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EC number: 203-710-0
CAS number: 109-83-1
Dose descriptor: LOAEL= 50 mg/kg
bw/day from the oral OECD 422 (BASF, 2010).
LOAEL corrected by an AF of 3 to
obtain a NOAEL; and corrected for differences in respiratory volumes
(1/0.38) and differences in Absorption (50/100) and respiratory volume
by light activity (6.7/10) and for differences in exposure duration
Corr. NOAEC = 20.6 mg/m³
It is assumed, that the dermal
absorption will not be higher than the oral absorption (ECHA's Guidance
R.8, v2.1, Nov 2012). Therefore, the NOAEL obtained via the oral route
is regarded as a worst-case starting point to determine the dermal DNEL.
This LOAEL is corrected by an AF of 3 to obtain a NOAEL; and corrected
for differences in exposure conditions (7/5)
Corr.NOAEC= 23.33 mg/kg bw/day
According to ECHA’s Guidance Part E
(v3, May 2016)
For MMEA, DNELs are needed for acute
and chronic exposures by the inhalation and dermal exposure routes.
The calculation of the DNELs is
performed in accordance with the principles given in ECHA (2008)
“Guidance of Information Requirements and Chemical Safety Assessment,
Chapter R.8: Characterisation of dose [concentration]-response for human
Available dose descriptors:
From all available data for the
different human health endpoints it is clear that MMEA exerts its effect
by a threshold mode of action. Thus, DNELs can be calculated for the
different threshold endpoints based on the most relevant dose
descriptors per endpoint. DNELs are derived from the available toxicity
data of MMEA, reflecting the routes, duration and frequency of exposure.
DNELs are derived for workers and general population. The general
population includes consumers and humans exposed via the environment.
There are following annotations for the whole database:
- DNELs for acute toxicity (inhalation
and dermal) should have been established because MMEA is classified for
acute toxicity. However, no repated dose toxicity data is available for
the exposure routs inhalation and dermal. Even though LD50values
are available for oral and dermal routes of exposures, these results are
not considered to be suitable starting points for DNEL derivation. As
MMEA is considered to be of moderate acute toxicity and can represent an
acute hazard in case if peaks of exposure are significantly higher the
average daily exposure level, and adequate data is missing, no DNELs can
be delineated. Instead a qualitative approach is followed and a "medium
hazard" is assigned, according to EHCA's Guidance Part E (v3, May, 2016).
- furthermore, a qualitative approach
for the DNEL derivation of eye and respiratory tract
irritation/corrosion, skin sensitization, mutagenicity and
carcinogenicity is used because no dose descriptors are available on
- A quantitative approach for the
derivation of DNELs of skin irritation/corrosion is also used because
MMEA is classified as a skin irritant. Moreover, it was possible to
identify a NOAEL from a sensitization study.
- DNELs for long-term systemic effects
are derived using data of the Combined Repeated Dose Toxicity with the
Reproduction/Developmental Toxicity Screening Test (BASF, 2010) (OECD
- For the non-threshold endpoints
(mutagenicity and carcinogenicity) no DNELs can be derived because a
No-Effect Level could not be established from the relevant studies.
Hence the hazard characterization is based on a qualitative approach.
In order to address the differences
between toxicological effect data obtained in animal studies and the
real human situation, assessment factors are applied. First of all,
available dose descriptors were converted into a correct starting point
to take account of differences in routes of exposure between
experimental animals and humans, differences in human and animal
exposure conditions and possible differences in absorption between
routes and between experimental animals and humans. Consecutively, the
assessment factors have been applied to the correct starting point to
obtain the endpoint specific DNELs. Assessment factors (AFs) correct
uncertainties and variability within and between species in the effect
The assessment factors are applied in
accordance with the default values given in ECHA (2012) “Guidance of
Information Requirements and Chemical Safety Assessment, Chapter R.8:
Characterisation of dose [concentration]-response for human health”.
Modification of the relevant dose
descriptors to the correct starting point:
Bioavailability for experimental
animals and humans for all exposure routes was assumed to be the same
because of the absence of information.
default factor (i.e. factor 1) is applied when oral-to-dermal
extrapolation is performed in accordance with Section R.8.4.2 (p.25).
default factor of 2 (50 % for oral absorption and 100 % for inhalation)
is applied when oral-to-inhalation extrapolation is performed.
times differed in the acute inhalation and repeated dose inhalation
studies. The dose descriptors were corrected as described in the
LOAEL obtained via the oral route is regarded as a worst-case staring
point to determine the dermal DNEL. This LOAEL is corrected by a factor
of 3 for extrapolation from LOAEL to NOAEL and a factor of 1.4 to
account for differences in exposure conditions (5 days/week for workers
and 7 days for week for animals in the test).
in the respiratory volumes between experimental animals and humans were
used when an oral LOAEL from a rat study was used to assess inhalation
exposure in humans.
