Ethyl acetoacetate

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

29.167 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

Modified dose descriptor starting point:

NOAEC

Value:

875 mg/m³

Explanation for the modification of the dose descriptor starting point:

Oral absorption is estimated to be approximately 50%; inhalation absorption of 100% is assumed

AF for dose response relationship:

1

Justification:

A default AF of 1 is used, according to ECHA REACH Guidance. The use of a larger AF is not warranted on the basis of the data available

AF for differences in duration of exposure:

6

Justification:

Starting point was extrapolated from a subacute to a chronic exposure period

AF for interspecies differences (allometric scaling):

4

Justification:

A default AF of 4 is used, according to ECHA REACH Guidance

AF for other interspecies differences:

1

Justification:

AF 1 used, no indication for differences in toxicokinetics and toxicodynamics

AF for intraspecies differences:

5

Justification:

A default AF of 5 is used, according to ECHA REACH Guidance

AF for the quality of the whole database:

1

Justification:

AF of 1 is appropriate: the database is comprehensive and of good quality

AF for remaining uncertainties:

1

Justification:

A default AF of 1 is used, according to ECHA REACH Guidance

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

8.333 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

Modified dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Data indicate a similar extent of absorption following oral and dermal exposure; correction for differences in the extent of absorption is not required.

AF for dose response relationship:

1

Justification:

A default AF of 1 is used, according to ECHA REACH Guidance. The use of a larger AF is not warranted on the basis of the data available.

AF for differences in duration of exposure:

6

Justification:

Starting point was extrapolated from a subacute to a chronic exposure period

AF for interspecies differences (allometric scaling):

4

Justification:

A default AF of 4 is used, according to ECHA REACH Guidance.

AF for other interspecies differences:

1

Justification:

AF 1 used, no indication for differences in toxicokinetics and toxicodynamics

AF for intraspecies differences:

5

Justification:

A default AF of 5 is used, according to ECHA REACH Guidance.

AF for the quality of the whole database:

1

Justification:

AF of 1 is appropriate: the database is comprehensive and of good quality.

AF for remaining uncertainties:

1

Justification:

A default AF of 1 is used, according to ECHA REACH Guidance.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

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

Toxicology summary

Toxicokinetics

EAA is a small, relatively mobile mobile, relatively volatile and uncharged molecule with good solubility in hydrophilic and hydrophobic solvents. It is rapidly and to a high degree absorbed after oral exposure, but also causes local toxicity to the intestines. Absorption via the dermis is comparatively lower which may also be due to the volatile behavior. EAA is rapidly excreted after hydrolysis of the ester function and also rapidly eliminated during metabolism. Tests with repeated dose administration demonstrate that cumulation in the body can be excluded.

Acute toxicity

Acute oral toxicity

The acute oral toxicity on rats was determined to be 10'800 mg/kg.

Acute dermal toxicity

The acute dermal toxicity on rats was found to be > 2000 mg/kg.

Acute inhalation toxicity

Study not performed; dermal route was chosen instead.

Irritation/Corrosion

MAA was found to be non-irritating to skin and eyes.

Sensitisation

MAA is not a skin sensitiser.

Repeated dose toxicity

The appropriate doese levels were evaluated in a range-finding test. Based on this RF-study, dose levels of 0, 50, 225 and 1000 mg/kg b.w./day were fixed for the main study, including 2-weeks recovery for low and high dose groups. There were neither premature deaths nor clinical signs as a result of treatment with EAA. No mortality and no clinical symptoms were noted. Furthermore, there were no treatment-related effects observed on body weights, hematology, clinical chemistry, urinalysis, and organ weights. There were also no necropsy and histological findings. In conclusion, in the absence of any effect, the NOEL and NOAEL were determined to be 1000 mg/kg/day.

Genetic toxicity

The test item EAA was tested for genetic toxicity in three in-vitro studies, all with and without metabolic activation. A reverse mutation assay (Ames test), a chromosomal aberration test and an HPRT-test (gene mutation) were performed, according to the corresponding OECD-guidelines. The Ames test used Salmonella typhimurium and E.coli strains and showed a negative result (non-mutagenic). The chromosomal aberration test performed with Chinese V79 cells did not induce clastogenic effects. The HPRT-test used V79 cells and showed neither genotoxicity nor cytotoxicity, therefore EAA was considered to be non mutagenic in this test system

Toxicity to reproduction

The study was performed according to OECD-guideline no. 421. The administration route was oral gavage. Ten animals were treated per sex and dose groups resulting in a total of 80 animals. Dose levels were 0, 50, 225 and 1000 mg/kg/day. There were no effects on clinical signs, mortality, body weights, food consumption. There were minor effects in the highest dose groups on reproduction. However, these findings were considered to be not relevant and therefore, a NOEL of 1000 mg/kg/day was established.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

6.25 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

Modified dose descriptor starting point:

NOAEC

Value:

375 mg/m³

Explanation for the modification of the dose descriptor starting point:

Oral absorption is estimated to be approximately 50%; inhalation absorption of 100% is assumed

AF for dose response relationship:

1

Justification:

A default AF of 1 is used, according to ECHA REACH Guidance. The use of a larger AF is not warranted on the basis of the data available

AF for differences in duration of exposure:

6

Justification:

Starting point was extrapolated from a subacute to a chronic exposure period

AF for interspecies differences (allometric scaling):

4

Justification:

A default AF of 4 is used, according to ECHA REACH Guidance

AF for other interspecies differences:

1

Justification:

AF 1 used, no indication for differences in toxicokinetics and toxicodynamics

AF for intraspecies differences:

10

Justification:

A default AF of 10 is used, according to ECHA REACH Guidance

AF for the quality of the whole database:

1

Justification:

AF of 1 is appropriate: the database is comprehensive and of good quality

AF for remaining uncertainties:

1

Justification:

A default AF of 1 is used, according to ECHA REACH Guidance

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

4.167 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

Modified dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Data indicate a similar extent of absorption following oral and dermal exposure; correction for differences in the extent of absorption is not required.

