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Administrative data

Description of key information

The acute oral LD50 of TAEE is greater than 2000 mg/kg bw. The acute inhalation LC50 of TAEE is greater than 23.2 mg/l. The acute dermal LD50 is expected to be greater than 2000 mg/kg bw.
Available human data on acute inhalation toxicity of TAME and ETBE showed a lower NOAEC for ETBE compared to TAME. The data on ETBE show minor complaints of sensory effects and pulmonary function changes at 50 ppm (210 mg/m3). Based on these data a NOAEC of 25 ppm (105 mg/m3) is established for ETBE.

Key value for chemical safety assessment

Acute toxicity: via oral route

Endpoint conclusion
Dose descriptor:
LD50
Value:
2 000 mg/kg bw

Acute toxicity: via inhalation route

Endpoint conclusion
Dose descriptor:
LC50
Value:
23 200 mg/m³

Acute toxicity: via dermal route

Endpoint conclusion
Dose descriptor:
LD50
Value:
2 000 mg/kg bw

Additional information

Animal data

Acute oral toxicity was determined in a GLP compliant guideline study (acute toxic class method, Method B1 of Directive 2004/73/EC) using 6 young adult female Sprague Dawley rats (Covance Laboratories Ltd, 2009b). The test substance was administered neat as a single dose by gavage (2000 mg/kg bw) following an overnight fast, and the animals observed for 14 days post-treatment. Access to food recommenced approximately 3 hour post-treatment. There were no deaths noted following treatment and the animals gained weight normally. Piloerection was observed in the first group of 3 animals, 3 hour after dosing. Piloerection and hunched posture were present in the second group of 3 animals 3 hour after dosing, with piloerection and ataxia recorded 4 hour after dosing. No gross abnormalities were detected on study day 14. The results demonstrate that the acute oral LD50 of TAEE is greater than 2000 mg/kg bw.

 

Acute inhalation toxicity was determined in a GLP compliant guideline study (OECD 403) using young adult Wistar rats of both sexes, 5 males and 5 females (Covance Laboratories Ltd., 2009c). Animals were exposed nose-only to a single vapour concentration (23.2 mg/L) of the test substance (the achieved concentration was confirmed using GC-FID). One male died during exposure, and the survivors exhibited signs of mild CNS depression with a slight (3%) reduction in body weight. Treatment-related clinical signs included ataxia, bradypnoea, dyspnoea, hunched posture, prone and ptosis. One male exhibited decreased activity on Day 2. All animals appeared normal thereafter. There were no deaths during the 14 day follow-up period and no gross abnormalities detected in survivors at necropsy. The results demonstrate that the acute inhalation LC50 of TAEE is greater than 23.2 mg/L.

In an early, pre-guideline non-GLP experimental investigation (Marsh and Leake, 1950), groups of mice were exposed to TAEE vapour for 15 min until the concentration required to kill 9-11 of 20 exposed animals was identified. This concentration was considered to be the LC50, and found to be 81 mg/l (15 min exposure).

 

No data regarding the dermal route is available. However, Article 13 of the REACH legislation states that, in case no appropriate animal studies are available for assessment, information should be generated whenever possible by means other than vertebrate animal tests, i. e., applying alternative methods such as in vitro tests, QSARs, grouping and read-across. For the structural analogues of the substance, TAME (2-methoxy-2-methylbutane) and ETBE (2-ethoxy-2-methylpropane), data are available regarding acute dermal toxicity (analogue approach).

ETBE:

In a GLP complaint study performed according to a method comparable to OECD guideline 402, ETBE was applied at a dose level of 2000 mg/kg bw to the shaved dorsum of 5 male and 5 female White rabbits under occlusion for 24 hr. There were no deaths. The LD50 was determined to be > 2000 mg/kg bw (IIT Research Institute, 1989).

 

TAME:

An acute dermal toxicity study with rabbits, performed under GLP and according to a procedure comparable with OECD Guideline 402 is available (IIT Research Institute, 1991a). TAME was applied undiluted at a dose of 2000 mg/kg bw to the shaved backs of five male and five female New Zealand White rabbits. No deaths occurred during the study. The LD50 for TAME was estimated to be greater than 2000 mg/kg bw.

 

Based on the comparable physico-chemical properties of TAEE, ETBE and TAME, the low biological activity of the three substances after acute inhalation and oral exposure and the low biological activity of TAME and ETBE regarding acute dermal toxicity (LD50 values >2000 mg/kg bw), the acute dermal toxicity of TAEE is also considered to be low (i.e. the dermal LD50 value is assumed to be >2000 mg/kg bw).

Human data

Some human data are available for the structural analogues of TAEE (TAME (2-methoxy-2-methylbutane) and ETBE (2-ethoxy-2-methylpropane)) (see section 7.10.5 of the IUCLID).

 

TAME:

In a volunteer study with six humans (men) per group (Pekari et al, 1997b), TAME caused only minor acute effects (exposure concentrations: 15 ppm (60 mg/m3) and 50 ppm (212 mg/m3)). The reporting on the effects is somewhat inconsistent and not very firm conclusions can be drawn from the study. Feelings characterised as heaviness of the head seemed to correlate inversely with increasing TAME concentration. Concentrations up to 50 ppm did not have an effect on reaction time, balance or mood during/after 4-hour exposure. In conclusion, 50 ppm (212 mg/m3) is considered the NOAEC in this study.

 

ETBE:

Human data (eight human subjects) (Nihlen et al, 1998b) showed a small (3-4%) but significant (P<0.05) decrease in forced vital capacity (FVC) and vital capacity (VC) in subjects exposed to 25 or 50 ppm ETBE vapour. The authors state that one-second forced expiratory volume (FEV1) and the transfer factor (TLco) were also decreased significantly (approx. 2% and 2-4%, respectively) after exposure, however data included in the publication was assigned non-significant P values. In conclusion, slightly decreased lung function was observed. The changes were mild in nature and minor in extent.They fall within the changes as part of the normal daily variation (circadian rhythm).

There was no statistically significant effect on eye redness, tear-film break-up, conjunctival damage or blinking frequency after exposure up to 50 ppm ETBE vapour for 2 hours. Subjective symptoms of ocular discomfort were greater in the 50 ppm group (compared to the 5 and 25 ppm group), but no dose-response relationship or statistically significant difference was present. The intensity of the response at 50 ppm appeared to be very mild (stated to be between "not at all" and "hardly at all").

Exposure to 50 ppm ETBE vapour for 2 hr was associated with subjective discomfort of the airways. Subjective symptoms of nasal discomfort were greater in the 50 ppm group, but no dose-response relationship or statistically significant difference was present. The intensity of the response at 50 ppm appeared to be very mild (stated to be between "not at all" and "hardly at all"). Symptoms had resolved 80 min after exposure ceased. The taste and odour of the test atmosphere was unpleasant and unacceptable to the subjects and suggest that subjective findings may be unreliable.

Justification for classification or non-classification

In accordance to Directive 67/548/EEC and EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008, classification is not necessary for acute oral, inhalation and dermal toxicity based on the available data.