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EC number: 200-820-0
CAS number: 74-89-5
The starting point - a systemic LOAEC (250
ppm corresponding to 322 mg/m³) - was obtained in the animal study and
was modified only accounting for the differences between
experimental and human exposure conditions. The conversion of an
inhalatory rat LOAEC into a corrected inhalatory LOAEC to assess human
inhalatory exposure was performed: to take into account the differences
in exposure duration a factor of 0.75 was included (6 h for the rodent
to 8 h for the worker), additionally a factor of 0.67 is included
(6.7m³, as a respiratory volume for humans for an 8-hour shift divided
by 10 m³, the respiratory volume for worker by light activity).
LOAEC = 322 mg/m³ * (100 %/100 %)*(100 %/100 %)*(6
h/8 h)* 0.67 m³ = 161.8 mg/m³
An oral NOAEL to a dermal NOAEL does not
need to be corrected, since the bioavailibility is considered to be
equivalent, no additional assessment factor needs to be included for the
different routes of exposure, assuming that dermal absorption will not
be higher than oral absorption. It is also assumed that there are no
differences in dermal absorption between rats and humans.
However, as this dose despriptor is derived
on an OECD 422 conducted with the close analogue methylamine
hydrochloride (Molecular weight of 67.52 g/mol). In order to convert
this into the corresponding value for methylamine (Molecular weight of
31.06 g/mol) the following correction is necessary:
NOAEL = 500 mg/kg bw/day *31.06/67.52
= 230 mg/kg bw/day
The REACH regulation defines the
Derived No-Effect Level (DNEL) as the level of exposure above which
humans should not be exposed. The calculation of the DNELs is done
in accordance to the principles given in ECHA (2012) “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 monomethylamine
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 monomethylamine (MMA) and of its close
analogue monomethylamine hydrochloride (MMA-HCl), reflecting the
routes, duration and frequency of exposure. DNELs are derived for
For the general population no DNEL
values have been derived, as no consumer uses are intended. However,
hazard conclusions were derived for the general population:
the hazard conclusion "medium hazard (no threshold derived)" or "low
hazard (no threshold derived)" is chosen and an explanation is
given, that theoretically a hazard exists, but this hazard is not
applicable for the general population as there are no consumer uses
There are following annotations
for each endpoint:
DNEL for acute systemic toxicity (inhalation) is established, even
though methylamine is a volatile substance of moderate acute
inhalatory toxicity (Acute Tox 3 according to GHS; STOT SE3
according to GHS; Affected organs respiratory tract, stomach and
intestines) and can represent an acute hazard for acute hazard in
case peaks of exposure are significantly higher that the average
exposure level. However, the available route-specific data (BASF,
1983) does not allow for a dose-response relationship. Instead
"medium hazard" is selected.
DNEL for acute local toxicity (inhalation) is not established
either, but is addressed qualitatively, because available data also
does not allow for a dose-response relation-ship. Instead "medium
hazard" is selected.
for acute systemic and local toxicity (dermal) and for long-term
local toxicity (dermal) are not established, but these are addressed
qualitatively ("medium hazard"), as methylamine is of low acute
qualitative approach for the risk assessment of skin, eye and
respiratory tract irritation/corrosion and skin sensitization is
used because no dose descriptors are available on these endpoints.
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.
case of repeated dose toxicity experimental data is incomplete
regarding each possible exposure route (dermal). In this case a
route-to-route extrapolation (oral-to-dermal) was performed.
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 data.
The assessment factors are applied
in accordance with
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:
for experimental animals and humans for all exposure routes was
assumed to be the same.
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), assuming that dermal absorption will not be
higher than oral absorption.
default factor of 2 is applied when oral-to-inhalation extrapolation
times differed in the repeated dose inhalation studies. The dose
descriptors were corrected as described in the Appendix R.8-2.
differences in the respiratory volumes between experimental animals
and humans were taken into account when an inhalatory NOAEC from a
rat study or rat and mouse 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 AF for allometric scaling from Table R.8-3
is applied in case of repeated dermal exposures.
species-specific default AF 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 AF are applied for
inhalation route to obtain a corrected starting point (Table R8-4,
Appendix R.8-2, part 2, example A.2).
additional AF of 2.5 is applied for other interspecies differences
for all DNELs, besides the local DNEL inhalation long-term for
workers, for which this assessement factor did not apply. This
additional assessment factor should be used to account for potential
significant quantitative differences in deposition, airflow
patterns, clearance rates and protective mechanisms between humans
and animals. However, in case of MMA - beeing highly corrosive - it
excerts its effect in the anterior parts of the nose. There is no
differences in airflow, clearance deposition to be expected in the
anterior part of the nose. As such, the default AF of 2.5 for
other interspecies differences normally applicable was omitted in
this case, as it does not apply in this case, as here local effects
at the immediate port of entry are expected. There no differences in
deposition, airflow patterns or clearance rate are in this case
expected between rat and human.)
Assessment Factor of 5 is applied for workers, respectively, for all
endpoints and all exposure routes.
Extrapolation of duration:
relevant default AF from Table R.8-5 are applied.
Issues related to dose response:
o No assessment factor is needed
to be applied for issues related to dose-response.
Quality of whole data base:
assessment factor for uncertainties to the quality of the database
is regarded to be 1.
Additional assessment factors:
additonal assessment factors are applied
Derivation of DNELs
inhalation and Acute systemic dermal as well as Long-term/Acute
There are no dose despcriptors
available, which allow for a dose-response relation-ship,
therefore only a qualitative approach is conducted.
