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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
9.2 mg/m³
DNEL related information
Modified dose descriptor starting point:
NOAEC
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
18.4 mg/m³
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
9.2 mg/m³
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
18.4 mg/m³
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.08 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
24
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
10.4 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
44 µg/cm²
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
Overall assessment factor (AF):
3
Dose descriptor starting point:
other: NOAEL

Workers - Hazard for the eyes

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 are established because MMEA is classified for acute toxicity. LD50values are available for oral and dermal routes of exposures.MMEAis 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.

- DNEL for the acute toxicity inhalation was calculated. An acute LOAEL is identified in the acute oral animal study (BASF, 1965).

- 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 ofthe 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 ECETOC Technical Report No 86, referenced in Table R.8-19 ofECHA (2008) “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.

Absorption:

o  Differences in the respiratory volumes between experimental animals and humans were used when an oral NOAEL 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  In deriving of dermal irritation DNEL (for local effects) no allometric scaling is applied (Section R.8.4.3.1., S.31-32 and Appendix R.8-9, p.119).

o  No additional assessment factors are applied for remaining interspecies differences.

 

Intraspecies differences

o  Assessment factors of 3 and 5 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:

o  An assessment factor of 10 was applied if an identified LOAEL was used as a starting point (in case of acute inhalation toxicity for systemic effects).

Quality of whole data base:

 

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

 

Additional assessment factors:

Acute toxicity:

o  An uncertainty factor of 100 was applied to cover all possible effects by the acute exposures (oral and dermal).

Acute/short-term dermal exposure - systemic effects

A DNELshort-termfor dermal systemic effects is derived using LD50value from an acute dermal study (BASF AG 1981).

No modification of the starting point is performed.

Overall assessment factors are 4 x 3 x 100: factor of 4 is the allometric scaling factor, factor of 3 is used for intraspecies differences between humans (ECHA REACH Guidance R.8, Table R.8-19, ECETOC default AFs). An assessment factor of 100 is used for severity of effect (severe irritation of gastrointestinal tract and corrosivity to the skin) (as suggested in Appendix R.8-8, Box 5).

 

Calculation:

DNEL = 2000/(4 x 3 x 100) = 1.7 mg/kg bw

The DNEL is uncertain because of applying of factor of 100. The calculated DNEL of 1.7 mg/kg bw is lower than that calculated for long-term dermal systemic effects (2.08 mg/kg bw). It is also possible to calculate an acute systemic DNEL using long-term DNEL. In this case, multiplication of the long-term DNEL by a factor of 5 would result in 10.4 mg/kg bw. This value possess also uncertainties because the NOAEL originates from an oral study and has already been extrapolated to dermal route to obtain a lon-term systemic DNEL. Since no modification concerning absorption between routes and between animals and humans was taken into account, such a DNEL may be higher than one calculated without extrapolation. Therefore, a qualitative risk charcterization is more appropriate in this case.

Acute/short-term inhalation exposure - systemic effects

An Occupational Exposure Limit (OEL) of 3 ppm (9.2 mg/m³) currently exists in Denmark (MAK). In this time, this value is provisional. This value covers both the acute and the long-term systemicexposure. This value can be exceeded on a short time base by a factor of 2 (6 ppm/18.4 mg/m³) and thus covers in addition the short time acute exposure. A scientific justification is required according to the REACh-guidance and understood as prerequisite to use such a value. The underlying health effect observed is corrosivity, but the value is also intended to prevent local effects as well as potential toxicity to reproduction.

It is proposed to use the existing MAK value of 3 ppm for the inhalation DNEL on the basis of the following:

A DNELshort-termfor inhalation derived from data of an acute oral animal study (BASF AG, 1965, Report No. XV/126) is similar to the existing OEL. The administration of 23.5 mg/kg bw (the lowest dose tested) to rats by gavage caused only calm behavior in the treated animals. This value was considered to be an acute LOAEL. Using of this LOAEL as a starting point and adjusting it for the difference in respiratory volume for humans to rats during 15 min and by light activity and absorption yields the following calculation:

Corrrected inhalatory LOAEC = oral LOAEL x (1/0.012) x (ABS oral-rat/ABS inh-human) x (0.21/0.31)

where 0.012 is the inhalatory volume (m³/kg) of rats during 15 min exposure, 0.21 m³ and 0.313 m3are respiratory volumes for workers during 15 min and at light activity during 15 min, respectively. These two adjustments take already into consideration the interspecies allometric scaling factor. Additional adjustment for species difference in absorption is required since the routes of exposures are different. ABS is absorption (in worst case considered to be 50% for oral absorption and 100% for inhalation). An adjustment in metabolism is not required since metabolism and kinetics have been shown to be similar in rats and humans. An assessment factor of 3 for intraspecies variability and factor of 10 because of LOAEL to NOAEC extrapolation are applied. No further assessment factors are required for database quality or study duration (acute study and assessment of acute effects).

