N,N-dimethyl-alkyl-1-amines, reaction products with alkali hydroxide and chloroacetic acid

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

42.6 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other: ECETOC Technical Report No. 110 and ECHA Guidance Guidance on information requirements and chemical safety assessment Chapter R.8 (2012)

Overall assessment factor (AF):

6

Modified dose descriptor starting point:

NOAEC

Value:

255.66 mg/m³

Explanation for the modification of the dose descriptor starting point:

No study on long-term inhalation toxicity available

AF for dose response relationship:

1

Justification:

Default value for NOAEL as starting point for DNEL calculation

AF for differences in duration of exposure:

2

Justification:

Subchronic to chronic exposure

AF for interspecies differences (allometric scaling):

1

Justification:

Allometric scaling is not necessary for the inhalation route

AF for other interspecies differences:

1

Justification:

No default additional interspecies factor is used (please refer to Discussion for further information)

AF for intraspecies differences:

3

Justification:

Default value for workers

AF for the quality of the whole database:

1

Justification:

Hazard assessment is conducted by means of read-across from a structural analogue. The selected study is the most adequate and reliable study based on the identified similarities in structure and intrinsic properties between source and target substance and overall quality assessment (refer to the endpoint discussion for further details).

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

60.42 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other: ECETOC Technical Report No. 110 and ECHA Guidance on information requirements and chemical safety assessment Chapter R.8 (2012)

Overall assessment factor (AF):

24

Modified dose descriptor starting point:

other: NOAEL corrected for dermal absorption

Value:

1 450 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No study on long-term dermal toxicity available

AF for dose response relationship:

1

Justification:

Default value for NOAEL as starting point for DNEL calculation

AF for differences in duration of exposure:

2

Justification:

Subchronic to chronic exposure

AF for interspecies differences (allometric scaling):

4

Justification:

Allometric scaling rat to human

AF for other interspecies differences:

1

Justification:

No default additional interspecies factor is used (please refer to Discussion for further information)

AF for intraspecies differences:

3

Justification:

Default value for workers

AF for the quality of the whole database:

1

Justification:

Hazard assessment is conducted by means of read-across from a structural analogue. The selected study is the most adequate and reliable study based on the identified similarities in structure and intrinsic properties between source and target substance and overall quality assessment (refer to the endpoint discussion for further details).

Acute/short term exposure

Hazard assessment conclusion:

no DNEL required: short term exposure controlled by conditions for long-term

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - workers

There are no data available on long-term systemic toxicity of N,N-dimethyl-alkyl-1-amines, reaction products with alkali hydroxide and chloroacetic acid.

However, there is reliable data for Betaines, coco alkyldimethyl (CAS 68424-94-2) which is considered to be suitable for read-across using the analogue approach. For details refer to analogue justification. No DNELs have been derived for the short-term dermal and inhalation exposure of the test substance for workers, as it is considered that the assessment of hazard is sufficiently covered by deriving the respective DNELs for long-term exposure.

Since there is no dose descriptor for every exposure route, dose descriptors were converted into a correct starting point by route-to route extrapolation based on the ECHA Guidance document "Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health" (2012).

The oral NOAEL of 500 mg/kg bw/d, corresponding to 145 mg/kg bw/d active ingredient for rats, derived from a 90-day oral gavage study (Pittermann, 1993), served as basis for the extrapolations.

Within the ECHA Guidance a factor of 2 is suggested for the extrapolation from oral to inhalation absorption. On the contrary, the Technical guidance document on risk assessment in support of Commission directive 93/67/EEC, 2003 appendix IV A and B gives a number of physico-chemical properties that normally determine oral, inhalation and dermal absorption. These parameters include molecular weight, log Kow, pKa values and for inhalation also particle size distribution, vapour pressure, etc.

Molecules with a molecular weight <500 and a log Kow between 0 and 4 can be assumed to be well absorbed equivalently by the oral and inhalation route. Oral absorption may be reduced for acids and bases depending on their pKa value and their electric charge in the GI tract. More lipophilic substances may be better absorbed in the GI tract due to solubilisation with bile acids and thus oral absorption may be higher than inhalation absorption. The consideration of physico-chemical parameters should be performed before using default assumptions. Unless valid data suggest that inhalation leads to higher absorption than oral ingestion, equal absorption will be assumed when extrapolating from oral to inhalation route. Route-to-route extrapolation within the rat was based on the respiratory volume of 0.8 L/min/kg bw, leading to an inhalation volume of 0.38 m³/kg bw for a time period of 8 hours, reflecting the duration of a normal work shift.

