3-methyl-2-butenyl acetate

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

5.77 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

Overall assessment factor (AF):

10

Modified dose descriptor starting point:

NOAEC

Value:

57.66 mg/m³

Explanation for the modification of the dose descriptor starting point:

see discussion

Acute/short term exposure

DNEL related information

Local effects

Acute/short term exposure

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

6.54 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

Overall assessment factor (AF):

10

Modified dose descriptor starting point:

NOAEL

Value:

65.4 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

see discussion

Acute/short term exposure

DNEL related information

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - workers

No data on repeated dose toxicity are available for prenyl acetate. However, repeated dose toxicity data on the structurally and metabolically related prenol (3-methylbut-2-en-1-ol; CAS No. 556-82-1) are taken into account for assessment via read across. This read across is justified, based on the high likelihood that prenyl acetate would rapidly be hydrolized to prenol and acetate in the GIT and liver, and/or show a similar GIT / liver metabolism profile as prenol.

 

In the subchronic oral (drinking water) repeated dose toxicity study in Wistar rats (BASF AG, 2002), major adverse test substance related effects were reduced food and water consumption, leading to significantly decreased body weights/ body weight gains, decreased urinary volume and increased urinary specific gravity. The NOAEL has been set at 1000 ppm (65.4 mg/kg bw/day in males, 82.1 mg/kg bw/day in females).

 

In the prenatal developmental toxicity study in Wistar rats (BASF AG, 2002), oral (gavage) administration of prenol (600 mg/kg bw/day) resulted in adverse clinical findings (salivation, lacrimation, abdominal position and piloerection), reduced food consumption, reduced body weight / body weight gain of the dams. The test substance administration evoked no signs of developmental toxicity. The NOAEL for maternal toxicity has been set at 200 mg/kg bw/day and >= 600 mg/kg bw/day (the highest dose tested) for developmental toxicity.

 

The respective NOAEL of 65.4 mg/kg bw/day for male rats (82.1 mg/kg bw/day for female rats) has been taken as conservative point of departure for the systemic DNELs derived, which covers findings observed in the subchronic repeated dose and developmental toxicity study. 

 

Route to route extrapolation:

No experimental data on absorption of prenyl acetate are available. Based on the physicochemical properties prenyl acetate is considered to show good bioavailability via the dermal and oral route. On the basis of the low vapour pressure, the exposure with prenyl acetate via inhalation as a vapour is low. According to Chapter R.8 of REACH Guidance on information requirements and chemical safety assessment, it is proposed in the absence of route-specific information to include a default factor in the case of inhalation-to-oral extrapolation, assuming 50% oral and 100% inhalation absorption. Due to the lack of experimental data a default factor of 1 for oral-to-dermal extrapolation is used for the DNEL derivation.

 

For the worker, the following DNELs were derived:

For derivation of the long-term systemic inhalative DNEL for prenyl acetate, the oral NOAEL of 65.4 mg/kg bw/d was taken as a basis and converted into a corrected inhalative NOAEC of 57.66 mg/m³according to the procedure, recommended in the current guidance document (R8, ECHA 2008). Applying all assessment factors, the inhalative long-term systemic DNEL was set at 5.77 mg/m³ for the worker.

 