% dermal absorption is assumed, based on the criteria set out in Annex
IV-B of the EU Technical Guidance Document on Risk Assessment (TGD;
2003, Part I).
Applying of assessment factors:
species-specific default assessment factor for allometric scaling from
Table R.8-3 is applied in case of repeated oral and dermal exposures.
species-specific default assessment factor for allometric scaling is
applied in case of inhalation exposure routes in animals which were
taken to assess human inhalatory exposure. Inhalatory dose descriptors
are modified into a correct starting point taken into account only the
differences of exposure conditions between experimental animals and
humans as well as differences in the respiratory volumes between
experimental animals and humans. No additional assessment factors are
applied for inhalation route and for local effects to obtain a corrected
starting point (Table R8-4, Appendix R.8-2, part 2, example A.2).
additional assessment factor if 2.5 is applied for remaining
factors of 5 and 10 are applied for workers and general population,
respectively, for all endpoints and all exposure routes
Extrapolation of duration:
The relevant default assessment factors from Table R.8.5 are applied.
Issues related to dose response:
assessment factor of 3 was applied if an identified LOAEL was used as a
Quality of whole data base:
assessment factor for uncertainties to the quality of the data base is
regarded to be 1.
Long-term dermal exposure -
long-term effects, data from the OECD 422 Combined Repeated-Dose
Toxicity Study with the Reproduction/Developmental Toxicity Screening
Test were used. A dermal DNEL is calculated using the oral rat LOAEL of
50 mg/kg bw, which did not need a correctionfor
absorption (Appendix R.8-2, Example A.1 and Table R.8 -4), assuming that
that dermal absorption will not be higher than oral absorption and there
are no differences in oral and dermal absorption between rats and
humans. However, this LOAEL is corrected by a factor of 3 (for
extrapolation from LOAEL to NOAEL) and a factor of 1.4 to account for
differences in exposure conditions (5 days/week for workers and 7 days
for week for animals in the test).
assessment factors are 4 x 2.5 x 5 x 6: Factor of 4 is used for
inter-species differences. Factor of 2.5 is used for remaining
inter-species differences. Factor of 5 is used to characterise
intra-species differences between humans. Factor of 6 is used to cover
differences in duration of exposure (sub-acute to chronic) (Table R.
8-5). MMEA was administered a 2-week pre-mating and mating period,
approximately 1 week post-mating in males, and the entire gestation
period as well as 4 days of lactation in females.
= 23.33/(4 x 2.5 x 5 x 6) = 0.08 mg/kg bw.
Long-term inhalation exposure -
the inhalation long-term systemic effects, DNEL was derived using the
oral rat LOAEL of 50 mg/kg bw (OECD 422). The conversion of an oral rat
LOEAL into a corrected inhalatory NOAEC was performed as described in
Figure R.8 -3 of the ECHA guidance. In a first step the LOAEL is
corrected by a factor of for extrapolation from LOAEL to NOAEL.
Subsequently the followgin corrections are undertaken:
inhalatory NOAEC = oral NOAEL x (1/0.38) x (ABS oral-rat / ABs
inh-human) x (6.7/10) =
corr. NOAEC = 16.67 mg/kg bw/d /0.38 m³/kg
bw * (6.7 m³/d /10 m³/d) * 1/2 * 7d / 5 d = 20.6 mg/m³
assessment factors are 2.5 x 5 x 6: Factor 5 is used for intraspecies
differences between humans. Factor 6 is used to cover differences in
duration of exposure from Table R. 8-5. No allometric scaling (factor 4)
is applied because of oral- to-inhalation extrapolation.
= 20.6/(75) = 0.275 mg/m³
LOAEL corrected by an AF of 3 to
obtain a NOAEL; and corrected for differences in respiratory volumes
(1/1.15) and differences in Absorption (50/100)
corrected NOAEC = 16.67 mg/kg bw/d /1.15
m³/kg bw /2 = 7.246 mg/m³
LOAEL of 50 mg/kg bw (BASF, 2010. OECD
422) is the dose descriptor starting point. This LOAEL is corrected by
an AF of 3 to obtain a NOAEL
Corr. NOAEC= 16.7 mg/m³
Calculation of Consumer DNELs is not
relevant, since no uses for consumers are intended.
However, the DNEL for systemic long-term
exposure via inhalation and via oral exposure are needed for the
exposure assessment part "man via environment".
Please also refer to the detailes remarks
under: " Additional information - workers".
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