Ethyl 2-methylvalerate

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

52.08 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):

37.5

Modified dose descriptor starting point:

NOAEC

Value:

1 953 mg/m³

Explanation for the modification of the dose descriptor starting point:

Short branched chain carboxylic acids and their esters are rapidly absorbed from the gastrointestinal tract and have low systemic toxicity therefore, for systemic toxicity, route-to-route extrapolation is considered valid.

AF for dose response relationship:

1

Justification:

Default AF: Clear discriminating dose

AF for differences in duration of exposure:

3

Justification:

Default AF not considered necessary. Value appropriate for AF converting extended exposure to chronic

AF for interspecies differences (allometric scaling):

1

Justification:

AF appropriate for inhalation-inhalation extrapolation (no allometric scaling)

AF for other interspecies differences:

2.5

Justification:

Default AF

AF for intraspecies differences:

5

Justification:

Default AF for workers

AF for the quality of the whole database:

1

Justification:

High quality studies Klimisch 1

AF for remaining uncertainties:

1

Justification:

Default AF; The assessment factors are already conservative. A further assessment factor is not necessary.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

other: A DNEL is not required according to ECHA guidance chapter R.8 since no acute toxicity hazard leading to C&L has been identified.

Modified dose descriptor starting point:

other: LC50 >5967

Justification:

N/A

Justification:

N/A

Justification:

N/A

Justification:

N/A

Justification:

N/A

Justification:

N/A

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

DNEL related information

DNEL derivation method:

other: A DNEL is not required according to ECHA guidance chapter R8 since no acute toxicity hazard leading to C&L has been identified.

Dose descriptor starting point:

other: LC50 >5967mg/m3

Justification:

N/A

Justification:

N/A

Justification:

N/A

Justification:

N/A

Justification:

N/A

Justification:

N/A

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

6.67 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):

150

Modified dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Short branched chain carboxylic acids and their esters are rapidly absorbed from the gastrointestinal tract and have low systemic toxicity therefore, for systemic toxicity, route-to-route extrapolation is considered valid.

AF for dose response relationship:

1

Justification:

Default AF: Clear discriminating dose

AF for differences in duration of exposure:

3

Justification:

Default AF not considered necessary Value appropriate for AF converting extended exposure to chronic

AF for interspecies differences (allometric scaling):

4

Justification:

Default AF; Rat

AF for other interspecies differences:

2.5

Justification:

Deafault AF

AF for intraspecies differences:

5

Justification:

Deafault AF for workers

AF for the quality of the whole database:

1

Justification:

High quality studies, Klimisch score 1

AF for remaining uncertainties:

1

Justification:

Default AF; The assessment factors are already conservative. A further assessment factor is not necessary.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - workers

Workers

Hazard via the inhalation route – systemic effects

Long term exposure

 

Hazard assessment conclusion	Most sensitive endpoint	Route of original study
DNEL 52.08 mg/m^3	Repeated dose toxicity	oral

 

DN(M)EL related information A DNEL is required according to ECHA guidance chapter R.8. Potential exposure of workers to EMV, a volatile ester, is considered highly likely. A long-term inhalation systemic DNEL can be derived from the repeated dose study conducted with EMB.   Read-across is appropriate because of the close structural similarity between EMV and EMB.

Justification and comments In an OECD 422 study in which EMB was administered orally for 51 days at doses of up to 1000 mg/kg, no adverse effects were observed on either the dam or the foetuses and therefore the highest dose is effectively a limit dose. The NOAEL was therefore identified as 1000 mg/kg. Therefore the data are limited since they do not identify any adverse effect or target organ.   The toxicity of EMB and EMV is considered to be very low based on information on structurally similar esters. WHO (1999).

Dose descriptor NOAEL 1000 mg/kg bw/d in the rat and this value is used to derive the systemic long-term DNEL. This is considered to be a conservative estimate.

Modification of dose descriptor According to ECHA guidance, convert the rat oral NOAEL into a human inhalation NOAEC (mg/m3) after adjusting for differences in uptake between the two routes of exposure (TGD, Appendix R.8-2, example B3). 

