Administrative data
The available animal and limited human data indicate that ETBE is not irritating to the skin, eyes and respiratory tract.
Key value for chemical safety assessment
Skin irritation / corrosion
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed (not irritating)
Eye irritation
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed (not irritating)
Respiratory irritation
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed (not irritating)
Additional information
Three dermal irritation/corrosion studies with
rabbits were available for assessment, performed according to OECD
Guideline 404 or to a similar method and under GLP and showed that ETBE
does not have to be classified for skin irritation. For one of the two
studies performed in accordance with OECD Guideline 404 (Pharmakon Europe,
1994b), the original study report is made available. Therefore that study
is considered the key study. The mean scores (24, 48 and 72 hours) for
erythema and oedema were 0.67 and 0.11, respectively in this study and
showed that ETBE is not irritating to the skin (test performed under
semi-occlusive conditions).
For the other OECD Guideline 404 study
(Centre International de Toxicologie, 1992a), no original study report was
available. In that study ETBE was also not irritating under semi-occlusive
dressing. During 24 hours, slight erythema and/or oedema was observed
(mean scores around 1). There was no erythema or oedema present at 72
hours.
For the study performed by MB Research
Laboratories (1988b) a study report was available. In that study, ETBE was
applied to two clipped region areas of intact skin and two of abraded skin
(area not specified) of 2 male and 4 female New Zealand White rabbits
under occlusion. The patch was removed after 4 hr and the test sites were
wiped. Erythema and oedema were observed to some extent (mean scores = 2
or less). Erythema, generally absent at 4 hr, was well-defined at 24 hr
and 48 hr, and slight-to-well defined at 72 hr. By day 7, erythema was
absent to well-defined. At day 14, no erythema was present. Oedema was
slight to well defined at 4, 24 or 48 hr, and absent to well defined at 72
hr. Flaking skin was present at majority of sites on day 7 (absent at
preceding and later time points). ETBE was concluded to be moderately
irritating to the skin based on this study by the authors. The mean scores
for edema and erythema at 24, 48 and 72 hours do not trigger
classification for skin irritation.
In conclusion, based on the available
studies, ETBE is not considered irritating to skin.
Three eye irritation studies with rabbits,
all performed according to OECD Guideline 405 and under GLP, were
available for assessment and showed the same effect (no eye irritation).
As no sample purity was specified in two of these studies, the remaining
study (Pharmakon Europe, 1994c) was considered to be the key study. ETBE
was instilled into the conjunctival sac of the right eye of 3 male New
Zealand White rabbits, the left eye serving as a control. Mean individual
scores for chemosis and redness (conjuntivae), congestion (iris) and
(opacity) cornea were less than 1 at 24, 48 or 72 hours, except the score
for redness which was 1.67 at 48 hours. Residual redness in one animal
(score = 1) and residual congestion in another (score = 1) had resolved
completely by day 7.
According to the available human data
(Nihlen et al, 1998b, see study summary in section on acute toxicity),
there was no statistically significant effect on eye redness, tear-film
break-up, conjunctival damage or blinking frequency in human volunteers
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, and the intensity of the response at
50 ppm appeared to be very mild (stated to be between "not at all" and
"hardly at all"). Overall, therefore, these findings do not provide
convincing evidence that 50 ppm ETBE vapour is irritating to the eye.
No animal studies regarding respiratory
tract irritation are available. The acute inhalation toxicity study and
the inhalation repeated dose toxicity studies with rats and mice do not
trigger a concern for respiratory tract irritation.
Regarding the available human data (Nihlen
et al, 1998b, see study summary in section on acute toxicity), 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"). Subjective symptoms had resolved 80 min after exposure
ceased. The taste and odour of the test atmosphere was unpleasant and may
have resulted in them reporting effects in the absence of measurable
tissue changes. Hence while the reliability of these findings is not
known, a conservative NOAEC of 25 ppm will form the basis of a DNEL for
effects after repeated inhalation exposure.
Regarding the objective measurements,
exposure to ETBE vapour was without effect on the composition of nasal
lavage fluid (i.e. leukocytes, epithelial cells, inflammatory markers etc).
Justification for classification or non-classification
Based on the available
studies and 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 skin and eye irritation.
Furthermore, the available data do not trigger classification for
respiratory tract irritation.
