Registration Dossier

Administrative data

Description of key information

Key value for chemical safety assessment

Acute toxicity: via oral route

Endpoint conclusion
Dose descriptor:
LD50
4 500 mg/kg bw

Acute toxicity: via inhalation route

Endpoint conclusion
Dose descriptor:
LC50
199 918 mg/m³

Additional information

Acute Oral Toxicity

The acute oral toxicity of tertiary butyl acetate is well understood. In the key study, an acute oral toxicity study conducted according to US EPA Guideline 798.1175, tertiary butyl acetate had acute oral LD50 values of 4100 mg/kg bw for male rats, 4750 mg/kg bw for female rats, and 4500 mg/kg bw for both sexes combined when groups of five animals/sex were administered single doses of 2000, 5000 or 7000 mg/kg bw. All animals receiving 7000 mg/kg bw of the test material died by the day after dosing. Death was noted in 4 of 5 male and 2 of 5 female rats at the mid-dose level. In survivors of both sexes of the 2000 and 5000 mg/kg bw dose groups, reversible clinical signs indicative of central nervous system depression included lethargy, ataxia, flaccid muscle tone, prostration, and piloerection (LOAEL = 2000 mg/kg bw). A single low-dose group male appeared clinically normal throughout the study. There were no adverse effects on body weight or gross abnormalities noted in animals surviving to study termination. A lesser non-guideline study in rats (Industrial Bio-Test Laboratories, 1958), in which there was no analytical confirmation of test material identity, supports the acute oral LD50 value and the prevalence of clinical signs indicating central nervous system toxicity for tertiary butyl acetate reported in the key study.

 

In addition to classification for acute lethality, as a liquid, tertiary butyl acetate should also be considered for classification as an aspiration hazard based on certain physical properties. 

  

Acute Dermal Toxicity

The acute dermal toxicity of tertiary butyl acetate is well understood. In the key study, an acute dermal toxicity study conducted to be in compliance with EPA OTS Guideline 798.1100, tertiary butyl acetate had an acute dermal LD50 value of >2000 mg/kg bw in male and female rabbits. All animals survived until study termination. There were no clinical findings of central nervous system effects or signs of skin irritation, ulceration, necrosis, or evidence of tissue destruction during the 14-day observation period. Diarrhea noted in 3 of 10 animals was not considered a treatment-related effect since this is a common occurrence in rabbits. Gross abnormalities noted at necropsy were limited to pitted kidneys (moderate) in one female rabbit. The NOAEL in this study was 2000 mg/kg bw. A lesser non-guideline study in rabbits (Industrial Bio-Test Laboratories, 1958), in which there was no analytical confirmation of test material identity, supports the acute dermal LD50 value and the absence of clinical signs and systemic effects for tertiary butyl acetate reported in the key study. The supporting study reported an acute dermal LD50 value of >23.0 mL/kg (equivalent to >19800 mg/kg bw based on the density of tertiary butyl acetate).

  

Acute Inhalation Toxicity

The acute inhalation toxicity of tertiary butyl acetate is well understood. One key and one supporting study were selected for the review. In the key study (Huntingdon Life Sciences, 1999), conducted by a method designed to comply with ECC, OECD, US-EPA and J-MAFF test guidelines for acute inhalation studies, tertiary butyl acetate had an acute inhalation LC50 value of 4211 ppm (19918 mg/m3) for a six-hour exposure in male and female rats. Purity of the test material was ≥ 95%. Test exposure concentrations were 0, 1873, 3502 and 5066 ppm (8859, 16564 and 23962 mg/m3) and were verified analytically. All deaths occurred on the day of exposure. All animals exposed to 5066 ppm either died during exposure or were sacrificed in extremis one hour after exposure. Four female rats died from exposure to 3502 ppm while no deaths were reported in either sex at 1873 ppm. Reversible clinical signs including whole body tremors, staggering, rapid shaking of the head and thorax, walking on tips of toes, and exaggerated breathing were reported in both sexes in the low exposure group. Similar effects were observed in males and the surviving female exposed to 3502 ppm. All surviving animals appeared clinically normal by Day 1. Gross observations at necropsy in exposed animals surviving to study termination were limited to minimal to moderate congestion of the lungs (one 3502 ppm group male) and dark foci on the lungs (one 1873 ppm and two 3502 ppm group males). There were no treatment-related effects for surviving animals on body weight gain, organ weights, or food/water consumption. 

