hexanedioic acid, mixed esters with decanoic acid, 12-hydroxyoctadecanoic acid, isostearic acid, octanoic acid, 3,3'-oxybis[1,2-propanediol] and stearic acid (CAS 130905-60-1) was applied by means of a Weight-of-Evidence approach.

A combined repeated dose and reproduction / developmental screening study according to OECD TG 422 and observing GLP critera has been performed with 1,2,3-Propanetriol, homopolymer, diisooctadecanoate (CAS 63705-03-3; BASF, 2013a). 12 rats per sex and dose have been administered the test item in concentrations of 100, 300 and 1000 mg/kg bw/day by oral gavage. Animals of the control group were treated with the vehicle corn oil only. While males were treated for 28 days, females received the test item for approx. 6 weeks. Due to a high number of non-pregnant females in groups 1 - 4, the expectations of the guideline of 8 pregnant females per group were not met with the initial number of 11 males and 11 females per group. Therefore, the number of animals per groups was increased by adding of further males and females after the in-life phase of the first delivery of rats was reached. The additional animals ran through the whole study as the animals from the first delivery with the exception that the males were terminated on day 24 of the after pairing period and not on day 16 of the pairing period as the males of the first delivery (logistical reasons). Because an impact of the light/dark cycle disturbance during the study on these results could not be excluded, the study was repeated with a third animal delivery of control and high-dose (1000 mg/kg bw/day) groups under proper light conditions.

At 1000 mg/kg bw/day, one male died spontaneously on day 1 of the after pairing period. No clinical signs were observed in that animal and a normal body weight gain was recorded. The death was therefore considered not treatment-related. At 1000 mg/kg bw/day, mean food consumption was statistical significantly reduced in males during the first 11 days of treatment. Since the reduction in food consumption occurred only transiently, it was considered to be not adverse. There were no effects on mean food consumption of females at any dose level and in any study phase. Mean body weight gain of males was statistical significantly lower in the high dose group during the pre-pairing period, resulting in slightly reduced mean body weights. The reduction in mean body weight gain and body weights were considered to be not adverse. No effect of the test item on mean body weights and mean body weight gain was noted for females at any dose level. Treatment with the test item at 1000 mg/kg bw/day resulted in statistical significantly higher absolute and relative liver and kidney weights in animals of both sexes. Since there was no evidence for an impairment of organ function by clinical pathology and histopathology, these findings were not considered to be adverse. Additionally, in females, absolute and relative heart weights were also increased. This finding was without histopathological correlation and was therefore considered to be incidental. The fertility index and conception rate were low across all groups in females of the first animal delivery only. This poor mating performance was considered to be due to a disturbance of the light / dark cycle during the conduct of this study and not test item-related. In females at 1000 mg/kg bw/day, the mean duration of gestation was slightly higher than in controls (22.1 days versus 21.3 days in the controls for first and second animal delivery, 21.7 days versus 21.3 days in the controls for third animal delivery) and not in the range or borderline to the historical control data (21.2 to 21.7 days). Also, the post-implantation loss was increased (16.2% versus 6.6% in controls for first and second animal delivery, 14.2% versus 3.3% in controls for third animal delivery), which was borderline regarding the historical control data (3.3% - 14.4% as a percentage of total implantations). Due to the higher post-implantation loss, mean litter size at first check was reduced at the high dose level. The NOEL (No Observed Effect Level) for general toxicity and for reproduction and development was established at 300 mg/kg bw/day. Since effects of general toxicity were not considered to be adverse and/or within (or borderline) to historical control data, the NOAEL (No Observed Adverse Effect Level) for general toxicity was established at 1000 mg/kg bw/day, corresponding to the highest dose tested.