AF for dose response relationship:

1

Justification:

A default AF of 1 is used, according to ECHA REACH Guidance. The use of a larger AF is not warranted on the basis of the data available.

AF for differences in duration of exposure:

6

Justification:

Starting point was extrapolated from a subacute to a chronic exposure period

AF for interspecies differences (allometric scaling):

4

Justification:

A default AF of 4 is used, according to ECHA REACH Guidance.

AF for other interspecies differences:

1

Justification:

AF 1 used, no indication for differences in toxicokinetics and toxicodynamics

AF for intraspecies differences:

10

Justification:

A default AF of 10 is used, according to ECHA REACH Guidance.

AF for the quality of the whole database:

1

Justification:

AF of 1 is appropriate: the database is comprehensive and of good quality.

AF for remaining uncertainties:

1

Justification:

A default AF of 1 is used, according to ECHA REACH Guidance.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

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:

4.167 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

Modified dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Data indicate a similar extent of absorption following oral and dermal exposure; correction for differences in the extent of absorption is not required.

AF for dose response relationship:

1

Justification:

A default AF of 1 is used, according to ECHA REACH Guidance. The use of a larger AF is not warranted on the basis of the data available.

AF for differences in duration of exposure:

6

Justification:

Starting point was extrapolated from a subacute to a chronic exposure period

AF for interspecies differences (allometric scaling):

4

Justification:

A default AF of 4 is used, according to ECHA REACH Guidance.

AF for other interspecies differences:

1

Justification:

AF 1 used, no indication for differences in toxicokinetics and toxicodynamics

AF for intraspecies differences:

10

Justification:

A default AF of 10 is used, according to ECHA REACH Guidance.

AF for the quality of the whole database:

1

Justification:

AF of 1 is appropriate: the database is comprehensive and of good quality

AF for remaining uncertainties:

1

Justification:

A default AF of 1 is used, according to ECHA REACH Guidance.

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

Toxicology summary

Toxicokinetics

EAA is a small, relatively mobile mobile, relatively volatile and uncharged molecule with good solubility in hydrophilic and hydrophobic solvents. It is rapidly and to a high degree absorbed after oral exposure, but also causes local toxicity to the intestines. Absorption via the dermis is comparatively lower which may also be due to the volatile behavior. EAA is rapidly excreted after hydrolysis of the ester function and also rapidly eliminated during metabolism. Tests with repeated dose administration demonstrate that cumulation in the body can be excluded.

Acute toxicity

Acute oral toxicity

The acute oral toxicity on rats was determined to be 10'800 mg/kg.

Acute dermal toxicity

The acute dermal toxicity on rats was found to be > 2000 mg/kg.

Acute inhalation toxicity

Study not performed; dermal route was chosen instead.

Irritation/Corrosion

MAA was found to be non-irritating to skin and eyes.

Sensitisation

MAA is not a skin sensitiser.

Repeated dose toxicity

The appropriate doese levels were evaluated in a range-finding test. Based on this RF-study, dose levels of 0, 50, 225 and 1000 mg/kg b.w./day were fixed for the main study, including 2-weeks recovery for low and high dose groups. There were neither premature deaths nor clinical signs as a result of treatment with EAA. No mortality and no clinical symptoms were noted. Furthermore, there were no treatment-related effects observed on body weights, hematology, clinical chemistry, urinalysis, and organ weights. There were also no necropsy and histological findings. In conclusion, in the absence of any effect, the NOEL and NOAEL were determined to be 1000 mg/kg/day.

Genetic toxicity

The test item EAA was tested for genetic toxicity in three in-vitro studies, all with and without metabolic activation. A reverse mutation assay (Ames test), a chromosomal aberration test and an HPRT-test (gene mutation) were performed, according to the corresponding OECD-guidelines. The Ames test used Salmonella typhimurium and E.coli strains and showed a negative result (non-mutagenic). The chromosomal aberration test performed with Chinese V79 cells did not induce clastogenic effects. The HPRT-test used V79 cells and showed neither genotoxicity nor cytotoxicity, therefore EAA was considered to be non mutagenic in this test system

Toxicity to reproduction

The study was performed according to OECD-guideline no. 421. The administration route was oral gavage. Ten animals were treated per sex and dose groups resulting in a total of 80 animals. Dose levels were 0, 50, 225 and 1000 mg/kg/day. There were no effects on clinical signs, mortality, body weights, food consumption. There were minor effects in the highest dose groups on reproduction. However, these findings were considered to be not relevant and therefore, a NOEL of 1000 mg/kg/day was established.