  

A supporting study (Stillmeadow Laboratories, 1997), conducted according to EPA OTS Guideline 798.1150, exposed male and female rats to a single exposure concentration of 470 ppm (2223 mg/m3) tertiary butyl acetate for four hours. The concentration of the test material at the animal breathing zone was determined analytically once per hour and nominally at the end of the exposure period. No deaths or clinical signs associated with exposure to the test material were reported. Body weight changes were generally unaffected and there were no observable abnormalities at gross necropsy. The usefulness of this study is somewhat limited by the lack of purity information for the test material and the use of a single, relatively low concentration tested for the acute inhalation toxicity endpoint. Based on the results of this study, the acute inhalation LC50 value for tertiary butyl acetate is > 470 ppm for a four hour exposure in male and female rats.

An earlier acute rat inhalation study for tertiary butyl acetate is also reported (Industrial Bio-Test Laboratories, Inc., 1958b). This study reported a 4-hour rat LC50 of 2810 ppm (13300 mg/m3) and a LOAEL of 1057 ppm (5000 mg/m3). This study, however, is of questionable value since: a) the study report identified the chemical tested as TFA-168; b) the report states that the animals were exposed to a “mist” ; and c) the chamber concentrations were not verified analytically. A detailed explanation of the shortcomings of this study is provided in Cruzan and Kirkpatrick (2006).

  

In addition to acute inhalation studies, subacute and subchronic inhalation studies in rats and mice are also briefly included here because they provide supporting evidence for the clinical signs of acute toxicity previously discussed. In a subacute mouse study (WIL Research Laboratories, 2007), conducted to be in general accordance with US EPA OPPTS Guideline 870.3465, groups of male and female mice were exposed (whole-body) for 6 hours/day, 7 days per week for 2 consecutive weeks to 0, 190, 375, 751, 1501 or 3000 ppm tertiary butyl acetate. Clinical examinations were performed 3 times daily, i.e., prior to exposure, at approximately the midpoint of each 6-hour exposure if animals were visible through the chamber windows, and within 0-1 hours post exposure. Purity of test material was >99% and the test concentrations at the animal’s breathing zone were verified analytically. Due to overt signs of toxicity including pronounced central nervous system depression and labored respiration, animals in the highest exposure group were removed from study. Clinical signs indicative of central nervous system effects were also observed in a few 751 and 1501 ppm animals during exposure or shortly after exposure termination. The NOAEC for acute CNS effects in the 14 day mouse study was 375 ppm. In a subacute study in rats (Huntingdon Life Science, Ltd., 2000), groups of male and female rats were exposed (nose only) to 120, 430, or 1643 ppm tertiary butyl acetate for 6 hours/day, 5 days a week for 2 consecutive weeks plus a single exposure on the Monday of the third week (11 exposures total). Clinical observations were performed pre-exposure, during exposure, and as the animals were returned to their home cages after exposure. There were no test-related clinical signs seen immediately pre-exposure or during exposure. Unsteady gait was observed immediately post-exposure in the high-exposure group animals. The NOAEC for acute CNS effects in the 14 day rat study was 430 ppm. For both species, these clinical findings were not observed on the morning following exposure, prior to the next 6-hr exposure. The clinical findings were transient and did not become persistent or increase in incidence or severity with two weeks of repeated exposure. Clinical signs of acute toxicity including hyperactivity, excessive grooming, impaired equilibrium, and/or labored respiration were also noted in a subchronic inhalation mouse study but not in a subchronic rat study conducted at WIL Research Laboratories (2006) when animals were exposed to 100, 400 or 1600 ppm of test material for 6 hours/day, 7 days/week for 13 weeks. The NOAEC for acute CNS effects in the 90 day rat study was 1600 ppm. The NOAEC for acute CNS effects in the 90 day mouse study was 100 ppm and when this data was used in a Benchmark Dose calculation exercise, the LEC10 value was 150 ppm (710 mg/m3).  These findings were acute and transient effects of daily exposure, with no test-substance-related findings present at the pre-exposure observations. 