The source substance Hexanedioic acid, mixed esters with decanoic acid, 12-hydroxyoctadecanoic acid, isostearic acid, octanoic acid, 3,3'-oxybis[1,2-propanediol] and stearic acid (CAS 130905-60-1) was investigated for effects on reproduction in a one-generation reproductive toxicity study according to OECD TG 415 (Sasol, 1996b). The study was performed as limit test under GLP conditions. 24 Sprague Dawley (CD(SD)BR) rats of each sex were administered 1000 mg/kg bw/day of the test item by oral gavage daily, 7 days/week. The animals of the control group received the vehicle (corn oil) only. Males were treated for 10 weeks prior to pairing, through the mating period and thereafter until the day prior to sacrifice (Study Day 99). Females were treated for 2 weeks prior to pairing, during the·mating period and through to weaning of the offspring. Clinical signs seen during the observations performed at weekly intervals in F0 males and females were limited to common conditions of the skin and fur. No reaction to treatment was seen at the observations performed before dosing, immediately after and 1 h after dosing during the first two weeks of treatment. There were no mortalities and no effects of treatment on pregnancy rate. Group mean body weight and body weight change in F0 males were comparable between the treated and control animals. No differences in body weight were seen in F0 females during the pre-pairing, post-coitum or post-partum periods compared to controls. Body weight change in F0 females was statistically significantly higher than controls before mating on study Day 64, and statistically significantly lower than controls on post-coitum Day 20. These occasional differences are not considered to be of toxicological significance. Mean body weight change was comparable to controls during the post-partum period. Food consumption was statistically significantly lower than controls in F0 treated males on study Days 64 and 71 and in F0 treated females on post-coitum day 8 and post-partum day 4. These occasional differences are not considered to be of toxicological significance. One control and one treated male showed ozoospermic unilaterally at microscopic examination. However, the treated male induced pregnancy. This case was not considered treatment related. No signs of toxicological significance were observed at macroscopic and microscopic examination in F0 females. Therefore, no toxicologically significant findings were observed during macroscopic and microscopic examination of F0 animals. Reproductive function, as assessed by oestrus cycles, mating performance, pregnancy rate and parturition were not affected by treatment. No effects on implantation, pre-birth loss data or gestation length were seen in F0 treated females. Total and live litter size, litter and mean pup weights and pup loss were similar in both groups. One female in the control and two in the treated group proved not to be pregnant. One female in the control group had total resorption. A total of 22 females per group with live pups was available at Day 21 post-partum. A total of three males, one in the control and two in the treated group failed to induce pregnancy. All dams gave birth by Day 22 post-coitum. The number of implantations and total litter size were similar in the treated group when compared to the control. Pre-birth loss was higher in the treated group when compared to the control. This was not considered to be of toxicological significance as values obtained were less than those of historical controls of the test laboratory (from 0.8 to 8.6%). Based on the findings, the No-Observed-Adverse-Effect-Level (NOAEL) for parental systemic toxicity and fertility was established at ≥ 1000 mg/kg bw/day. As the study was performed as limit test, the NOAEL corresponds to the highest dose tested.

Conclusion on toxicity to reproduction

Since no significant adverse effects on parental animals have been observed in both studies, no hazard with respect to reproduction toxicity after oral exposure is identified for the target substance.

Effects on developmental toxicity

Description of key information

Oral (OECD TG 422, Combined repeated dose toxicity study with the reproduction / developmental toxicity screening test, rat): NOAEL (development) ≥ 1000 mg/kg bw/day

Read-across from source substance 1,2,3-Propanetriol, homopolymer, diisooctadecanoate (CAS 63705-03-3)

Oral (OECD TG 415, One-generation reproductive toxicity study): NOAEL (development) ≥ 1000 mg/kg bw/day

Read-across from source substance Hexanedioic acid, mixed esters with decanoic acid, 12-hydroxyoctadecanoic acid, isostearic acid, octanoic acid, 3,3'-oxybis[1,2-propanediol] and stearic acid (CAS 130905-60-1)

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
The available information comprises adequate and reliable studies (Klimisch score 1) from analogue substances with similar structure and intrinsic properties. Read-across is justified based on common precursors and breakdown products of hydrolysis and consistent trends in environmental fate, ecotoxicological and toxicological profile. The selected studies are thus sufficient 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 (REACH).
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 read-across

The read-across from structural analogue source substances approach comprises aliphatic esters of the poly-functional alcohols di- and triglycerol. The fatty acid rests of the esters exhibit carbon chain lengths in the range C5 - C20. They are either linear and saturated in nature but also unsaturated C16 and C18 and branched C6 and C18 moieties are present. Since the alcohols employed provide 4 - 5 reactive hydroxyl functions, the esterification degree found in source and target substances ranges from mono- to penta-esters.