NOAEC_inhalation = Oral NOAEL x [1/sRV] x[ABS_oral-rat/ABS_{inhalation-human}] x[sRV_human/wRV]

NOAEC_inhalation =1000 x [1/0.343] x [100 / 100] x [6.7/10]

= 1953 mg/m³

 

Assessment factors

Uncertainty	ECHA AFs	Justification
Dose-response relationship	1	Default AF: Clear discriminating dose
Differences in duration of exposure	3	Default AF not considered necessary Value appropriate for AF converting extended exposure to chronic
Interspecies differences (allometric scaling)	1	AF appropriate for inhalation-inhalation extrapolation (no allometric scaling
Other interspecies differences	2.5	Default AF
Intraspecies differences	5	Default AF for workers
Quality of database	1	High quality studies, Klimisch score 1
Remaining uncertainties	1	Default AF; The assessment factors are already conservative. A further assessment factor is not necessary.
Overall AF	37.5

 

Calculated DNEL for long-term inhalation systemic exposure for consumers is 52.08 mg/m³using an overall assessment factor of 37.5.

 

Hazard via the dermal route – systemic effects

Long term exposure

 

Hazard assessment conclusion	Most sensitive endpoint	Route of original study
DNEL6.67 mg/kg bw/day	Repeated dose toxicity	oral

 

DN(M)EL related information A DNEL is required according to ECHA guidance chapter R.8. Potential exposure of the workers to EMV is considered highly likely. A long-term dermal systemic DNEL can be derived from the repeated dose study conducted with EMB.   Read-across is appropriate because of the close structural similarity between EMV and EMB.

Justification and comments In an OECD 422 study in which EMB was administered orally for 51 days at doses of up to 1000 mg/kg, no adverse effects were observed on either the dam or the foetuses and therefore the highest dose is effectively a limit dose. The NOAEL was therefore identified as 1000 mg/kg. Therefore the data are limited since they do not identify any adverse effect or target organ. The toxicity of EMB and EMV is considered to be very low based on information on structurally similar esters. WHO (1999)   

Dose descriptor NOAEL 1000 mg/kg bw/d in the rat and this value is used to derive the systemic long-term DNEL. This is considered to be a conservative estimate.

Modification of dose descriptor According to ECHA guidance, convert the rat oral NOAEL into a human dermal NOAEL (mg/kg bw) after adjusting for differences in uptake between the two routes of exposure (TGD, Appendix R.8-2, example B3). 

NOAEL_dermal= Oral NOAEL x[ABS_oral-rat/ABS_dermal-human]

NOAEL_dermal=1000 x [100 / 100]

= 1000 mg/kg bw/day

 

Assessment factors

Uncertainty	ECHA AFs	Justification
Dose-response relationship	1	Default AF: Clear discriminating dose
Differences in duration of exposure	3	Default AF not considered necessary Value appropriate for AF converting extended exposure to chronic
Interspecies differences (allometric scaling)	4	Default AF; Rat
Other interspecies differences	2.5	Default AF
Intraspecies differences	5	Default AF for workers
Quality of database	1	High quality studies, Klimisch score 1
Remaining uncertainties	1	Default AF; The assessment factors are already conservative. A further assessment factor is not necessary.
Overall AF	150

 

Calculated DNEL for long-term dermal systemic exposure for consumers is 6.67 mg/kg bw/day using an overall assessment factor of 150. This is considered to be a conservative DNEL based on the low toxicity of other short-chain alkyl esters.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

12.95 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:

971 mg/m³

Explanation for the modification of the dose descriptor starting point:

Short branched chain carboxylic acids and their esters are rapidly absorbed from the gastrointestinal tract and have low systemic toxicity therefore, for systemic toxicity, route-to-route extrapolation is considered valid.

AF for dose response relationship:

1

Justification:

Default AF: Clear discriminating dose

AF for differences in duration of exposure:

3

Justification:

Default AF not considered necessary Value appropriate for AF converting extended exposure to chronic

AF for interspecies differences (allometric scaling):

1

Justification:

AF appropriate for inhalation-inhalation extrapolation (no allometric scaling)

AF for other interspecies differences:

2.5

Justification:

Default value

AF for intraspecies differences:

10

Justification:

Default value for the general population

AF for the quality of the whole database:

1

Justification:

High quality studies, Klimisch 1

AF for remaining uncertainties:

1

Justification:

Default AF; The assessment factors are already conservative. A further assessment factor is not necessary.te.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

other: A DNEL is not required according to ECHA guidance chapter R8 since no acute toxicity hazard leading to C&L has been identified.

Modified dose descriptor starting point:

other: LC50 >5967

Justification:

N/A

Justification:

N/A

Justification:

N/A

Justification:

N/A

Justification:

N/A

Justification:

N/A

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

DNEL derivation method:

other: A DNEL is not required according to ECHA guidance chapter R8 (Appendix 8-8) since no acute toxicity hazard leading to C&L has been identified.

