2-amino-2-ethylpropanediol

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

58.8 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):

30

Dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

1 763.2 mg/m³

AF for dose response relationship:

1

AF for differences in duration of exposure:

6

AF for interspecies differences (allometric scaling):

1

AF for other interspecies differences:

1

AF for intraspecies differences:

5

AF for the quality of the whole database:

1

AF for remaining uncertainties:

1

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

58.8 mg/m³

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

high 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:

10.4 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):

120

Dose descriptor starting point:

NOAEL

Value:

1 000 mg/m³

Modified dose descriptor starting point:

NOAEL

Value:

1 250 mg/kg bw/day

AF for dose response relationship:

1

AF for differences in duration of exposure:

6

AF for interspecies differences (allometric scaling):

4

AF for other interspecies differences:

1

AF for intraspecies differences:

5

AF for the quality of the whole database:

1

AF for remaining uncertainties:

1

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Acute/short term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

high hazard (no threshold derived)

Additional information - workers

No DNELs have been derived for the short-term dermal and inhalation exposure of 2 -amino-2 -ethyl-1,3 –propanediol (AEPD) for workers, as it is assumed that the assessment of hazard is sufficiently covered by deriving the respective DNELs for long-term exposure.

No quantitative dose-response data are available for local short-term effects on skin and respiratory tract of AEPD. Therefore, an absolute value for the local effects has been determined. The most sensitive local endpoint is eye corrosion (Parekh, 1982).

The long-term worker DNEL for dermal systemic effects is based on the combined oral repeated dose toxicity and reproduction/developmental screening test (Ishida, 2004) performed according to OECD 422 in rats. In this study, no animals died and no effects with toxicological relevance were observed on body weights, organ weights, haematologic and clinical chemistry parameters, or gross and histopathologic examinations. As no effects were observed up to and including the highest dose level, the NOAEL is ≥ 1000 mg/kg bw/day. This study was chosen as the starting point for deriving the DNEL as there is no dermal repeated dose study. To convert the oral NOAEL [mg/kg bw/day] into a dermal NOAEL [mg/kg bw/day], the differences in absorption between routes as well as differences in dermal absorption between rats and humans have to be accounted for (Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health, European Chemicals Agency, Version 2, December 2010).

For neat AEPD (i.e. basic solution), a dermal absorption of 80% was calculated using QSAR and the available physico-chemical properties. Based on practical experience, the dermal absorption of 80% has to be regarded as a worst case scenario: AEPD is usually used in applications where the pH will be closer to neutral. As a consequence AEPD will predominantly be present in an ionised form which will not easily penetrate the skin. This fact needs to be addressed when performing the exposure assessment.

The long-term worker DNEL for inhalation systemic effects is again based on the combined oral repeated dose toxicity and reproduction/developmental screening test performed according to OECD 422 (Ishida, 2004). This study was chosen as the starting point for deriving the DNEL as there is no inhalation repeated dose study. According to the “Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health” (European Chemicals Agency, Version 2, December 2010), the oral NOAEL should be converted into an inhalatory NAEC: the oral dose for the rat is converted to the corresponding air concentration using a standard breathing volume for the rat (0.38 m³/kg for 8 h exposure). Additionally, it should be taken into account that during 8 hours light activity at work the respiratory rate becomes higher (10 m³/person) than standard (6.7 m³/person). Considering these differences, the correct starting point is a NAEC of 1763.2 mg/m³. The absorption via the inhalative route is considered to be in the same order as via the oral route.

In general, assessment factors (AF) recommended by ECHA (Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose[concentration]-response for human health. European Chemicals Agency, Version 2, December 2010) were used when applicable to derive the DNELs. Several AFs for which there is additional information were refined. The difference in metabolic rate between humans and the test species has been taken into account, where relevant. The AF for remaining interspecies differences has been set at 1, as the toxicokinetic data indicates that AEPD will not be metabolised. Due to its polarity and size, AEPD will mainly be excreted unmetabolised via the urine (see toxicokinetics). An AF for exposure duration is applied to take into account the difference between experimental exposure duration and the exposure duration for the population. In the combined oral repeated dose toxicity and reproduction/developmental screening test (OECD 422) that is used to derive the long-term exposure DNELs, rats were exposed for at least 42 days. Based on a recent publication (Batke et al., 2011), an AF of 3 has been chosen in this case, as it reflects the exposure duration accurately. The study of Batke et al. (2011) performed an assessment of the time extrapolation factors based on the comparison of NOELs from different duration studies. Batke et al. (2011) concluded that in the majority of cases a factor of 3 is sufficient to convert a subacute exposure duration to chronic exposure duration. As in the present case, the NOAEL corresponds to the highest dose tested with no evidence of treatment related adverse effects, a factor of 3 can be used according to Batke et al. (2011).

