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EC number: 216-653-1
CAS number: 1634-04-4
Appendix R.8-13 of the Guidance on information requirements and chemical
safety assessment Chapter R.8: Characterisation of dose
[concentration]-response for human health (ECHA, 2008) it is noted that:
an EU IOEL exists the registrant may, under conditions as described
below, use the IOEL in place of developing a DNEL. A registrant is
allowed to use an IOEL as a DNEL for the same exposure route and
duration, unless new scientific information that he has obtained in
fulfilling his obligations under REACH does not support the use of the
IOEL for this purpose. This could be because the information obtained is
more recent than the information that was used to support setting the
IOEL at EU level and because it leads to another value being derived
which requires different risk management measures (RMMs) and operational
the case of MTBE a final SCOEL evaluation is available (SCOEL, 2006). The
summary of the SCOEL evaluation is as follows:
studies in mice and rats reveal a spectrum of tumours induced by MTBE in
liver, kidney, parathyroid and Leydig-cells that occur only at high
doses (> 250 mg/bw after oral administration and > 3000 ppm in
inhalation studies). Neither the kidney tumours caused by
alpha-2-microglobulin and, consequently, the parathyroid tumours seen in
male rats, nor the liver tumours in female mice which were seen also in
the control animals seem to be of relevance for human health. The same
is true for the Leydig-cell tumours. There are neither epidemiological
studies addressing a possible association of MTBE with human cancer, nor
grounds for assuming there to be a concern. MTBE is not genotoxic.
Therefore, a threshold for the carcinogenic potential of this compound
on toxicokinetics concluded that MTBE or its metabolites do not
accumulate in humans.
animal studies involving repeated inhalation exposure indicate no
effects of toxicological significance for human health below 1000 ppm,
with effects having been reported only at 3000 ppm and above. There are
no relevant data for the toxicity of MTBE in man after repeated
a human volunteers study (FIOH, 1997), mild symptoms, mainly feeling of
"heaviness in the head", and mild mucosal irritation were reported. The
frequency of symptoms was related to the exposure level (0, 25, 75 ppm)
and reached statistical significance at 75 ppm after 3h of exposure to
MTBE. No effects were seen on simple reaction time or body sway
posturography. This study suggests a LOAEC of 75 ppm.
another volunteer study Nihlén et al (1998) found no increased ratings
of either irritation, or CNS effects. Further, none of the objective
measurements indicated any irritative or inflammatory response (blinking
frequency, eye redness score, tear-film break-up time, conjunctival
epithelial damage score, inflammatory markers in nasal lavage, nasal
acoustic rhinometry, nasal blockage index). This study suggests a NOAEC
for short-term exposure of 50 ppm.
into account the low inhalation toxicity in animal studies, the NOAEC of
50 ppm for irritation in humans and the mild effects seen after several
hours at 75 ppm, the SCOEL proposed an 8-h TWA of 50 ppm (178.5 mg/m3)
and a 15-min STEL of 100 ppm (357 mg/m3).
oral, inhalation and dermal absorption percentages used for DNEL
derivation (in cases of route-to-route extrapolation) are 100%, 40% and
acute toxicity, the DNELacute needs only be derived if an
acute toxicity hazard (leading to classification and labelling) has been
identified and peak exposures are likely to occur. The data support
classification of MTBE for skin irritation, however, it is not possible
to derive a DNEL on the basis of the available data. It is necessary to
implement risk management measures that prevent dermal exposure that
will cause skin irritation.
there is a published IOELV STEL (derived by the SCOEL, see above) of 100
ppm for MTBE. This value will used in the risk characterisation as an
acute DNEL (workers) or as an starting point to derive an acute DNEL
inhalation NOAEC for MTBE is 800 ppm (2856 mg/m3) (6
hours/day, 5 days/week) based on mild liver effects noted in a 90-day
inhalation rat study. The oral NOAEL for MTBE is 209 mg/kg bw/day based
on increased relative kidney weights in male and female rats in a 13
week drinking water study.
dermal repeated dose toxicity studies are available. In general, due to
the effective lipid extraction properties of MTBE, it can be presumed
that repeated skin exposure may result in skin fatigue (and consequent
risk of toxic eczema), an effect common to a variety of organic
solvents. No quantitative data on this effect are available. Therefore a
qualitative risk characterisation will be performed.
is assessed as being non-mutagenic and not carcinogenic. Based on this,
no separate risk characterisation for mutagenicity and carcinogenicity
on the available data, MTBE is not considered as toxic to fertility in
rats and mice. Therefore,
no DNEL has to be derived for this endpoint.
Developmental effects were only observed at maternally toxic
concentrations in rats and mice (from 3000 ppm (10710 mg/m3)) and do not
trigger classification for developmental toxicity. The long-term DNEL
(repeated dose toxicity) will also prevent the occurrence of
there are no indications from the available data that dams are more
sensitive regarding systemic effects compared to non-pregnant animals
exposed in the repeated dose toxicity studies.
the date of finalisation of the SCOEL evaluation, some new toxicological
data was published (which are included in this dossier). These new data
are not considered key and do not change the conclusions of the SCOEL.