There are no dose descriptors
available, therefore only a qualitative approach is conducted.
irritation specific DNEL for the local effects could be derived
from dermal acute, sub-acute or sub-chronic studies in animals
(Appendix R.8-9). In the available acute dermal studies on MMA, no
dose-response information is available. There is no repeated dose
dermal toxicity data on MMA from that a non-irritant
dose/concentration could be derived. A qualitative approach to
assessing and controlling the risks is more appropriate in this
case. Severe irritation and corrosive effects on skin, respiratory
and gastrointestinal tract were reported in several studies. MMA
is considered to be corrosive/irritating to skin.
There is no identified
quantitative dose descriptor available from animal data for this
endpoint. The test material is considered to be irritating /
corrosive to the eyes.
acute and developmental inhalation toxicity studies it is clear,
that MMA caused irritation of respiratory tract. High peak
inhalation exposures should be avoided.
There is no experimental data
available for this endpoint, therefore only a qualitative approach
Repeated dose toxicity:
inhalation (long-term systemic):
Long-term dermal exposure -
The oral rat NOAEL from the combined
repeated dose and reproduction / developmental screening study
(Munley 2007) is used to assess dermal systemic effects in humans.
No conversion of the oral NOAEL obtained in the animal study into
a corrected dermal NOAEL was necessary (an oral NOAEL to a dermal
NOAEL does not need to be corrected, since the bioavailability is
considered to be equivalent), no additional assessment factor
needs to be included for the different routes of exposure,
assuming that dermal absorption will not be higher than oral
absorption. It is also assumed that there are no differences in
dermal absorption between rats and humans.
However, as this dose descriptor is
derived on an OECD 422 conducted with the close analogue
methylamine hydrochloride (Molecular weight of 67.52 g/mol). In
order to convert this into the corresponding value for methylamine
(Molecular weight of 31.06 g/mol) the following correction is
NOAEL = 500 mg/kg bw/day *31.06/67.52
= 230 mg/kg bw/day
= 230 mg/kg bw/day / (4 x 2.5 x 5 x 6) = 0.77 mg/kg bw/day
Long-term inhalation exposure -
inhalatory systemic LOAEC established in a repeated dose toxicity
study (Kinney et al., 1990) is used to assess the inhalatory
systemic effects in humans. The starting point LOAEC (250 ppm =
322 mg/m³) obtained in the animal study was modified only
accounting for the differences between experimental and human
exposure conditions. The convertion of an inhalatory rat LOAEC
into a corrected inhalatory LOAEC (161.8 mg/m³) to assess human
inhalatory exposure was performed: to take into account the
differences in exposure duration a factor of 0.75 was included (6
h for the rodent to 8 h for the worker), additionally a factor of
0.67 is included (6.7 m³, as a respiratory volume for humans for
an 8-hour shift divided by 10 m³, the respiratory volume for
worker by light activity). No allometric scaling is applied
because a ventilation rate and food intake directly depends on the
basal metabolic rate and has already been scaled according to the
allometric principle (inhalation study and inhalation exposure in
assessment factors are 3 x 2.5 x 5 x 6 (= 225): Factor 3 is used
to account for the use of a LOAEC, factor of 2.5 is used for
remaining interspecies differences and factor 5 is used to cover
intraspecies differences in workers. Additionally a factor of 6
needs to be included to account for subacute to chronic
= 161.8 mg/m³ / (3 x 2.5 x 5 x 6 ) = 0.72 mg/m³
Long-term inhalation exposure
- local effects
inhalatory local NOAEC established in a repeated dose
toxicity study (Kinney et al., 1990) is used to assess the
inhalatory systemic effects in humans. The starting point is
a NOAEC (75 ppm = 96 mg/m³) did not need to be modified i.e.
accounting for the differences between experimental and
human exposure conditions, so no convertion of the
inhalatory rat NOAEC into a corrected inhalatory NOAEC to
assess human inhalatory exposure was necessary.
assessment factors are 5 x 6 (= 30): Factor 5 is used to
cover intraspecies differences in workers. Additionally a
factor of 6 needs to be included to account for subacute to
= 96 mg/m³ / (5 x 6 ) = 3.2 mg/m³
OEL / MAK values:
Occupational Exposure Limit (OEL) of 10 ppm (13 mg/m³) currently
exists in Germany (MAK); in other regions of the European Union
the value lies often at 5 ppm (6.4 mg/m³). This
value covers the long-term systemic exposure. A scientific
justification is available which is required according to the
REACh-guidance and understood as a prerequisite to use such a
value. The underlying effect for repeated dose exposure is
irritation of the upper respiratory tract, but the value is also
intended to prevent local effects on skin and especially in the
eyes. Respiratory or ocular
irritation has not been reported in workers exposed to
concentrations at or near the existing MAK value.
No DNELs for reproductive
toxicity were derived, because MMA is not characterized as an
The derivation of DNELs for the general
population is considered not to be applicable, as no exposure occurs (no
consumer uses). Therefore, no specific general population DNELs are
derived and the hazard assessment conclusion "medium hazard (no
threshold derived)" or "low hazard (no threshold derived)" were chosen
for the inhalation and dermal or the oral DNELs instead. The hazard
assessment conclusion of Monomethalmine for the eyes for the general
population is - due to its classification as Eye Dam 1 (H318 - Causes
serious eye damage) a "medium hazard (no threshold derived)" according
to ECHA's Guidance Part E (v3, May 2016).
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