In order to convert an oral NOAEL derived from rats into a dermal NAEL, the differences in absorption between routes as well as differences in dermal absorption between species have to be accounted for. The percutaneous absorption of betaines (C12BET, CAS 683-10-3) was measured in a skin permeation study in hairless mouse skin in vitro (Ridout et al., 1991). In this study a 16 mM dilution of C12BET was applied to isolated full thickness mouse skin, and after 12 and 24 hours 10.3% and 46.5%, respectively, of the applied C12BET had penetrated, with about 25% of the applied dose associated with the skin at the end of the permeation runs. Actual dermal absorption in man is expected to be much lower, as human skin is much thicker and less penetrable than rat or mouse skin (ECETOC, 1993), which have very similar characteristics (Panchagnula, 1997). This view is further supported by data showing absorption of only 0.4% in 30 min through human skin in vivo. Therefore, the corrected oral NOAEL was adapted to dermal absorption by inclusion of a very conservative factor of 10, assuming a dermal absorption of 10% via the intact skin represents a sufficient conservative approach.

It is assumed that use of default AFs recommended by ECHA will in most cases lead to DNELs that are not scientifically justified and consequently lead to unrealistically low exposure levels for establishing safe use. Moreover, ECHA provides limited scientific justification for the default AFs; it is supposed they have relied on 'standard approaches' used by other organisations. In contrast, ECETOC based its AFs on a critical review of the literature; in consequence they should be used preferentially.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

12.61 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

DNEL derivation method:

other: ECETOC Technical Report No. 110 and ECHA Guidance on information requirements and chemical safety assessment Chapter R.8 (2012)

Overall assessment factor (AF):

10

Modified dose descriptor starting point:

NOAEC

Value:

126.1 mg/m³

Explanation for the modification of the dose descriptor starting point:

No study on long-term inhalation toxicity available

AF for dose response relationship:

1

Justification:

Default value for NOAEL as starting point for DNEL calculation

AF for differences in duration of exposure:

2

Justification:

Subchronic to chronic exposure

AF for interspecies differences (allometric scaling):

1

Justification:

Allometric scaling is not necessary for the inhalation route

AF for other interspecies differences:

1

Justification:

No default additional interspecies factor is used (please refer to Discussion for further information)

AF for intraspecies differences:

5

Justification:

Default value for consumers

AF for the quality of the whole database:

1

Justification:

Hazard assessment is conducted by means of read-across from a structural analogue. The selected study is the most adequate and reliable study based on the identified similarities in structure and intrinsic properties between source and target substance and overall quality assessment (refer to the endpoint discussion for further details).

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

36.25 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other: ECETOC Technical Report No. 110 and ECHA Guidance on information requirements and chemical safety assessment Chapter R.8 (2012)

Overall assessment factor (AF):

40

Modified dose descriptor starting point:

other: NOAEL corrected for dermal absorption

Value:

1 450 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No study on long-term dermal toxicity available

AF for dose response relationship:

1

Justification:

Default value for NOAEL as starting point for DNEL calculation

AF for differences in duration of exposure:

2

Justification:

Subchronic to chronic exposure

AF for interspecies differences (allometric scaling):

4

Justification:

Allometric scaling rat to human

AF for other interspecies differences:

1

Justification:

No default additional interspecies factor is used (please refer to Discussion for further information)

AF for intraspecies differences:

5

Justification:

Default value for consumers

AF for the quality of the whole database:

1

Justification:

Hazard assessment is conducted by means of read-across from a structural analogue. The selected study is the most adequate and reliable study based on the identified similarities in structure and intrinsic properties between source and target substance and overall quality assessment (refer to the endpoint discussion for further details).

Acute/short term exposure

Hazard assessment conclusion:

no DNEL required: short term exposure controlled by conditions for long-term

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3.63 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other: ECETOC Technical Report No. 110 and ECHA Guidance Guidance on information requirements and chemical safety assessment Chapter R.8 (2012)

Overall assessment factor (AF):

40

Modified dose descriptor starting point:

NOAEL

Value:

145 mg/kg bw/day

AF for dose response relationship:

1

Justification:

Default value for NOAEL as starting point for DNEL calculation

AF for differences in duration of exposure:

2

Justification:

Subchronic to chronic exposure

AF for interspecies differences (allometric scaling):

4

Justification:

Allometric scaling rat to human

AF for other interspecies differences:

1

Justification:

No default additional interspecies factor is used (please refer to Discussion for further information)

AF for intraspecies differences:

5

Justification:

Default value for consumers

AF for the quality of the whole database:

1

Justification:

Hazard assessment is conducted by means of read-across from a structural analogue. The selected study is the most adequate and reliable study based on the identified similarities in structure and intrinsic properties between source and target substance and overall quality assessment (refer to the endpoint discussion for further details).