The available data allows for an accurate hazard and risk assessment of the target substance and the read-across 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 substances by interpolation to the target substance applying the read-across concept in accordance with Annex XI, Item 1.5, of Regulation (EC) No. 1907/2006 (REACH). In particular, for each specific endpoint the source substances structurally closest to the target substance 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 substances 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).

Discussion

As no data on developmental toxicity are available for the target substance, again read-across from the source substances 1,2,3-Propanetriol, homopolymer, diisooctadecanoate (CAS 63705-03-3) and Hexanedioic acid, mixed esters with decanoic acid, 12-hydroxyoctadecanoic acid, isostearic acid, octanoic acid, 3,3'-oxybis[1,2-propanediol] and stearic acid (CAS 130905-60-1) was applied in a Weight-of-Evidence approach. The two studies have been discussed in detail above. Here, only findings related to developmental toxicity are summarised.

In the combined repeated dose and reproduction / developmental screening study according to OECD TG 422 and observing GLP critera performed with 1,2,3-Propanetriol, homopolymer, diisooctadecanoate (CAS 63705-03-3; BASF, 2013a), no test item-related findings were noted in pups during first litter check and during lactation at any dose level. Sex ratios and mean pup weights at first litter check and on day 4 post partum were unaffected by exposure to the test item. No test item-related findings were noted at macroscopic examination of F1 pups. One male pup treated at 100 mg/kg bw/day had a missing right testicle at planned necropsy and two pups treated at 1000 mg/kg bw/day showed sores on the skin. These isolated findings were incidental and unrelated to treatment. Concluding on the findings in pups, the developmental No-Adverse-Observed-Effect-Level (NOAEL) was determined to be 1000 mg/kg bw/day.

In addition, the one-generation reproductive toxicity study according to OECD TG 415 and GLP conditions (Sasol, 1996b) performed with source substance Hexanedioic acid, mixed esters with decanoic acid, 12-hydroxyoctadecanoic acid, isostearic acid, octanoic acid, 3,3'-oxybis[1,2-propanediol] and stearic acid (CAS 130905-60-1) did not result in toxicologically relevant findings in F1 pups which died during the lactation period or in F1 pups which were culled on Day 4 post-partum. No changes were seen at the necropsy in F1 pups on or shortly after Day 21 post-partum. There were no meaningful differences in the incidence of the abnormalities recorded at the necropsy of F1 pups at weaning. Moreover, there were no differences between the two groups in litter size, litter weight, mean pup weight or pup loss throughout the whole lactation period. Sex ratios of offspring at birth and on Day 21 post-partum did not show any differences between groups. The number of deaths per sex was similar in the treated and the control group. There were no differences between groups in the results obtained from the parameters used to monitor the pre-weaning physical and functional development. Based on the findings, the No-Observed-Adverse-Effect-Level (NOAEL) for pup development was established at ≥ 1000 mg/kg bw/day, the highest dose tested.

Conclusion on toxicity to reproduction

No significant adverse effects have been observed in pups in both studies. Therefore, no hazard with respect to developmental toxicity after oral exposure is identified for the target substance.

Justification for classification or non-classification

According to Article 13 of Regulation (EC) No. 1907/2006 (REACH) information on intrinsic properties of substances may be generated by means other than tests, e.g. using information from structurally related substances (grouping or read-across), provided that conditions set out in Annex XI are met. Annex XI 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 read-across concept is applied to the target substance Isooctadecanoic acid, mixed esters with oxybis[propanediol], data gaps can be filled by interpolation from representative structural analogue source substances to avoid unnecessary animal testing.

The read-across concept is also used to derive the classification of the target substance taking the properties of the source substances into account. Based on the analogue read-across approach, all available data on toxicity to reproduction do not meet the classification criteria according to Regulation (EC) No. 1272/2008 (CLP) and are therefore conclusive but not sufficient for classification. Under Regulation (EC) No. 1907/2006 (REACH), Annex VIII, a pre-natal developmental toxicity study is not required. Under these circumstances, the available data on reproductive and developmental toxicity are considered as sufficient to allow a conclusive evaluation in regard to ‘reproductive toxicity’ as defined in Regulation (EC) No. 1272/2008 (CLP).

Additional information