Batke et al., 2011, Evaluation of time extrapolation factors based on the database RepDose. Toxicol Lett, 205(2):122 -129

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

29.4 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):

60

Dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

1 763.2 mg/m³

AF for dose response relationship:

1

AF for differences in duration of exposure:

6

AF for interspecies differences (allometric scaling):

1

AF for other interspecies differences:

1

AF for intraspecies differences:

10

AF for the quality of the whole database:

1

AF for remaining uncertainties:

1

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

29.4 mg/m³

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

5.2 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):

240

Dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

1 250 mg/kg bw/day

AF for dose response relationship:

1

AF for differences in duration of exposure:

6

AF for interspecies differences (allometric scaling):

4

AF for other interspecies differences:

1

AF for intraspecies differences:

10

AF for the quality of the whole database:

1

AF for remaining uncertainties:

1

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Acute/short term exposure

Hazard assessment conclusion:

high 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:

4.17 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):

240

Dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

AF for dose response relationship:

1

AF for differences in duration of exposure:

6

AF for interspecies differences (allometric scaling):

4

AF for intraspecies differences:

10

AF for the quality of the whole database:

1

AF for remaining uncertainties:

1

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

high hazard (no threshold derived)

Additional information - General Population

The general population is not exposed to 2-amino-2-ethyl-1,3–propanediol (AEPD), based on its identified uses. However, the long-term consumer DNELs for oral, dermal and inhalation systemic effects have been derived. No DNELs have been derived for the short-term dermal, inhalation and oral exposure of AEPD for the general population, as it is assumed that the assessment of hazard is sufficiently covered by deriving the respective DNELs for long-term exposure. No quantitative dose-response data are available for local short-term effects on skin and respiratory tract of AEPD. Therefore, an absolute value for local effects has been determined. The most sensitive local endpoint is eye corrosion (Parekh, 1982).

The long-term DNEL for the general population, dermal systemic effects is based on the combined oral repeated dose toxicity and reproduction/developmental screening test (Ishida, 2004) performed according to OECD 422 in rats. In this study, no animals died and no effects with toxicoloical relevance were observed on body weights, organ weights, haematologic and clinical chemistry parameters, or gross and histopathologic examinations. As no effects were observed up to and including the highest dose level, the NOAEL is ≥ 1000 mg/kg bw/day. This study was chosen as the starting point for deriving the DNEL as there is no dermal repeated dose study. To convert the oral NOAEL [mg/kg bw/day] into a dermal NOAEL [mg/kg bw/day], the differences in absorption between routes as well as differences in dermal absorption between rats and humans have to be accounted for (Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health. European Chemicals Agency, Version 2, December 2010).

For neat AEPD (i.e. basic solution), a dermal absorption of 80% was calculated using QSAR and the available physico-chemical properties. Based on practical experience, the dermal absorption of 80% has to be regarded as a worst case scenario: AEPD is usually used in applications where the pH will be closer to neutral. As a consequence AEPD will predominantly be present in an ionised form which will not easily penetrate the skin. This fact needs to be addressed when performing the exposure assessment.

The long-term DNEL for the general population, inhalation systemic effects is again based on the combined oral repeated dose toxicity and reproduction/developmental screening test performed according to OECD 422 (Ishida, 2004). This study was chosen as the starting point for deriving the DNEL as there is no inhalation repeated dose study. According to the Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose[concentration]-response for human health (European Chemicals Agency, Version 2, December 2010), the oral NOAEL should be converted into an inhalatory NAEC: the oral dose for the rat is converted to the corresponding air concentration using a standard breathing volume for the rat (1.15 m³/kg for 24 h exposure). Therefore, the corrected starting point is a NAEC of 869.6 mg/ m³. The absorption via the inhalative route is considered to be in the same order of magnitude as via the oral route. The long-term DNEL for the general population, oral systemic effects is also based on the combined oral repeated dose toxicity and reproduction/ developmental screening test (Ishida, 2004) performed according to OECD 422 in rats. In this study, no animals died and no treatment-related effects were observed on body weights, organ weights, haematologic and clinical chemistry parameters, or gross and histopathologic examinations. As no effects were observed up to and including the highest dose level, the NOAEL is ≥ 1000 mg/kg bw/d. The study was performed via the oral route and the value can be used directly to derive the oral DNEL.

 

In general, assessment factors (AF) recommended by ECHA (Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose[concentration]-response for human health. European Chemicals Agency, Version 2, December 2010) were used when applicable to derive the DNELs. Several AFs for which there is additional information were refined. The difference in metabolic rate between humans and the test species has been taken into account, where relevant. The AF for remaining interspecies differences has been set at 1, as the toxicokinetic data indicates that AEPD will not be metabolised. Due to its polarity and size, AEPD will mainly be excreted unmetabolised via the urine (see toxicokinetics). An AF for exposure duration is applied to take into account the difference between experimental exposure duration and the exposure duration for the general population. In the combined oral repeated dose toxicity and reproduction/developmental screening test (OECD 422) that is used to derive the long-term exposure DNELs, rats were exposed for at least 42 days. Based on a recent publication (Batke et al., 2011), an AF of 3 has been chosen in this case, as it reflects the exposure duration accurately. The study of Batke et al. (2011) performed an assessment of the time extrapolation factors based on the comparison of NOELs from different duration studies. Batke et al. (2011) concluded that in the majority of cases a factor of 3 is sufficient to convert a subacute exposure duration to chronic exposure duration. As in the present case, the NOAEL corresponds to the highest dose tested with no evidence of treatment related adverse effects, a factor of 3 can be used according to Batke et al. (2011).

Batke et al., 2011, Evaluation of time extrapolation factors based on the database RepDose. Toxicol Lett, 205(2):122 -129.