Justification for classification or non-classification

Based on an acute dermal LD50 value of >2000 mg/kg bw in male and female rabbits, tertiary butyl acetate is not classified for acute lethality by the dermal route according to EU CLP (Regulation (EC) No. 1272/2008), and UN GHS. Based on an LD50 value of 4500 mg/kg bw for male and female rats administered a single oral dose of tertiary butyl acetate, tertiary butyl acetate is classified as Category V for acute lethality by the oral route according to UN GHS; however, there is no Category V in EU CLP (Regulation (EC) No. 1272/2008). Therefore, tertiary butyl acetate is not classified for acute lethality by the oral route according to EU CLP (Regulation (EC) No. 1272/2008). Tertiary butyl acetate meets the criteria as Category IV for acute toxicity under EU CLP (Regulation (EC) No. 1272/2008) based on an inhalation LC50 (6-hr) of 4211 ppm.  A harmonized classification for tertiary butyl acetate exists, however this hazard category is not included. A recommendation is made to add the classification for Acute Toxicity Category IV, H-332 "Harmful if inhaled" to Table 3.1 of Annex VI. In addition Acute Toxicity Category IV for acute inhalation toxicity is recommended for the UN GHS classification.

 

In accordance with EU CLP (Regulation (EC) No. 1272/2008) and UN GHS, tertiary butyl acetate meets the criteria for classification as Category 3 for Specific Target Organ Toxicity – Single Exposure (STOT-SE) based on the presence of reversible central nervous effects observed during and immediately following exposure by the oral and inhalation routes and respiratory tract irritation during and following inhalation exposures. A harmonized classification exists for tertiary butyl acetate; however, this hazard category is not included. A recommendation is made to STOT-SE Category 3, H-335 "May cause respiratory irritation" and H-336 "May cause drowsiness or dizziness" to Table 3.1 of Annex VI. 

  

Because it is a liquid, tertiary butyl acetate should also be evaluated for classification as an aspiration hazard. Tertiary butyl acetate does not meet the criteria for a Category 1 aspiration hazard, i. e., (a) a chemical known to be an aspiration hazard, or (b) a hydrocarbon with a kinematic viscosity of ≤ 20.5 mm2/s, measured at 40 °C according to EU CLP (Regulation (EC) No. 1272/2008) and UN GHS. Tertiary butyl acetate does not belong to a class of chemicals specifically noted in the UN GHS regulations for Category 2, i. e., n-primary alcohol with 3-13 carbon atoms, isobutyl alcohol, and ketones with ≤ 13 carbon atoms, but based on some of its physical and chemical properties, it should be considered a Category 2 Aspiration Hazard. Tertiary butyl acetate has a surface tension of 21.8 dyne/cm at 22.5 °C , a low water solubility (0.8% at 23 °C), a kinematic viscosity of < 14 mm2/s (based on a viscosity of < 1.2 cSt at 20 °C), and a boiling point of 98 °C at 760 mm Hg. Although tertiary butyl acetate would be considered a Category 2 aspiration hazard according to the UN GHS, there is no Category 2 included in EU CLP (Regulation (EC) No. 1272/2008). Therefore, tertiary butyl acetate is not classified as an aspiration hazard according to EU CLP (Regulation (EC) No. 1272/2008).