methyl 2-hydroxybut-3-enoate

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.47 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):

50

Dose descriptor starting point:

NOAEL

Value:

100 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

123.42 mg/m³

Explanation for the modification of the dose descriptor starting point:

Standard respiratory volume, human (sRVhuman) for 8 h per person (70 kg): 6.7 m³

Standard respiratory volume of the rat (sRVrat) for 8 hours: 0.38 m³/kg bw

Worker respiratory volume (wRV) for 8 hours with light physical activity per person: 10 m³

Oral absorption of the rat/ inhalation absorption of humans (ABS oral-rat / ABS inh-human): 1/2

Correction for difference between human and experimental exposure conditions: 7 d rat/5 d worker

Corrected NOAEC (inhalation) for workers:

NOEC_corr = NOAEL_oral x 1/0.38 m³/kg bw/day x 6.7 m³/10m³ x 7d/5d x ABS_oral/ABS_inh

NOEC_corr = 100 mg/kg bw/day x 1/0.38 m³/kg bw/day x 6.7 m³/10m³ x 7d/5d x 1/2

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

4

Justification:

The exposure duration of the OECD 422 study performed with the test item was up to 63 days for females and 29 days for males. In comparison to a subacute 28-day study, the OECD 422 study provides additional information on fertility and developmental toxicity, which justifies the assessment factor of 4.

AF for interspecies differences (allometric scaling):

1

Justification:

No allometric scalling is applied for inhalation as the inhalative data is standardized with reference to the respiratory rates. Respiratory rates depend directly on caloric demand, therefore inhalative study results are already extrapolated to humans on the basis of metabolic rate scaling (=allometric scaling).

AF for other interspecies differences:

2.5

Justification:

The recommended AF for other interspecies differences is applied.

AF for intraspecies differences:

5

Justification:

The default value for the relatively homogenous group "worker" is used.

AF for the quality of the whole database:

1

Justification:

The OECD 422 toxicity study was conducted according to regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute to uncertainty and it is therefore not necessary to apply an additional factor.

AF for remaining uncertainties:

1

Justification:

DNEL Derivation is considered conservative, reflecting reasonable worst case assumptions. Therefore, no further AF for remaining uncertainties is applied.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

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:

0.7 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):

200

Dose descriptor starting point:

NOAEL

Value:

100 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

140 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Oral absorption of the rat/ dermal absorption of humans (ABS oral-rat / ABS derm-human): 1/1

Correction for difference between human and experimental exposure conditions: 7 d rat/5 d worker

Corrected NOAEL (dermal) for workers:

NOAEL_corr = NOAEL_oral x 7d/5d x ABS_oral/ABS_inh

NOAEL_corr = 100 mg/kg bw/day x 7d/5d x 1/1

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

4

Justification:

The exposure duration of the OECD 422 study performed with the test item was up to 63 days for females and 29 days for males. In comparison to a subacute 28-day study, the OECD 422 study provides additional information on fertility and developmental toxicity, which justifies the assessment factor of 4.

AF for interspecies differences (allometric scaling):

4

Justification:

The recommended AF for other interspecies differences is applied.

AF for other interspecies differences:

2.5

Justification:

The recommended AF for other interspecies differences is applied.

AF for intraspecies differences:

5

Justification:

The default value for the relatively homogenous group "worker" is used.

AF for the quality of the whole database:

1

Justification:

The OECD 422 toxicity study was conducted according to regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute to uncertainty and it is therefore not necessary to apply an additional factor.

AF for remaining uncertainties:

1

Justification:

DNEL derivation is considered conservative, reflecting reasonable worst case assumptions. Therefore, no further AF for remaining uncertainties is applied.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

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)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - workers

Systemic long-term DNEL for inhalation exposure

The respective NOAEC is based on a NOAEL of 100 mg/kg bw/day from a subacute oral rat study according to OECD guideline 422, considering an oral bioavailability of 100%. It was modified  using a human standard respiratory volume (sRVhuman) of 6.7 m³ for 8 hours per person (70 kg), a rat standard respiratory volume (sRVrat) of 0.38 m³/kg bw for 8 hours, a worker respiratory volume (wRV) of 10 m³ for 8 hours with light physical activity, the default quotient of ½ for oral absorption of the rat and inhalation absorption of humans (ABS oral-rat / ABS inh-human) and a correction for difference between human and experimental exposure conditions (7 days exposure of the rats/5 days exposure of worker per week) to 123.42 mg/m³ using the equation provided in the Guidance Document on Information Requirement, Chapter R8:

NOEC_corr = NOAEL_oral x 1/0.38 m³/kg bw/day x 6.7 m³/10m³ x 7d/5d x ABS_oral/ABS_inh

Using assessment factors of (i) 4 for duration of exposure, (ii) 2.5 for remaining species differences and (iii) 5 for intraspecies extrapolation, a DNEL of 2.47  mg/m³ for long-term, systemic inhalative exposure was calculated.

