Amines, C12-18-alkyl, reaction products with acrylic acid, sodium salts

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3.8 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):

75

Modified dose descriptor starting point:

NOAEC

Value:

282.1 mg/m³

Explanation for the modification of the dose descriptor starting point:

Standard oral-to-inhalation route-to-route extrapolation, assuming absorption rate of 100% for both routes

AF for dose response relationship:

1

Justification:

Oral NOAEL used as a starting point

AF for differences in duration of exposure:

6

Justification:

Subacute (OECD 422 study) to chronic duration extrapolation

AF for interspecies differences (allometric scaling):

1

Justification:

No allometric scaling used in derivation of inhalation DNEL

AF for other interspecies differences:

2.5

Justification:

Standard factor for remaining interspecies differences

AF for intraspecies differences:

5

Justification:

Standard factor for workers

AF for the quality of the whole database:

1

Justification:

Appropriate completeness and adequacy of the database

AF for remaining uncertainties:

1

Justification:

Not applicable

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:

5.3 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

Modified dose descriptor starting point:

NOAEL

Value:

1 600 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Oral-to-dermal route-to-route extrapolation, assuming worst case absorption of 10% by dermal route

AF for dose response relationship:

1

Justification:

Oral NOAEL used as a starting point

AF for differences in duration of exposure:

6

Justification:

Subacute (OECD 422 study) to chronic duration extrapolation

AF for interspecies differences (allometric scaling):

4

Justification:

Standard factor for the rat species

AF for other interspecies differences:

2.5

Justification:

Standard factor for remaining interspecies differences

AF for intraspecies differences:

5

Justification:

Standard factor for workers

AF for the quality of the whole database:

1

Justification:

Appropriate completeness and adequacy of the database

AF for remaining uncertainties:

1

Justification:

Not applicable

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - workers

Based on a comparison of the different available studies the most reliable and relevant NOAEL for the derivations of a DNEL can be obtained from the following studies:

 

·        Systemic effects:

 

Most sensitive record for systemic effects is:

- Subacute (OECD 422) toxicity study, 28days, oral, rat, up to 600 mg/kg bw/day: NOAEL = 160 mg/kg bw/day, (Joint Inerts Task Force, 2008, Harlan B61132)

 

All DNEL were derived using, if necessary, route-to-route extrapolation as there is no adequate subacute/subchronic studies for dermal and/or inhalation route available.

 

As only slight effects of general toxicity were observed in a OECD 422 study with a structural similar substances and furthermore only rat specific effect are noted (α-2µ-globulin, histophatological findings in kidney) the substance is considered to be of low toxicity. Hence the determined NOAEL of 160 mg/kg bw/d represents a conservative value. It could be argued that the “real” threshold for adverse effects would be a concentration dose higher than used as NOAEL (600mg/kg bw/d). Using the conservative value of 160 mg/kg bw/d for the deviation of the DNELs thus introduces an additional safety factor.

 

Another overestimation of risk might be introduced by using the safety factor of 3 for subacute to subchronic exposure as lately it has been shown that the difference of dosages, leading to effects, between subacute and subchronic study is often below 3 [Ref. Batke et al. Toxicology Letters 205 (2011) 122– 129]. Additionally the safety factor chosen is also believed to be conservative, as the female animals in the OECD 422 are dosed for a time between subacute and subchronic ( approx. 49 days).

 

In summary a few conservative factors were taken into account for human risk assessment and the applicant believes that the risk for human can be assessed and adequate RMMs can be established based on the available data even if there is no information from a 90 day study available. As both the NOAEL used and the assessment factors include conservative assumptions and no severe effect is observed in the OECD 422 study even at the highest dosage, no additional relevant information is expected if further studies are conducted.

 

According to Annex XI REGULATION (EC) No 1907/2006 chapter 1.2 "weight of evidence .... Where sufficient weight of evidence for the presence or absence of a particular dangerous property is available:.....—further testing on vertebrate animals for that property shall be omitted, ... " further testing is therefore not suggested and not proposed.

