Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.72 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
225
Dose descriptor starting point:
LOAEC
Value:
322 mg/m³
Modified dose descriptor starting point:
LOAEC
Value:
161.8 mg/m³
Explanation for the modification of the dose descriptor starting point:

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).

corrected LOAEC = 322 mg/m³ * (100 %/100 %)*(100 %/100 %)*(6 h/8 h)* 0.67 m³ = 161.8 mg/m³

AF for dose response relationship:
3
Justification:
Factor 3 is used to account for the use of a LOAEC
AF for differences in duration of exposure:
6
Justification:
default (for extrapolation of subacute to chronic exposure durations)
AF for interspecies differences (allometric scaling):
1
Justification:
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 humans).
AF for other interspecies differences:
2.5
Justification:
default (no substance and route specific information on toxicokinetic and toxicodynamic is available for animals and humans)
AF for intraspecies differences:
5
Justification:
default (for workers)
AF for the quality of the whole database:
1
Justification:
default value
AF for remaining uncertainties:
1
Justification:
there are no further remaining uncertainties to be taken into account
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
DNEL related information
AF for remaining uncertainties:
1

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.427 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
225
Dose descriptor:
LOAEC
Value:
96 mg/m³
AF for dose response relationship:
3
Justification:
Factor 3 is used to account for the use of a LOAEC
AF for differences in duration of exposure:
6
Justification:
default (for extrapolation of subacute to chronic exposure durations)
AF for interspecies differences (allometric scaling):
1
Justification:
default (no allometric scalling should be applied in case of local effects)
AF for other interspecies differences:
2.5
Justification:
default (no substance and route specific information on toxicokinetic and toxicodynamic is available for animals and humans)
AF for intraspecies differences:
5
Justification:
default (for workers)
AF for the quality of the whole database:
1
Justification:
default
AF for remaining uncertainties:
1
Justification:
there are no further remaining uncertainties to be taken into account
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.77 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
300
Dose descriptor starting point:
NOAEL
Value:
500 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
230 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

An oral NOAEL to a dermal NOAEL does not need to be corrected, since the bioavailibility is considered to be equivalent, no additonal 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 correpsonding value for methylamine (Molecular weight of 31.06 g/mol) the following correction is necessary:

corr. NOAEL = 500 mg/kg bw/day *31.06/67.52 = 230 mg/kg bw/day

AF for dose response relationship:
1
Justification:
default value
AF for differences in duration of exposure:
6
Justification:
default (for extrapolation of subacute to chronic exposure durations)
AF for interspecies differences (allometric scaling):
4
Justification:
default (for rats)
AF for other interspecies differences:
2.5
Justification:
default (no substance and route specific information on toxicokinetic and toxicodynamic is available for animals and humans)
AF for intraspecies differences:
5
Justification:
default (for workers)
AF for the quality of the whole database:
1
Justification:
default value
AF for remaining uncertainties:
1
Justification:
There are no further remaining uncertainties. The use of available data from the structural analogue Methylamine hydrochloride for the derivation of the long-term systemic dermla worker DNEL does not lead to an increased uncertainty. Consequently the default Assessmenf Factor of 1 does not need to be replaced by a higher assessment factor.
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - workers

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 health.”

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 workers. 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 intended.

There are following annotations for each endpoint:

o No 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 significanlty 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.

o  The DNEL for acute local toxicity (inhalation) is not established either, but is adressed qualitatively, because available data also does not allow for a dose-response relation-ship. Instead "medium hazard" is selected.

o  DNELs for acute systemic and local toxicity (dermal) and for long-term local toxicity (dermal) are not established, but these are adressed qualitatively ("medium hazard"), as methylamine is of low acute dermal toxicity.

o  A 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.

o  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.

o  In 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:

Bioavailability

o  Bioavailability for experimental animals and humans for all exposure routes was assumed to be the same.

Route-to-route extrapolation:

o  No 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.

o  A default factor of 2 is applied when oral-to-inhalation extrapolation is performed

Exposure conditions:

o  Exposure times differed in the repeated dose inhalation studies. The dose descriptors were corrected as described in the Appendix R.8-2.

Absorption:

o  The differences in the respiratory volumes between experimental animals and humans were taken into account when an inhalatory LC50or a inhalatory LOAEC from a rat study or rat and mouse study was used to assess inhalation exposure in humans.

o  100 % 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 (AF):

Interspecies differences:

o  The species-specific default AF for allometric scaling from Table R.8-3 is applied in case of repeated dermal exposures.

o  No 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).

o  An additional AF of 2.5 is applied for other interspecies differences for all DNELs.

Intraspecies differences (worker):

o  An Assessment Factor of 5 is applied for workers, respectively, for all endpoints and all exposure routes.

Extrapolation of duration:

o  The relevant default AF from Table R.8-5 are applied.

Issues related to dose response:

o  An AF of 3 was applied if an identified LOAEC was used as a starting point (in case ofrepeated dose toxicity for systemic effects).

Quality of whole data base:

o  The assessment factor for uncertainties to the quality of the database is regarded to be 1.

Additional assessment factors:

o No additonal assessment factors are applied

Derivation of DNELs

Long-term/Acute local inhalation and Acute systemic dermal as well as Long-term/Acute local dermal:

There are no dose despcriptors available, which allow for a dose-response relation-ship, therefore only a qualitatitve approach is conducted.

Irritation/corrosivity (skin):

There are no dose descriptors available, therefore only a qualitative approach is conducted.

Qualitative approach:

An 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.

 

Irritation/corrosivity (eye):

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.

 

Irritation/corrosivity (respiratory tract):

Qualitative approach:

From acute and developmental inhalation toxicity studies it is clear, that MMA caused irritation of respiratory tract. High peak inhalation exposures should be avoided.

 

Sensitization:

There is no experimental data available for this endpoint, therefore only a qualitative approach is conducted.

Repeated dose toxicity: inhalation (long-term systemic):

Long-term dermal exposure - systemic effects

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 bioavailibility is considered to be equivalent), no additonal 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 correpsonding value for methylamine (Molecular weight of 31.06 g/mol) the following correction is necessary:

corr. NOAEL = 500 mg/kg bw/day *31.06/67.52 = 230 mg/kg bw/day

Overall assessment factors are 4 x 2.5 x 5 x 6.  The factor 4 is used for interspecies differences between rats and humans, the factor 2.5 is used for remaining interspecies differences and a factor of 5 is included for intraspecies differences for workers; an additional assessment factor of 6 for conversion of the subacute data to chronic exposure scenarios.

Calculation:

DNEL = 230 mg/kg bw/day / (4 x 2.5 x 5 x 6) = 0.77 mg/kg bw/day

Long-term inhalation exposure - systemic effects

An 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 (6.7m³, 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 humans).

Overall 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 extrapolation.

Calculation:

DNEL = 161.8 mg/m³ / (3 x 2.5 x 5 x 6 ) = 0.72 mg/m³

OEL / MAK values:

An 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.

Reproductive toxicity

No DNELs for reproductive toxicity were derived, because MMA is not characterized as an reprotoxic substance.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - General Population

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).