Calculation:
DNEL=(23.5 x (1/0.012) x (50%/100%) x (0.21/0.31))/(3 x 10) = 21.9 mg/m³

 

Since the value of 21.9 mg/m³ is similar to the existing OEL value of 18.4 mg/m³ (in case of exceeding the OEL in two times), the existing OEL is proposed to be used as the acute inhalation DNEL for systemic effects.

Acute/short-term local effects (dermal)

Since MMEA is corrosive to the skin and eyes, a DNELshort-term for local effects has also been derived. The data from a sensitization study were used to establish a NOAEL (Leung and Blaszcak, 1998).

In this study, the concentration 5% of DMAE produced only local tissue damage (no extensive ulceration). This concentration was used for the intradermal induction. 25% was the highest concentration that produced only mild irritation and was used for the epicutaneous induction. 5 % was the highest concentration which did not produce irritation and was used for epicutaneous challenge. 5 % concentration was decided to be a concentration by which no adverse effects occurred (NOAEL). 5% in 0.2 ml pro guinea pig (average weight of 0.8 kg) corresponds to 11.8 mg/kg bw (the calculation is performed using density 0.94 g/mL of the test material).

The conversion of the epicutaneous NOAEL from the sensitization study into a corrected skin irritation NOAEL was performed as described in the ECHA REACH Guidance R.8, Appendix R.8-9, Section “Modification of the dose descriptor”. The dose in mg/kg bw /day was converted into mg/cm2/day to enable the comparison with the human exposure. Skin NOAELmodified is calculated as following:

Corrected NOAEL = NOAEL test (11.8 mg/kg bw) x (0.8 kg/71 cm²) = 0.13 mg/cm²

where 0.8 is average weight of guinea pigs (kg) and 71 is approximately 10% of the total body surface of guinea pigs (in cm2). Surface area of guinea pig was calculated as following:

Surface area = 9.85 x W^0.64 = 710 cm²

where W is average body weight of guinea pigs (0.8 kg) (Kibler et al., 1946).

Overall assessment factors include only the factor of 3 to cover the intra-species variation. No allometric scaling is applied because of local effects since the mechanism of skin irritation is considered to be same in experimental animals and in human (ECHA REACH Guidance, Section R.8.4.3.1., p.31-32 and Appendix R.8-9, p.119).No additional assessment factors are used.

Calculation:

DNEL = (11.8 x (0.8/71))/3 = 0.044 mg/cm²

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 NOAEL of 50 mg/kg bw. The conversion of the oral rat NOAEL into a corrected dermal NOAEL was not necessary (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. Overall assessment factors are 4 x 3 x 2: Factor of 4 is used for inter-species differences. Factor of 3 is used to characterise intra-species differences between humans (Table R.8-19, ECETOC values). Factor of 2 is used to cover differences in duration of exposure (sub-chronic 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. The period of administration is considered to be rather sub-chronic (for both sexes).

Calculation:

DNEL = 50/(4 x 3 x 2) = 2.08 mg/kg bw.

Long-term inhalation exposure - systemic effects

For the inhalation long-term systemic effects, DNEL was derived using the oral rat NOAEL of 50 mg/kg bw (OECD 422). The conversion of an oral rat NOAEL into a corrected inhalatory NOAEC was performed as described in the Figure R.8 -3 of the ECHA guidance. Corrected inhalatory NOAEC = oral NOAEL x (1/0.38) x (ABS oral-rat/ABS inh-human) x (6.7/10).

Overall assessment factors are 3 x 6: Factor 3 is used for intraspecies differences between humans (Table R.8-19, ECETOC). 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 = (50 x (1/0.38) x (50%/100%) x (6.7/10))/(3 x 6) = 2.4 mg/m³

The calculated value is lower than existing OEL of 9.2 mg/m³. Considering a high priority of OEL value compared to a calculated value, the OEL value of 9.2 mg/m³ is considered to be a DNEL for short-term exposures. 

General Population - Hazard via inhalation route

Systemic effects

Acute/short term exposure
DNEL related information

Local effects

Acute/short term exposure
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Acute/short term exposure
DNEL related information

General Population - Hazard via oral route

Systemic effects

Acute/short term exposure
DNEL related information

General Population - Hazard for the eyes

Additional information - General Population

Calculation of Consumer DNELs is not relevant, since no uses for consumers are intended.