Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Additional information

The potential for isobutyric acid, monoester with 2,2,4 -trimethylpentane-1,3 -diol to cause reproductive toxicity is well understood. In a combined repeated dose toxicity study with the reproduction/developmental toxicity screening test conducted according to OECD Guideline 422, both sexes were exposed to up to 1000 mg/kg bw/day by oral gavage with no gross or microscopic effects on reproductive organs of either sex. There were no treatment-related effects on sexual function, fertility, or any reproductive parameters of parental animals exposed continuously during premating, mating, gestation, and through lactation Day 4. The gestation period, numbers of corpora lutea, implantation sites, pups born and live pups born, sex ratio, number of live pups on Day 4 after birth, and number of stillborns were similar across groups. All pregnant animals delivered normally and there were no adverse effects during the lactation period. The NOEL for reproductive toxicity was 1000 mg/kg bw/day when the test material was administered by oral gavage.

In a prenatal developmental toxicity study, the test substance, Texanol™, was administered orally by gavage to 3 groups of 25 bred female Crl:CD(SD) rats once daily from gestation days 1 through 19. Dosage levels were 100, 300, and 1000 mg/kg/day administered at dosage volumes of 0.11, 0.32, and 1.05 mL/kg, respectively. A concurrent control group composed of 25 bred females received the vehicle (deionized water) on a comparable regimen at a dosage volume of 1.05 mL/kg. The females were approximately 13 weeks of age at the initiation of dose administration. All animals were observed twice daily for mortality and moribundity. Clinical observations, body weights, and food consumption were recorded daily. On gestation day 20, a laparohysterectomy was performed on each female. The uteri, placentae, and ovaries were examined, and the numbers of fetuses, early and late resorptions, total implantations, and corpora lutea were recorded. Gravid uterine weights were recorded, and net body weights and net body weight changes were calculated. The fetuses were weighed, sexed, and examined for external, visceral, and skeletal malformations and developmental variations. All females survived to the scheduled necropsy on gestation day 20. Test substance-related increased incidences of red and/or clear material around the mouth were noted for females in the 100, 300, and 1000 mg/kg/day groups approximately 1 hour following dose administration. In addition, low incidences of red material around the nose and yellow material around the urogenital area were noted for females in the 100, 300, and/or 1000 mg/kg/day groups at the daily examinations and/or approximately 1 hour following dose administration. However, the post-dose findings did not generally persist to the daily examinations the following day, and in the absence of other signs of systemic toxicity at these dosage levels, these clinical findings were considered non-adverse. Test substance-related reductions in mean food consumption values with corresponding decreases in mean body weight gains were noted in the 1000 mg/kg/day group during gestation days 1-3 and 3-6 compared to the control group. Mean body weight gains and food consumption in this group were similar to the control group during the remainder of the dosing period (gestation days 6-20). The initial lower mean body weight gains in this group resulted in a lower mean body weight gain when the overall dosing period (gestation days 1-20) was evaluated compared to the control group; however, this change occurred in the absence of reduced food consumption. Mean net body weight gain in this group was also lower than the control group, while mean net body weight and gravid uterine weight were similar to the control group. The test substance-related changes in mean body weight gain and food consumption at 1000 mg/kg/day during gestation days 1-6 were considered adverse. There were no test substance-related effects on mean maternal body weights, body weight gains, food consumption, net body weights, net body weight gains, and gravid uterine weights at 100 and 300 mg/kg/day. No test substance-related macroscopic findings were noted at any dosage level. Intrauterine growth and survival were unaffected by test substance administration at 100, 300, and 1000 mg/kg/day. In addition, there were no test substance-related external, visceral, or skeletal fetal malformations or developmental variations observed at any dosage level. Based on reduced mean food consumption values with corresponding decreases in mean body weight gains at 1000 mg/kg/day during the first week of treatment, a dosage level of 300 mg/kg/day was considered to be the no-observed-adverse-effect level (NOAEL) for maternal toxicity. Intrauterine growth, survival, and external, visceral, and skeletal fetal morphology were unaffected by test substance administration at all dosage levels. Based on these results, a dosage level of 1000 mg/kg/day (the highest dosage level tested) was considered to be the no-observed-adverse-effect level (NOAEL) for embryo/fetal developmental toxicity when Texanol™ was administered orally by gavage to bred Crl:CD(SD) rats.

Effects on developmental toxicity

Additional information

The potential for isobutyric acid, monoester with 2,2,4 -trimethylpentane-1,3 -diol to cause developmental toxicity is well understood. In a combined repeated dose toxicity study with the reproduction/developmental toxicity screening test conducted according to OECD Guideline 422, both sexes were exposed to up to 1000 mg/kg bw/day by oral gavage. There was no evidence of embryo/fetal toxicity at any dose level tested. There was no increase in the incidence of pup mortality across dose groups, no treatment-related effects detected on external examination of pups born, pup body weights increased until Day 4 of lactation, and pups surviving until Day 4 of lactation did not demonstrate any treatment-related effects. The NOEL for embryo/fetal toxicity was 1000 mg/kg bw/day when the test material was administered by oral gavage.

To obtain conclusive evidence that the test material is not a developmental/reproductive toxicant, a prenatal developmental toxicity study (OECD 414) will be conducted using the related substance 2,2,4 -trimethyl-1,3 -pentanediol diisobutyrate (TXIB) in accordance with US Good Laboratory Practices (GLPs).

Justification for classification or non-classification

There were no adverse effects on reproductive organs in either sex of rats and no adverse effects on any reproductive or developmental parameters in a combined repeat dose and reproductive/developmental toxicity screening test in which both sexes were exposed to up to 1000 mg/kg bw/day isobutyric acid, monoester with 2,2,4 -trimethylpentane-1,3 -diol by oral gavage from 2 weeks prior to mating through early lactation (Day 4).  Based on a weight-of-the-evidence assessment, isobutyric acid, monoester with 2,2,4 -trimethylpentane-1,3 -diol is not selectively toxic to the fetus and is not classified for “Reproductive/Developmental Toxicity” according to EU GHS.