Dose descriptor starting point:

other: LC50 >5967mg/m3

Justification:

N/A

Justification:

N/A

Justification:

N/A

Justification:

N/A

Justification:

N/A

Justification:

N/A

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3.33 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:

1 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Short branched chain carboxylic acids and their esters are rapidly absorbed from the gastrointestinal tract and have low systemic toxicity therefore, for systemic toxicity, route-to-route extrapolation is considered valid.

AF for dose response relationship:

1

Justification:

Default AF: Clear discriminating dose

AF for differences in duration of exposure:

3

Justification:

Default AF not considered necessary Value appropriate for AF converting extended exposure to chronic

AF for interspecies differences (allometric scaling):

4

Justification:

Default AF; Rat

AF for other interspecies differences:

2.5

Justification:

Deafult AF

AF for intraspecies differences:

10

Justification:

Deafult AF for the general population

AF for the quality of the whole database:

1

Justification:

High quality studies, Klimisch 1

AF for remaining uncertainties:

1

Justification:

Default AF; The assessment factors are already conservative. A further assessment factor is not necessary.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3.33 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:

1 000 mg/kg bw/day

AF for dose response relationship:

1

Justification:

Default AF: Clear discriminating dose

AF for differences in duration of exposure:

3

Justification:

Default AF not considered necessary Value appropriate for AF converting extended exposure to chronic

AF for interspecies differences (allometric scaling):

4

Justification:

Default AF; Rat

AF for other interspecies differences:

2.5

Justification:

Default value

AF for intraspecies differences:

10

Justification:

Default value for the general population

AF for the quality of the whole database:

1

Justification:

High quality studies, Klimisch 1

AF for remaining uncertainties:

1

Justification:

Default AF; The assessment factors are already conservative. A further assessment factor is not necessary.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - General Population

General population

Hazard via the inhalation route – systemic effects

Long term exposure

 

Hazard assessment conclusion	Most sensitive endpoint	Route of original study
DNEL 12.95 mg/m^3	Repeated dose toxicity	oral

 

DN(M)EL related information A DNEL is required according to ECHA guidance chapter R.8. Exposure of the general population to EMV is considered highly likely according to the identified conditions of use. A long-term inhalation systemic DNEL can be derived from the repeated dose study conducted with EMB.   Read-across is appropriate because of the close structural similarity between EMV and EMB.

Justification and comments In an OECD 422 study in which EMB was administered orally for 51 days at doses of up to 1000 mg/kg, no adverse effects were observed on either the dam or the foetuses and therefore the highest dose is effectively a limit dose. The NOAEL was therefore identified as 1000 mg/kg. Therefore the data are limited since they do not identify any adverse effect or target organ.    

 

Dose descriptor NOAEL 1000 mg/kg bw/d in the rat and this value is used to derive the systemic long-term DNEL. This is considered to be a conservative estimate.

Modification of dose descriptor According to ECHA guidance, convert the rat oral NOAEL into a human inhalation NOAEC (mg/m³) after adjusting for differences in uptake between the two routes of exposure (TGD, Appendix R.8-2, example B3). 

NOAEC_inhalation = Oral NOAEL x [1/sRV] x[ABS_oral-rat/ABS_{inhalation-human}]

NOAEC_inhalation =1000 x [1/1.030] x [100 / 100]

= 971 mg/m³

 

Assessment factors

Uncertainty	ECHA AFs	Justification
Dose-response relationship	1	Default AF: Clear discriminating dose
Differences in duration of exposure	3	Default AF not considered necessary Value appropriate for AF converting extended exposure to chronic
Interspecies differences (allometric scaling)	1	AF appropriate for inhalation-inhalation extrapolation (no allometric scaling)
Other interspecies differences	2.5	Default AF; Rat
Intraspecies differences	10	Default AF for the general population
Quality of database	1	High quality studies, Klimisch 1
Remaining uncertainties	1	Default AF; The assessment factors are already conservative. A further assessment factor is not necessary.
Overall AF	75

 

Calculated DNEL for long-term inhalation systemic exposure for consumers is 12.95 mg/m³using an overall assessment factor of 75.

 

Hazard via the dermal route – systemic effects

Long term exposure

 

Hazard assessment conclusion	Most sensitive endpoint	Route of original study
DNEL3.33 mg/kg bw/day	Repeated dose toxicity	oral

 

DN(M)EL related information A DNEL is required according to ECHA guidance chapter R.8. Exposure of the general population to EMV is considered highly likely according to the identified conditions of use. A long-term inhalation systemic DNEL can be derived from the repeated dose study conducted with EMB.   Read-across is appropriate because of the close structural similarity between EMV and EMB.

