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Key value for chemical safety assessment

Effects on fertility

Additional information

The potential for tertiary butyl acetate to cause reproductive toxicity is well understood.  In the key study, a reproductive and developmental toxicity screening study conducted according to EPA OPPTS Guideline 870.3650, male and female Sprague-Dawley rats were exposed to up to 1600 ppm tertiary butyl acetate by inhalation for 6 hours/day, 7 days/week during premating, mating, gestation, and lactation for a total of 109-110 exposure days for males and 97-119 exposure days for females. There were no treatment-related effects on reproductive endpoints for males (weight of testis, epididymis, and cauda; sperm motility, production rate, count or morphology) or females (estrous cycle length or percentage of time spent in the various estrous stages). There also were no test material-related effects on reproductive performance as measured by male and female mating indices, male and female fertility indices, male copulation and female conception indices, and mean numbers of days between pairing and coitus when compared to control group values. In a key repeat-exposure study conducted according to EPA OPPTS Guideline 870.3465, male and female CD-1 mice were exposed to up to 1600 ppm tertiary butyl acetate for 6 hours/day, 7 days/week for 13 weeks. There were no treatment-related effects on estrous cycle length or macroscopic/ microscopic effects on reproductive organs including epididymides, mammary gland, ovaries/oviducts, prostate, seminal vesicles, testes, uterus or vagina.

These studies have been discussed and expertly reviewed in a publication by Faber et al (2014), with the citation appearing in the relevant toxicity to reproduction and developmental toxicity endpoint study records

 

In addition to data for tertiary butyl acetate, read-across data for tertiary butyl alcohol, the primary in vivo metabolite of tertiary butyl acetate, should be considered in the overall evaluation of reproductive toxicity. In a reproduction/ developmental toxicity screening study in rats (Huntingdon Life Sciences, 2004), tertiary butyl alcohol was administered to male and female rats by oral gavage at dose levels of 0, 64, 160, 400 and 1000 mg/kg bw/day for up to 63 days in males and from 4 weeks prior to mating through Post Natal Day 21 in females. Even at dose levels that caused mild to moderate transient systemic toxicity in both sexes of the parental generation and reduced feed consumption and weight gain, there were no adverse effects on any reproductive parameters including mating index, fertility index, pregnancy index, or gestation index.

 

Effects on developmental toxicity

Additional information

The potential for tertiary butyl acetate to cause developmental toxicity is well understood. Three key guideline studies were available for review. In a developmental/reproductive screening study conducted according to EPA OPPTS Guideline 870.3650, there were no treatment-related effects on post-natal development when the parental generation was exposed to up to 1600 ppm tertiary butyl acetate by inhalation for 6 hours/day, 7 days/week during premating, mating, gestation, and lactation for a total of 109-110 exposure days for males and 97-119 exposure days for females. For dams, no test material-related effects were noted on mean gestation lengths or the process of parturition at any exposure concentration. Mean number of pups born, live litter size, percentage of males per litter, postnatal survival on Post Natal Day (PND) 0 and during pre-selection and post-selection periods, and the physical condition of F1 pups were not affected by exposure level. Offspring body weights and body weight gains were not significantly affected by exposure to the test material via milk during the lactation phase or when pups were directly exposed by the inhalation route on PND 22-26 at the same concentrations to which their parents had been exposed. Developmental landmarks, including pinnal detachment, attainment of surface righting response, hair growth, eye opening and incisor eruption were not affected by parental exposure to the test material, and there were no gross malformations noted at pup necropsies. No exposure-related clinical findings were noted when pups selected for direct exposure to the test substance on PND 22-26 were examined before, during or one hour following exposure and all pups directly exposed via inhalation survived to scheduled necropsy.

This study has been discussed and expertly reviewed in a publication by Faber et al, with the citation appearing in the relevant toxicity to reproduction and developmental toxicity endpoint study records.

