Butyl glycollate

Endpoint summary

Key value for chemical safety assessment

Effects on developmental toxicity

Description of key information

Butyl glycollate (Polysolvan O) induced prenatal developmental toxicity including morphological alterations in rats at a very high maternal toxic dose level only.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

250 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

Reliabiiity 2

Additional information

Polysolvan O (butyl glycollate, 97.3%) was investigated in a prenatal developmental toxicity study in pregnant female Wistar rats according to OECD guideline 414 under GLP conditions. Each 20 pregnant females received dose levels of 0, 62.5, 250 and 1250 mg/kg bw/day orally by gavage from implantation at gestation day (GD) 7 through GD 16 (counting from day 1 of pregnancy). The test item was dissolved in sesame oil.

Signs of maternal toxicity occurred at 1250 mg/kg bw/day only and consisted of one premature death on gestation day 17. One additional dams had to be sacrificed due to severe clinical signs on gestation day 14. At this dose level, clinical findings in form of respiratory noise and pilo-erection was noted. Food consumption and body weight/body weight gain were reduced and there was an increase in kidney weights. The oral administration of the test substance to the dams at all 3 dose levels had no influence on the gestational parameters.

Signs of prenatal developmental toxicity including morphological alterations were only observed at 1250 mg/kg bw/day. The findings occurred in form of reduced fetal weight, reduced crown/rump length and lower placental weights. Morphological alterations were observed in form of an increased incidence of external and skeletal malformations of head, rump, vertebral column and hind limbs (exencephaly, craniochisis totalis, hydrocephalus internus, dysplasia of skull bones, bachygnathia, aplasia lentis, craniochisis, anophthalmia, spina bifida, scoliosis, omphalocele, gastrochisis, bend hind limbs). In addition, there was a general retardation of the fetal skeleton and an increased incidence of variations of vertebra column, ribs and sternebrae.

The dose levels of 62.5 and 250 mg/kg bw/day were tolerated without maternal or developmental toxicity and especially without morphological alterations in the fetuses.

Butyl glycollate (Polysolvan O, 97.3% ) was shown to induce prenatal developmental toxicity including morphological alterations in Wistar rats at a maternal toxic dose level only. The no observed adverse effects level (NOAEL) for maternal toxicity as well as for developmental toxicity including teratogenicity was 250 mg/kg bw/day (Albrecht M, Baeder C, 1992a).

Noteworthy to mention that the morphological examination of fetuses of 3 litters from dams receiving 1000 mg/kg bw/day in the respective range-finding study confirmed the prenatal developmental toxicity as comparable effects including slight teratogenicity were observed again at a dose level inducing also maternal toxicity (Albrecht M, Baeder C, 1992b).

Butyl glycollate and ethylene glycol form the common compound glycollic acid in their metabolisms. Because of the systemic toxicity observed in the kidneys when testing butyl glycollate and ethylene glycol in repeated dose studies in rats (durations from 2 to 13 weeks), it is concluded that these substances behave similarly due to the central role of glycollic acid in their systemic toxicity.

In consistency with the developmental toxicity effects (mice >rats > rabbits) showing only at high doses when maternal toxicity occurs and with the lack of reproductive toxicity in rats, rabbits and humans, the same toxicological outcome is expected for butyl glycollate if a pre-natal developmental toxicity study (OECD 414) in a second species (rabbit) and an extended one-generation reproductive toxicity study (OECD 443) in rats, via oral route are conducted.

More importantly, the extensive amount of data available on ethylene glycol and glycollic acid in addition to butyl glycollate data allows the conclusion that there is no reason to expect that conducting a pre-natal developmental toxicity study (OECD 414) in rabbits and an extended one year generation reproductive study (OECD 443) in rats with butyl glycollate will reveal new information or additional adverse developmental and/or reproductive effects in animals exposed to butyl glycollate. Developmental adverse effects are expected to be seen in rats when butyl glycollate is administered at high doses in the presence of severe maternal toxicity, but not in rabbits.

 

In conclusion, based on available in vitro data including an enzymatic hydrolysis with butyl glycollate and in vivo data, the use of toxicity data from ethylene glycol, glycollic acid and n-butanol is fully justified for this read across evaluation for butyl glycollate. No additional animal studies are required to fulfill the REACH information requirements.

Justification for classification or non-classification

According to EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008, the substance is classified as reproductive toxicant category 2 (Repr. 2) based on the observed developmental toxicity in rats. The basis for this proposed classification is also supported by an expert judgement (Buschmann, 2010).