2-methylaminoethanol

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.275 mg/m³

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

75

Dose descriptor starting point:

LOAEC

Value:

50 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

20.6 mg/m³

Explanation for the modification of the dose descriptor starting point:

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 (7/5)

Corr. NOAEC = 20.6 mg/m³

AF for dose response relationship:

1

Justification:

default as correction factor of 3 for using a LOAEL as starting point already regarded above during modification of soe descriptor starting point

AF for differences in duration of exposure:

6

Justification:

default for sub-acute to chronic

AF for interspecies differences (allometric scaling):

1

Justification:

already accounted for by correction for differences in respiratory volumes

AF for other interspecies differences:

2.5

Justification:

default

AF for intraspecies differences:

5

Justification:

default

AF for the quality of the whole database:

1

Justification:

default

AF for remaining uncertainties:

1

Justification:

there are no other remaining uncertainties

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

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.08 mg/kg bw/day

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

300

Dose descriptor starting point:

LOAEL

Value:

50 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

23.33 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

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

AF for dose response relationship:

1

Justification:

default as correction factor of 3 for using a LOAEL as starting point already regarded above during modification of soe descriptor starting point

AF for differences in duration of exposure:

6

Justification:

default for sub-acute to chronic

AF for interspecies differences (allometric scaling):

4

Justification:

default for allometric scaling from rat to human

AF for other interspecies differences:

2.5

Justification:

default for remaining interspecies differences

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:

default

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

DNEL related information

Explanation for the modification of the dose descriptor starting point:

According to ECHA’s Guidance Part E (v3, May 2016)

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

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 health.”

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 these endpoints.

- 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 422).

- 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 data.

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

Bioavailability for experimental animals and humans for all exposure routes was assumed to be the same because of the absence of information.

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).

o  A default factor of 2 (50 % for oral absorption and 100 % for inhalation) is applied when oral-to-inhalation extrapolation is performed.

Exposure conditions:

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

o  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).

Absorption:

o  Differences 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.

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:

Interspecies differences:

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

o  No 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).

o  an additional assessment factor if 2.5 is applied for remaining interspecies differences.

 

Intraspecies differences: 

o  Assessment factors of 5 and 10 are applied for workers and general population, respectively, for all endpoints and all exposure routes

Extrapolation of duration:

o  The relevant default assessment factors from Table R.8.5 are applied.

Issues related to dose response:

o  An assessment factor of 3 was applied if an identified LOAEL was used as a starting point.

Quality of whole data base:

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

 

Long-term dermal exposure - systemic effects

For 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).

Overall 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.

Calculation:

DNEL = 23.33/(4 x 2.5 x 5 x 6) = 0.08 mg/kg bw.

Long-term inhalation exposure - systemic effects

For 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:

Corrected 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

Overall 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.

Calculation:

DNEL = 20.6/(75) = 0.275 mg/m³

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.048 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

150

Dose descriptor starting point:

LOAEL

Value:

50 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

7.246 mg/m³

Explanation for the modification of the dose descriptor starting point:

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 (1/1.15) and differences in Absorption (50/100)

corrected NOAEC = 16.67 mg/kg bw/d /1.15 m³/kg bw /2 = 7.246 mg/m³

AF for dose response relationship:

1

Justification:

default as correction factor of 3 for using a LOAEL as starting point already regarded above during modification of soe descriptor starting point

AF for differences in duration of exposure:

6

Justification:

default for subacute to chronic

AF for interspecies differences (allometric scaling):

1

Justification:

already regarded by deriving a corrected NOAEC

AF for other interspecies differences:

2.5

Justification:

default for remaining interspecies differences

AF for intraspecies differences:

10

Justification:

default for general population

AF for the quality of the whole database:

1

Justification:

default

AF for remaining uncertainties:

1

Justification:

default

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.028 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):

600

Dose descriptor starting point:

LOAEL

Value:

50 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

16.7 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

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

AF for dose response relationship:

1

Justification:

default as correction factor of 3 for using a LOAEL as starting point already regarded above during modification of soe descriptor starting point

AF for differences in duration of exposure:

6

Justification:

default for subacute to chronic

AF for interspecies differences (allometric scaling):

4

Justification:

default for allometric scaling from rat to human

AF for other interspecies differences:

2.5

Justification:

default for remaining interspecies differences

AF for intraspecies differences:

10

Justification:

default for general population

AF for the quality of the whole database:

1

Justification:

default

AF for remaining uncertainties:

1

Justification:

default

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Additional information - General Population

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".