Justification and comments In an OECD 422 study in which EMB was administered orally for 51 days at doses of up to 1000 mg/kg, no adverse effects were observed on either the dam or the foetuses and therefore the highest dose is effectively a limit dose. The NOAEL was therefore identified as 1000 mg/kg. Therefore the data are limited since they do not identify any adverse effect or target organ. The toxicity of EMB and EMV is considered to be very low based on information on structurally similar esters. WHO (1999)   

 

Dose descriptor NOAEL 1000 mg/kg bw/day in the rat and this value is used to derive the systemic long-term DNEL. This is considered to be a conservative estimate.

Modification of dose descriptor According to ECHA guidance, convert the rat oral NOAEL into a human dermal NOAEL (mg/kg bw/day) after adjusting for differences in uptake between the two routes of exposure (TGD, Appendix R.8-2, example B3). 

NOAEL_dermal= Oral NOAEL x[ABS_oral-rat/ABS_dermal-human]

NOAEL_dermal=1000 x [100 / 100]

= 1000 mg/kg bw/day

 

Assessment factors

Uncertainty	ECHA AFs	Justification
Dose-response relationship	1	Default AF: Clear discriminating dose
Differences in duration of exposure	3	Default AF not considered necessary Value appropriate for AF converting extended exposure to chronic
Interspecies differences (allometric scaling)	4	Default AF; Rat
Other interspecies differences	2.5	Default AF
Intraspecies differences	10	Default value for the general population
Quality of database	1	High quality studies, Klimisch 1
Remaining uncertainties	1	Default AF; The assessment factors are already conservative. A further assessment factor is not necessary.
Overall AF	300

 

Calculated DNEL for long-term dermal systemic exposure for consumers is 3.33 mg/kg bw/day using an overall assessment factor of 300. This is considered to be a conservative DNEL based on the low toxicity of other short-chain alkyl esters.

Hazard via the oral route – systemic effects

Long term exposure

 

Hazard assessment conclusion	Most sensitive endpoint	Route of original study
DNEL 3.33 mg/kg bw/day	Repeated dose toxicity	oral

 

DN(M)EL related informationA DNEL is required according to ECHA guidance chapter R.8. Exposure of the general population to EMV is considered probable according to the identified conditions of use. A long-term oral systemic DNEL can be derived from the repeated dose study conducted with EMB.   Read-across is appropriate because of the close structural similarity between EMV and EMB.

Justification and comments In an OECD 422 study in which EMB was administered orally for 51 days at doses of up to 1000 mg/kg, no adverse effects were observed on either the dam or the foetuses and therefore the highest dose is effectively a limit dose. The NOAEL was therefore identified as 1000 mg/kg. Therefore the data are limited since they do not identify any adverse effect or target organ. The toxicity of EMB and EMV is considered to be very low based on information on structurally similar esters. WHO (1999)   

 

Dose descriptorNOAEL 1000 mg/kg bw/day in the rat and this value is used to derive the systemic long-term DNEL. This is considered to be a conservative estimate.

Modification of dose descriptor According to ECHA guidance, convert the rat oral NOAEL into a human oral NOAEL (mg/kg bw/day) after adjusting for differences in uptake between the two species (TGD, Appendix R.8-2, example B3). 

NOAEL_oral     = Oral NOAEL x[ABS_oral-rat/ABS_oral-human]

NOAEL_oral     =1000 x [100 x 100]

= 1000 mg/kg bw/day

 

Assessment factors

Uncertainty	ECHA AFs	Justification
Dose-response relationship	1	Default AF: Clear discriminating dose
Differences in duration of exposure	3	Default AF not considered necessary Value appropriate for AF converting extended exposure to chronic
Interspecies differences (allometric scaling)	4	Default AF; Rat
Other interspecies differences	2.5	Default value
Intraspecies differences	10	Default value for the general population
Quality of database	1	High quality studies, Klimisch 1
Remaining uncertainties	1	Default AF; The assessment factors are already conservative. A further assessment factor is not necessary.
Overall AF	300

 

Calculated DNEL for long-term oral systemic exposure for consumers is 3.33 mg/kg bw/day using an overall assessment factor of 300. This is considered to be a conservative DNEL based on the low toxicity of other short-chain alkyl esters.