 

Systemic acute DNEL for inhalation exposure

No acute inhalation toxicity study is available for the substance. According to CLP Regulation (EC 1272/2008), the test substance is classified for acute oral toxicity (category 4). An acute dermal toxicity study was stopped due to delayed corrosive properties of the substance. Due to its low vapour pressure (123 Pa), high peak inhalation exposure is not considered as relevant. The test item is unlikely to be available as a vapour to a large extent. Therefore, no acute systemic inhalation DNEL was derived. Furthermore, long-term DNELs are considered sufficient to ensure that acute systemic effects do not occur.

 

Local long-term and acute DNELs for inhalation exposure

The test item is classified for skin and eye corrosion (category 1) and for skin sensitization (category 1B) according to Regulation (EC) No 1272/2008 (CLP). Furthermore, acute oral and dermal as well as subacute oral exposure to rats mainly showed local effects. Thus, respiratory irritation after exposure to the substance is likely and thus, a qualitative risk assessment is conducted. Appropriate qualitative risk managements measures should be implemented to avoid exposure. The substance is assigned to the moderate hazard band in accordance with ECHA Guidance on information requirements and chemical safety assessment Part E: Risk Characterisation (2016).

 

Systemic long-term DNEL for dermal exposure

The NOAEL of 100 mg/kg bw/day from a subacute oral toxicity study according to OECD guideline 422 is used as POD. It was modified using a correction for difference between human and experimental exposure conditions (7 days exposure of the rats/5 days exposure of worker per week) to 140 mg/kg bw/day using the equation provided in the Guidance Document on Information Requirement, Chapter R8:

NOAEL_corr = NOAEL_dermal x 7d/5d

Using assessment factors of (i) 4 for duration of exposure, (ii) 4 for interspecies differences (allometric scaling), (iii) 2.5 for remaining interspecies differences and (iiii) 5 for intraspecies extrapolation, a DNEL of 0.7 mg/kg bw/day for long-term, systemic dermal exposure was calculated.

 

Systemic acute DNEL for dermal exposure

An acute dermal toxicity study was conducted but stopped due to delayed corrosive properties of the substance. Furthermore, the substance is classified as corrosive to skin and eye (category 1) and as skin sensitising (category 1B). Therefore, local effects are considered the primary mode of action of the substance and thus, no acute systemic dermal DNEL was derived. Furthermore, long-term DNELs are considered sufficient to ensure that acute effects do not occur.

 

Local long-term and acute DNELs for dermal exposure

The test item is classified for skin and eye corrosion (category 1) and for skin sensitization (category 1B) according to Regulation (EC) No 1272/2008 (CLP). Furthermore, acute oral and dermal as well as subacute oral exposure to rats mainly showed local effects. Thus, local dermal effects after short- and long-term exposure to the substance are likely and thus, a qualitative risk assessment is conducted. Appropriate qualitative risk managements measures should be implemented to avoid exposure. The substance is assigned to the moderate hazard band in accordance with ECHA Guidance on information requirements and chemical safety assessment Part E: Risk Characterisation (2016).

 

Hazard for the eyes

The test item is classified for serious eye damage (category 1) according to Regulation (EC) No 1272/2008 (CLP). Thus, a qualitative risk assessment is conducted. Appropriate qualitative risk managements measures should be implemented to avoid exposure. The substance is assigned to the moderate hazard band in accordance with ECHA Guidance on information requirements and chemical safety assessment Part E: Risk Characterisation (2016).

General Population - Hazard via inhalation 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

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:

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 for the eyes

Local effects

Hazard assessment conclusion:

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

Additional information - General Population

Inhalation, dermal and oral effects, local and systemic, short- and long-term

The general population is not exposed to the substances (no professional or consumer uses, see IUCLID section 3), thus no further hazard information for the general population is required.