Therefore, the 15-min STEL of 100 ppm (357 mg/m3) and the 8-h
TWA of 50 ppm (178.5 mg/m3) as recommended by the SCOEL will be used as
DNEL for acute and long-term for inhalation exposure, respectively.These
figures will also protect against the occurrence of reproductive
toxicity as the SCOEL also considered the available reproductive
toxicity data for MTBE.
dermal exposure, no dermal repeated dose toxicity studies are available.
To arrive at a long-term value for workers, route to route extrapolation
will be applied starting with the inhalation long-term value of the
178.5 mg/m3* 40/0.2 (a) * 10 m3(b) / 70 kg (c) = 5100 mg/kg bw/day
correction for absorption (40% inhalation and 0.2% dermal
(b) 8 hour respiratory volume for workers
(c) body weight for workers
information relevant to the development of DNELs for the general
population (including the available key animal data its interpretation
by SCOEL (2006)) is discussed above.
exposure, the SCOEL has established a15-min STEL of 100 ppm (357 mg/m3).
The SCOEL value is derived for workers. To arrive at a long-term value
for the general population, a factor for intraspecies differences will
be applied to the 15-min STEL. This factor is derived from the
scientifically based assessment factors reported by ECETOC (2010) (see
100 ppm (357 mg/m3) * 3/5 (a) = 60 ppm (214 mg/m3)
(a) correction for intraspecies differences: workers default factor: 3, general population default factor: 5
No correction for exposure duration isapplied as the STELvalue is largely driven by sensory irritation effects which are influenced by concentration and not time.
No correction for differences in activity levels between workers and the general population is applied. As workers have a higher ventilation rate compared to the general population, the current proposed acute DNEL for the general population is considered a worst-case acute DNEL.
long-term exposure, the SCOEL has established an 8-h TWA of 50 ppm
(178.5 mg/m3). The SCOEL value is derived for workers. To arrive at a
long-term value for the general population, a factor for exposure
modification and intraspecies differences will be applied to the 8-h TWA
(assuming ‘recovery’ to ‘no recovery’):
50 ppm (178.5 mg/m3) * 10/20 (a) * 3/5 (b) = 15 ppm (53.6 mg/m3)
(a) modification based on differences in exposure duration and activity (10 m3 in 8 h for workers, 20 m3 in 24 h for the general population)
(b) correction for intraspecies differences: workers default factor: 3, general population default factor: 5
Using the overall inhalation NOAEC of 800 ppm (2856 mg/m3) as starting
point for the DNEL derivation and applying a factor of 6/24 (exposure
duration adjustment) and the ECETOC assessment factors for interspecies
(1), intraspecies (5) and semichronic to chronic exposure (2) results in
DNEL of 20 ppm (71.4 mg/m3). The DNEL derived from the 8-h TWA SCOEL
figure is more conservative and hence selected for the risk
SCOEL has established an 8-h TWA of 50 ppm (178.5 mg/m3). The SCOEL
value is derived for workers. To arrive at a long-term value for the
dermal route for the general population, route to route extrapolation
will be applied starting with the inhalation long-term value calculated
for the general population:
53.6 mg/m3* 40/0.2 (a) * 20 m3(b) / 60 kg (c) = 3570 mg/kg bw/day
(a) correction for absorption (40% inhalation and 0.2% dermal absorption)
(b) 24 hour respiratory volume for the general population (to calculate the internal dose corresponding to 24 hour exposure)
(c) body weight for the general population
SCOEL has established an 8-h TWA of 50 ppm (178.5 mg/m3) for workers. To
arrive at a long-term value for the oral route for the general
population, route to route extrapolation will be applied starting with
the inhalation long-term value calculated for the general population:
53.6 mg/m3* 40/100 (a) * 20 m3(b) / 60 kg (c) = 7.1 mg/kg bw/day
(a) correction for absorption (40% inhalation and 100% oral absorption)
sensitivity extrapolation from rat to man is done by extrapolation from
the already interspecies extrapolated rodent EC05 (= EC05 interspecies
adjusted rat to human) to an assumed human EC05 (= NOAEL human). It
is assumed, that the rodent EC05 is a NOAEL and is conservatively 3.16
times smaller than the rodent EC50 and 10 times smaller than the rodent
EC95. So the ratio between the rat EC95 and EC05 is assumed to be a
factor of 10. This is in agreement with the applied dose range in a
rodent study being at least a factor of 10.
ECETOC intraspecies factor of 3, applied to the interspecies
extrapolated rodent EC05 (= EC05 interspecies adjusted rat to human)
means that the ratio between worker EC95 and EC05 is assumed to be 90.
ECETOC intraspecies factor of 5 applied to the interspecies extrapolated
rodent EC05 (= EC05 interspecies adjusted rat to human) means, that the
ratio between consumer EC95 and EC05 is assumed to be 250.
general population the ratio between the EC95 and EC05 is about a factor
of 25. That is
larger than that in the rat. The intraspecies assessment factors of
ECETOC account for this factor of 25 and in addition, for statistical
uncertainty in the comparison between human and animal studies on
repeated tolerable dose levels. Therefore, the ECETOC intraspecies
assessment factors are conservative for deriving a DNEL for workers and
for consumers (=general population).
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
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