 

An additional factor which has to be taken into account is that the toxic effects induced by the substance are mainly irritating effects. After dermal contact prior to systemic effects irritation will occurs. This irritation does also limit the exposure. Overall, the use of an oral NOAEL and assuming 10% dermal absorption is considered to be worst case and is believed to be reflecting an adequate risk assessment even if no 90-day study information is available.

 

·        Local effects:

 

Most sensitive records for local effects are:

- Skin irritation/corrosion in vitro, OECD 431/439: corrosion test 86 (98) / 100 viability, irritation test 12/100 viability, result: irritating (BASF SE, 2013, 61V0727/12A427).

- Eye irritation, Rabbit, modified Draize protocol, 16% active ingredient: Eye reaction observed, not reversible (0.3 – 0.0 – 1.3 for corneal opacity, 2.0 – 2.3 – 2.3 for redness, and 3.7 – 2.7 – 3.0 for chemosis, persistent ocular damage (day 7)) (PSL, 1982, T-2230)

- Guinea-pig sensitization study, Draize protocol (10% active ingredient), 0.1% induction (by injection): not sensitising, 0/10 positive (BASF, IBT 4451,1963)

 

The available data for irritation do not provide quantitative dose-response information; thus, no short-term / long term local DNELs can be derived and no quantitative risk assessment was performed for irritation. Exposure assessment and risk characterization are instead performed on a qualitative basis.

 

Therefore a qualitative risk assessment will be performed for irritation.

 

Skin irritation is considered a low hazard while eye damage represents a moderate hazard therefore the substance is categorized to the moderate hazard group.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.9 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

Modified dose descriptor starting point:

NOAEC

Value:

139.1 mg/m³

Explanation for the modification of the dose descriptor starting point:

Standard oral-to-inhalation route-to-route extrapolation, assuming absorption rate of 100% for both routes

AF for dose response relationship:

1

Justification:

according to ECETOC

AF for differences in duration of exposure:

6

Justification:

Subacute (OECD 422 study) to chronic duration extrapolation

AF for interspecies differences (allometric scaling):

1

Justification:

No allometric scaling used in derivation of inhalation DNEL

AF for other interspecies differences:

2.5

Justification:

Standard factor for remaining interspecies differences

AF for intraspecies differences:

10

Justification:

Standard factor for general population

AF for the quality of the whole database:

1

Justification:

Appropriate completeness and adequacy of the database

AF for remaining uncertainties:

1

Justification:

Not applicable

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:

2.7 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

Modified dose descriptor starting point:

NOAEL

Value:

1 600 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Oral-to-dermal route-to-route extrapolation, assuming worst case absorption of 10% by dermal route

AF for dose response relationship:

1

Justification:

Oral NOAEL used as a starting point

AF for differences in duration of exposure:

6

Justification:

Subacute (OECD 422 study) to chronic duration extrapolation

AF for interspecies differences (allometric scaling):

4

Justification:

Standard factor for the rat species

AF for other interspecies differences:

2.5

Justification:

Standard factor for remaining interspecies differences

AF for intraspecies differences:

10

Justification:

Standard factor for general population

AF for the quality of the whole database:

1

Justification:

Appropriate completeness and adequacy of the database

AF for remaining uncertainties:

1

Justification:

Not applicable

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.3 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

Modified dose descriptor starting point:

NOAEL

Value:

160 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Not applicable

AF for dose response relationship:

1

Justification:

Oral NOAEL used as a starting point

AF for differences in duration of exposure:

6

Justification:

Subacute (OECD 422 study) to chronic duration extrapolation

AF for interspecies differences (allometric scaling):

4

Justification:

Standard factor for the rat species

AF for other interspecies differences:

2.5

Justification:

Standard factor for remaining interspecies differences

AF for intraspecies differences:

10

Justification:

Standard factor for general population

AF for the quality of the whole database:

1

Justification:

Appropriate completeness and adequacy of the database

AF for remaining uncertainties:

1

Justification:

Not applicable

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - General Population

Based on a comparison of the different available studies the most reliable and relevant NOAEL for the derivations of a DNEL can be obtained from the following studies:

 

·        Systemic effects:

 

Most sensitive record for systemic effects is:

- Subacute (OECD 422) toxicity study, 28days, oral, rat, up to 600 mg/kg bw/day: NOAEL = 160 mg/kg bw/day, (Joint Inerts Task Force, 2008, Harlan B61132)

 

All DNEL were derived using, if necessary, route-to-route extrapolation as there is no adequate subacute/subchronic studies for dermal and/or inhalation route available.

