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Description of key information

Oral; OECD TG 422 Combined repeated dose toxicity study with the reproduction / developmental toxicity screening test and OECD TG 407: NOAEL (rat, m/f) > 1000 mg/kg bw

Read-across from analogue source substances 1,2,3-Propanetriol, homopolymer, diisooctadecanoate (CAS No. 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 No. 130905-60-1) in a Weight-of-Evidence approach

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: oral
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
Key result
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: NOAEL is highest dose tested
Remarks on result:
other: Source, CAS 63705-03-3, BASF, 2013a
Key result
Critical effects observed:
no

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

CAS 130905-60-1, Sasol, 1990f: NOAEL (rat, m/f) = 1800 mg/kg bw/day

Conclusions:
Oral exposure of male and female rats to the test substances by gavage for 28 days and oral exposure of female rats for approx. 6 weeks did not yield any adverse effects of toxicological relevance and hence resulted in NOAEL values of 1000 mg/kg bw/day, corresponding to the highest doses tested.
Executive summary:

The oral repeated dose toxicity of the target substance is estimated based on adequate and reliable short-term oral toxicity studies of structural analogue source substances, including a combined repeated dose and reproduction / developmental screening test. Oral exposure of male and female rats to the test substances by gavage for 28 days and oral exposure of female rats for approx. 6 weeks (in the screening study) did not yield any adverse effects of toxicological relevance and hence resulted in NOAEL values of 1000 mg/kg bw/day, corresponding to the highest doses tested. Based on these findings, a NOAEL for repeated dose toxicity after oral exposure of ≥ 1000 mg/kg bw/day is also identified 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 in oral repeated dose toxicity.

Endpoint conclusion
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 (Klimisch score 1 and 2) studies from various source substances with similar structures and intrinsic properties. Read-across is justified based on common precursors and hydrolysis products 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 Annexes VIII - X, 8.6, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006 (REACH).

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
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).

There are no data available regarding the repeated dose toxicity of the target substance. Hence, two studies performed with adequate analogue source substances are used to read-across information 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. 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. No other mortalities occured during the entire study period. Clinical signs observed in several females were considered not related to treatment with the test item. No findings were noted at detailed weekly clinical observation during the whole course of the study. There were no treatment-related changes noted at functional observational battery and locomotor activity. At 1000 mg/kg bw/day, mean food consumption was statistically 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 statistically 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. The assessment of the hematology as well as the clinical biochemistry data did not reveal any test item-related effects in males and females at any dose level. Treatment with the test item at 1000 mg/kg bw/day resulted in statistically 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. There were no treatment-related necropsy and histopathological findings. Based on the overall results, the NOAEL for repeated dose toxicity after oral exposure in male and female rats was established at 1000 mg/kg bw/day, corresponding to the highest dose tested.

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) has been tested for its short-term (28-day) repeated dose toxicity in a study performed according to OECD TG 407 and under GLP conditions (Sasol, 1990f). The test substance was administered daily to groups of 5 rats per sex and dose by oral gavage for 4 weeks (7 days/week) in doses of 180, 1800 and 4500 mg/kg bw/day. A test group received the vehicle corn oil. No unplanned mortalities occurd during the course of the study. All histopathological findings noted in the study were considered to be unrelated to the administration of the test article. There were no abnormal clinical signs in any dose group. All hematology and clinical chemistry parameters were within the limits of the respective normal range and urinalysis gave no indication of treatment-related changes in any group. Macroscopic examination during necropsy revealed no changes which were attributed to the treatment of the test substance. The only significant finding was an increase in prostate weight in high dose males. Since nothing abnormal was found microscopically in this organ, the effect was considered either a coincidental finding or a result of a test article induced load reaction without histopathological  manifestation. The NOAEL for repeated dose toxicity after oral exposure in male and female rats was determined to be 1800 mg/kg bw/day.

Conclusion on repeated dose toxicity

Since no significant adverse effects have been observed in any of the studies performed with the two relevant source substances, no hazard with respect to repeated dose toxicity after oral exposure is identified for the target substance Isooctadecanoic acid, mixed esters with oxybis[propanediol] as well. A NOAEL > 1000 mg/kg bw/day is used for hazard assessment.

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 read-across concept, all available data on repeated dose toxicity following the oral route of exposure do not meet the classification criteria according to Regulation (EC) No. 1272/2008 (CLP) and are therefore conclusive but not sufficient for classification.

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