 

In a published developmental toxicity/teratogenicity study (Yang et al., 2007) conducted according to OECD Guideline 414, there was no evidence of teratogenicity when pregnant Sprague-Dawley rats were exposed to 0, 400, 800 or 1600 mg/kg bw/day tertiary butyl acetate by oral gavage on Gestation Days 6-19, even though the highest dose level caused maternal mortality, adverse clinical signs primarily related to central nervous system depression, reductions in mean body weights and food consumption, and changes in mean adrenal gland, liver and thymus weights. There was a statistically significant exposure-related increase in the number of skeletal variations in the offspring of dams receiving 800 or 1600 mg/kg bw/day. These variations are typical of embryo/fetotoxicity, particularly reduced ossification. In this study, tertiary butyl acetate was also minimally embryo/fetotoxic at 800 mg/kg bw/day, a dose level not reported to cause maternal toxicity.

 

Since the Yang et al. (2007) study had minimal evaluation of the dams for maternal toxicity, a second study was conducted focusing on maternal toxicity and selected fetal endpoints. Groups of pregnant Sprague-Dawley rats were administered 0, 400, 800, 1000 or 1600 mg/kg bw/day of test material by oral gavage on Gestation Days 6-19. In this study, mortality was again observed at 1600 mg/kg bw/day and some or all of the animals receiving 800, 1000 or 1600 mg/kg bw/day of tertiary butyl acetate exhibited behavior-related clinical signs indicative of central nervous system depression at one or more times during the dosing period. In addition, decreased body weight gains and reductions in food consumption were also reported at the three highest dose levels. Although this study limited fetal parameters to external examinations, there were no reported adverse effects on intrauterine survival, early and late resorptions, fetal sex ratio, number of implantation sites, pre- and post-implantation loss, corpora lutea or live litter size at any dose level. Intrauterine growth, as evidence by a statistically significant decrease in mean fetal body weights, was observed at dose levels also found to be maternally toxic.

 

In addition to data for tertiary butyl acetate, read-across data for tertiary butyl alcohol, the primary in vivo metabolite of tertiary butyl acetate, should be considered in the overall evaluation of developmental toxicity. In a published study by Faulkner et al. (1989), pregnant mice were administered tertiary butyl alcohol twice daily by oral gavage at a dose level of 10.5 mmoles/kg (~750 mg/kg bw) on Gestation Days 6 through 18. Although this study used a limited number of animals at a single dose level, it found no evidence of teratogenicity, even at a dose level causing fetolethality and significant fetotoxicity. In a published study by Nelson et al. (1989) in which pregnant rats were exposed to 2000, 3500 or 5000 ppm tertiary butyl alcohol for 7 hr/day on Gestation Days 1-19, there was no evidence of teratogenicity, even at maternally toxic exposure concentrations. An exposure-related increase in the incidence of fetotoxicity (decreases in fetal weights and increases in the number of skeletal variations) was associated with maternal toxicity.

    

Justification for classification or non-classification

There were no test material-related effects on reproductive parameters including mating performance; fertility; length of estrous cycle; sperm numbers, production rate, motility or morphology; or reproductive organs in either sex in a reproduction and developmental toxicity screening test in which adult male and female rats were exposed via inhalation to concentrations of up to 1600 ppm tertiary butyl acetate for 6 hours/day, 7 days/week during premating, mating, gestation and lactation for a total of 109-100 exposure days for males and 97-119 exposure days for females. There were also no test material-related effects on estrous cycle length or reproductive organs in either sex when male and female mice were exposed via inhalation to concentrations of up to 1600 ppm tertiary butyl acetate for 6 hours/day, 7 days/week for 13 weeks. Based on a weight-of–the-evidence assessment, tertiary butyl acetate is not classified for Reproductive Toxicity according to EU CLP (Regulation (EC) No. 1272/2008) and UN GHS.

  

There were no reported malformations or adverse developmental effects in the offspring of male and female rats exposed to tertiary butyl acetate by the inhalation route during premating, mating, gestation and lactation at concentrations up to 1600 ppm. There were no increases in any type of external, skeletal or visceral malformation in the offspring of pregnant rats receiving up to 1600 mg/kg bw/day of tertiary butyl acetate by the oral route. Skeletal variations reported in this study at 800 and 1600 mg/kg bw/day appear to be secondary effects to maternal toxicity. Based on a weight-of-the-evidence assessment, tertiary butyl acetate is not selectively toxic to the fetus and is not classified for Developmental Toxicity according to EU CLP (Regulation (EC) No. 1272/2008) and UN GHS.