 

As only slight effects of general toxicity were observed in a OECD 422 study with a structural similar substances and furthermore only rat specific effect are noted (α-2µ-globulin, histophatological findings in kidney) the substance is considered to be of low toxicity. Hence the determined NOAEL of 160 mg/kg bw/d represents a conservative value. It could be argued that the “real” threshold for adverse effects would be a concentration dose higher than used as NOAEL (600mg/kg bw/d). Using the conservative value of 160 mg/kg bw/d for the deviation of the DNELs thus introduces an additional safety factor.

 

Another overestimation of risk might be introduced by using the safety factor of 3 for subacute to subchronic exposure as lately it has been shown that the difference of dosages, leading to effects, between subacute and subchronic study is often below 3 [Ref. Batke et al. Toxicology Letters 205 (2011) 122– 129]. Additionally the safety factor chosen is also believed to be conservative, as the female animals in the OECD 422 are dosed for a time between subacute and subchronic ( approx. 49 days).

 

In summary a few conservative factors were taken into account for human risk assessment and the applicant believes that the risk for human can be assessed and adequate RMMs can be established based on the available data even if there is no information from a 90 day study available. As both the NOAEL used and the assessment factors include conservative assumptions and no severe effect is observed in the OECD 422 study even at the highest dosage, no additional relevant information is expected if further studies are conducted.

 

According to Annex XI REGULATION (EC) No 1907/2006 chapter 1.2 "weight of evidence .... Where sufficient weight of evidence for the presence or absence of a particular dangerous property is available:.....—further testing on vertebrate animals for that property shall be omitted, ... " further testing is therefore not suggested and not proposed.

 

An additional factor which has to be taken into account is that the toxic effects induced by the substance are mainly irritating effects. After dermal contact prior to systemic effects irritation will occurs. This irritation does also limit the exposure. Overall, the use of an oral NOAEL and assuming 10% dermal absorption is considered to be worst case and is believed to be reflecting an adequate risk assessment even if no 90-day study information is available.

 

·        Local effects:

 

Most sensitive records for local effects are:

- Skin irritation/corrosion in vitro, OECD 431/439: corrosion test 86 (98) / 100 viability, irritation test 12/100 viability, result: irritating (BASF SE, 2013, 61V0727/12A427).

- Eye irritation, Rabbit, modified Draize protocol, 16% active ingredient: Eye reaction observed, not reversible (0.3 – 0.0 – 1.3 for corneal opacity, 2.0 – 2.3 – 2.3 for redness, and 3.7 – 2.7 – 3.0 for chemosis, persistent ocular damage (day 7)) (PSL, 1982, T-2230)

- Guinea-pig sensitization study, Draize protocol (10% active ingredient), 0.1% induction (by injection): not sensitising, 0/10 positive (BASF, IBT 4451,1963)

 

The available data for irritation do not provide quantitative dose-response information; thus, no short-term / long term local DNELs can be derived and no quantitative risk assessment was performed for irritation. Exposure assessment and risk characterization are instead performed on a qualitative basis.

 

Therefore a qualitative risk assessment will be performed for irritation.

 

The general population will not come into direct contact with the neat substance. By dilution of the substance in a product/preparation the hazard potential will decrease accordingly. Furthermore suited risk management measures may be used to prevent consumer exposure (e.g. increased viscosity of products in order to avoid splashes and spills during handling, child-resistant fastenings or further product-integrated measures, like increase of particle size to decrease the inhalable fraction of powders or tableting of powders etc.). Additional general handling instructions will be provided with the product (like wash of immediately if in contact with skin, use only in well ventilated room, etc.).

 

Thus, the irritating potential of the substance in consumer products is assumed to be sufficiently controlled, via a variety of risk management measures, under regular conditions of use.