Reaction mass of 1,3-diacetoxypropan-2-yl 12-acetoxyoctadecanoate and 2,3-diacetoxypropyl 12-acetoxyoctadecanoate

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

NA

Effect on fertility: via oral route

Dose descriptor:

NOAEL

1 159 mg/kg bw/day

Additional information

Reproducttive toxicity of TS-ED 532 was investigated in a preliminary reproduction study and subsequently in a combined 2 -generation reprodution/developmental neurotoxicity study. The preliminary study was performed to establish a relevant dosing regime for the combined study. There were no findings considered to be of toxicological significance and the lowest identified NOAEL in the preliminary reproduction toxicity study was ≥ 1105 mg/kg bw/day (F0 male) at exposure level 20000 ppm.

 

The combined two-generation reproduction/developmental neurotoxicity study formed represents a combination study design specifically taking into consideration the requirements of the OECD guideline 416 and 426. A combination study design was chosen based on the requirements of using the minimum number of test animals. The study was performed to investigate the effects of TS-ED 532 on reproduction, pre-natal development and post-natal development of the rat when administered to two successive generations. Measurement of antiandrogen endpoints (nipple retention at PND 12-15 and anogenital distance at PND 1) was included to evaluate a possible endocrine disrupting effect. The study also investigated the potential of TS-ED 532 to cause developmental neurotoxicity in the offspring, including assessment of neurobehavior. The assessment of pre-weaning offspring, adolescent and young adult animals in a programme of neurobehavioural tests was validated in advance of the study. The study incorporated a positive control group for endocrine disruption endpoints (ano-genital distance and nipple retention), which were validated in advance of the combined study.

TS-ED 532 was administered orally by dietary admixture continuously over each generation, including a maturation period of at least 10 weeks, mating, gestation and lactation. Control animals were handled in an identical manner to those receiving TS-ED 532 and were given laboratory diet treated with amounts of Arachis oil equivalent to the amount of TS-ED 532 added to the high dose group dietary admixtures to ensure comparable calorific intake. In order to achieve a high dose level that approximated a TS-ED 532 intake equivalent to 1000 mg/kg bw/day, the dietary concentration of TS-ED 532 in diet for this group was reviewed and periodically adjusted during maturation.

The animals were exposed to 1500, 6000 or 25000 ppm TS-ED 532 in the feed. Dietary administration of TS-ED 532 up to 25000 ppm, giving exposure of at least 1000 mg/kg bw/day throughout all of the study, was found not to have effects on reproduction, pre-natal development and post-natal development of the rat over two successive generations, including no endocrine disrupting effect using ano-genital distance and nipple count as effect parameters. Furthermore, TS-ED 532 was found not to induce developmental neurotoxicity in the offspring. The mean achieved dosages at exposure level 25000 ppm were 1159 mg/kg bw/day (F0 male), 2200 mg/kg bw/day (F0 female), 1320 mg/kg bw/day (F1 male) and 2262 (F1 female). The lowest identified NOAEL at exposure level 25000 ppm was ≥ 1159 mg/kg bw/day (F0 male).

Short description of key information:
In a preliminary reproduction study using dietary administration of TS-ED 532 up to 20000 ppm, no findings considered to be of toxicological significance was identified including assessment of reproductive parameters and pre-natal and post-natal development. The mean achieved dosages were 1105 mg/kg bw/day (F0 male), 1928 mg/kg bw/day (F0 female), 2228 mg/kg bw/day (F1 male) and 2505 (F1 female). The lowest identified NOAEL in this preliminary reproduction study was ≥ 1105 mg/kg bw/day (F0 male) at exposure level 20000 ppm.

Overall, TS-ED 532 was found not to have effects on reproduction, pre natal development and post-natal development of the rat when administered to two successive generations, including no endocrine disrupting effect using ano-genital distance and nipple count as effect parameters. Furthermore, TS-ED 532 was found not to induce any developmental neurotoxicity in the offspring. The animals were exposed to 1500, 6000 or 25000 ppm TS-ED 532 in the feed. NOEL of TS-ED 532 for adult toxicity and reproduction over the two generations was 25000 ppm, giving exposure of at least 1000 mg/kg bw/day throughout all of the study. Other than a decrease in spleen weights for female offspring, the NOEL of TS-ED 532 for offspring development was 25000 ppm and this dosage represents a clear NOAEL for offspring development. NOEL of TS-ED 532 for offspring survival and growth, and for developmental neurotoxicity was 25000 ppm. The mean achieved dosages at this exposure level were 1159 mg/kg bw/day (F0 male), 2200 mg/kg bw/day (F0 female), 1320 mg/kg bw/day (F1 male) and 2262 (F1 female). The lowest identified NOAEL at exposure level 25000 ppm was ≥ 1159 mg/kg bw/day (F0 male).

Effects on developmental toxicity

Description of key information

In preliminary prenatal studies performed in rats and rabbits using oral gavage dosing with TS-ED 532,  the preliminary NOEL for maternal and developmental toxicity was established at 1000 mg/kg bw/day. In the main prenatal studies studies performed in rats and rabbits using oral gavage dosing with TS-ED 532 at dose levels of 100, 300 and 1000 mg/kg bw/day, no significant toxicological maternal effects were observed at any dose level. The NOEL was therefore, considered to be 1000 mg/kg bw/day. No significant toxicological changes were detected in the offspring parameters studied. The NOEL for developmental toxicity was therefore considered to be 1000 mg/kg bw/day. A NOAEL > 1000 mg/kg bw/day for developmental toxicity was established in rats and rabbits. 

Effect on developmental toxicity: via oral route

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Additional information

Preliminary prenatal studies were performed in rats and rabbits to establish relevant dose levels for main prenatal studies. A dosing regimen of 0, 250, 500 and 1000 mg/kg bw/ day was used. In these studies, a preliminary NOEL for maternal and developmental toxicity was established at1000 mg/kg bw/day.

Main prenatal studies studies were performed in rats and rabbits. The oral administration of TS-ED 532 to pregnant rats and rabbits by oral gavage during organogenesis at dose levels of 100, 300 and 1000 mg/kg/day did not result in any toxicological significant maternal effects at any dose level. The NOEL was therefore, considered to be 1000 mg/kg/day. No toxicological significant changes were detected in the offspring parameters measured. The NOEL for developmental toxicity was therefore considered to be 1000 mg/kg/day.

A NOAEL > 1000 mg/kg bw/day for developmental toxicity usnig rat and rabbit was established.

Toxicity to reproduction: other studies

Additional information

NA

Justification for classification or non-classification

TS-ED 532 did not show any evidence of developmental and reproductive effects, including endocrine disrupting effects, at maximum recommended dose levels in accordance with guideline. The identified NOAEL was > 1000 mg/kg bw/day for developmental toxicity in rats and rabbits, and NOAEL ≥ 1159 mg/kg bw/day for reproductive and developmental neurotoxicity in rats.

Based on these results, TS-ED 532 is not expected to have hazardous properties and shall not be classified according to GHS and DSD-DPD.