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - General Population

There are no data available on long-term systemic toxicity of N,N-dimethyl-alkyl-1-amines, reaction products with alkali hydroxide and chloroacetic acid.

However, there are reliable data for Betaines, coco alkyldimethyl (CAS 68424-94-2) which is considered to be suitable for read-across using the analogue approach. For details refer to analogue justification. No DNELs have been derived for the short-term oral, dermal and inhalation exposure of the test substance for consumers, as it is considered that the assessment of hazard is sufficiently covered by deriving the respective DNELs for long-term exposure.

Since there is no dose descriptor for every exposure route, dose descriptors were converted into a correct starting point by route-to route extrapolation based on the ECHA Guidance document "Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health" (2012).

The oral NOAEL of 500 mg/kg bw/d, corresponding to 145 mg/kg bw/d active ingredient for rats, derived from a 90-day oral gavage study (Pittermann, 1993), served as basis for the extrapolations.

Within the ECHA Guidance a factor of 2 is suggested for the extrapolation from oral to inhalation absorption. On the contrary, the Technical guidance document on risk assessment in support of Commission directive 93/67/EEC, 2003 appendix IV A and B gives a number of physico-chemical properties that normally determine oral, inhalation and dermal absorption. These parameters include molecular weight, log Kow, pKa values and for inhalation also particle size distribution, vapour pressure, etc.

Molecules with a molecular weight <500 and a log Kow between 0 and 4 can be assumed to be well absorbed equivalently by the oral and inhalation route. Oral absorption may be reduced for acids and bases depending on their pKa value and their electric charge in the GI tract. More lipophilic substances may be better absorbed in the GI tract due to solubilisation with bile acids and thus oral absorption may be higher than inhalation absorption. The consideration of physico-chemical parameters should be performed before using default assumptions. Unless valid data suggest that inhalation leads to higher absorption than oral ingestion, equal absorption will be assumed when extrapolating from oral to inhalation route. Route-to-route extrapolation within the rat was based on the respiratory volume of 0.8 L/min/kg bw, leading to an inhalation volume of 1.15 m³/kg bw for a time period of 24 hours, reflecting continuous exposure via the environment.

In order to convert an oral NOAEL derived from rats into a dermal NAEL, the differences in absorption between routes as well as differences in dermal absorption between species have to be accounted for. The percutaneous absorption of betaines (C12BET, CAS 683-10-3) was measured in a skin permeation study in hairless mouse skin in vitro (Ridout et al., 1991). In this study a 16 mM dilution of C12BET was applied to isolated full thickness mouse skin, and after 12 and 24 hours 10.3% and 46.5%, respectively, of the applied C12BET had penetrated, with about 25% of the applied dose associated with the skin at the end of the permeation runs. The corrected NOAEL was adapted to dermal absorption by inclusion of a factor of 10, assuming a dermal absorption of 10% via the intact skin. This approach can be considered as sufficiently conservative for 3 reasons: 1) Mouse and rat skin (very similar penetration characteristics; Panchagnula, 1997) are more penetrable than human skin (factor of 2 - 10 compared to human; ECETOC, 1993), occasionally permeability resembles that of human skin, depending on the respective rat strain (Ross, 2000; Panchagnula, 1997); under no circumstances permeability of intact human skin is higher than that of rats or mice. 2) The measured absorption of 46.5% was obtained for an at least 24-times longer period than actually occurring during a 24h day. 3) The in vitro study was performed with 98.9% pure substance, whereas consumer products only contain concentrations up to 15%. This view is further supported by data showing absorption of only 0.4% in 30 min through human skin in vivo, which is comparable to actual exposure times during the day.

It is assumed that use of default AFs recommended by ECHA will in most cases lead to DNELs that are not scientifically justified and consequently lead to unrealistically low exposure levels for establishing safe use. Moreover, ECHA provides limited scientific justification for the default AFs; it is supposed they have relied on 'standard approaches' used by other organisations. In contrast, ECETOC based its AFs on a critical review of the literature; in consequence they should be used preferentially.