Long-term – inhalation, systemic effects

Description	Value	Remark
Step 1) Relevant dose-descriptor	NOAEL: 65.4 mg/kg bw/day
Step 2) Modification of starting point	50%/100%     0.38 m^3/kg bw     6.7 m^3/10 m^3	Ratio of oral (rat) to inhalation (human) absorption (default value, as proposed in the REACH guidance (R.8.4.2)   Standard respiratory volume of a rat, corrected for 8 h exposure, as proposed in the REACH Guidance (R.8.4.2)   Correction for activity driven differences of respiratory volumes in workers compared to workers in rest (6.7 m^3/10 m^3)
Modified dose-descriptor	NOAEC corrected inhalative = 65.4 * (50/100) * (1/0.38) * (6.7/10) = 57.66 mg/m^3
Step 3) Assessment factors
Allometric scaling	1	No allometric scaling has to be applied in case of oral to inhalation route to route extrapolation according to R8 ECHA 2008.
Remaining differences	1	Substance specific assessment factor: Besides unspecific general effects such as clinical signs, impaired body weights and changes in urine, predominantly as secondary consequence of reduced water and food consumption, no specific test substance related organ toxicity has been observed. The intensive taste and odor of the test substance solutions used is likely to be the cause of the major adverse effects observed after oral application. Since oral administration is not a relevant route of exposure, the relevance of these findings is doubtful for workers. On the basis of these findings, no toxicodynamic and/or additional toxicokinetic differences between test animals and humans is to be expected. Overall, no additional AF for remaining differences is considered mandatory.
Intraspecies	5	Default assessment factor according to R8 ECHA 2008 was used as worst case to cover uncertainties due to the read across made.
Exposure duration	2	Use of a subchronic study as starting point for long-term systemic DNEL derivation (default assessment factor according to R8 ECHA 2008).
Dose response	1	according to R8 ECHA 2008
Quality of database	1	according to R8 ECHA 2008 (GLP guideline Study)
DNEL	Value
	57.66 / (1 x 1 x 5 x 2 x 1 x 1) = 5.77 mg/m^3

 

For derivation of the long-term systemic dermal DNEL of prenyl acetate, the oral NOAEL of 65.4 mg/kg bw/d was taken as a basis and was converted into a corrected dermal NOAEL of 65.4 mg/kg bw/d according to the procedure, recommended in the current guidance document (R8, ECHA 2008). Applying all assessment factors, the dermal long-term systemic DNEL derived was 6.54 mg/kg bw/d for the worker.

 

Long-term – dermal, systemic effects 

Description	Value	Remark
Step 1) Relevant dose-descriptor	NOAEL: 65.4 mg/kg bw/day
Step 2) Modification of starting point	1	Default assessment factor for oral to dermal extrapolation according to R8 ECHA 2008 was used due to lack of experimental data on dermal penetration rate.
Modified dose-descriptor	NOAEL corrected dermal = 65.4 * 1 = 65.4 mg/kg bw/d
Step 3) Assessment factors
Allometric scaling	1	Substance specific assessment factor: Adverse effects observed were unspecific general effects such as clinical signs, impaired body weights and changes in urine, predominantly as secondary consequence of reduced water and food consumption. The intensive taste and odor of the test substance solutions used is likely to be the cause of the major adverse effects observed after oral application. These findings are not expected to depend on a systemic toxic parent compound/metabolite being excreted dependent of caloric demand. Therefore, use of AF >1 for allometric scaling is not considered necessary based on the nature of effects observed.
Remaining differences	1	Substance specific assessment factor: Besides unspecific general effects such as clinical signs, impaired body weights and changes in urine, predominantly as secondary consequence of reduced water and food consumption, no specific test substance related organ toxicity has been observed. The intensive taste and odor of the test substance solutions used is likely to be the cause of the major adverse effects observed after oral application. Since oral administration is not a relevant route of exposure, the relevance of these findings is doubtful for workers. On the basis of these findings, no toxicodynamic and/or additional toxicokinetic differences between test animals and humans is to be expected. Overall, no additional AF for remaining differences is considered mandatory.
Intraspecies	5	Default assessment factor according to R8 ECHA 2008 was used as worst case to cover uncertainties due to the read across made.
Exposure duration	2	Use of a subchronic study as starting point forlong-term systemic DNEL derivation (default assessment factor according to R8 ECHA 2008).
Dose response	1	according to R8 ECHA 2008
Quality of database	1	according to R8 ECHA 2008 (GLP guideline Study)
DNEL	Value
	65.4 / (1 x 1 x 5 x 2 x 1 x 1) = 6.54 mg/kg bw/day

 

No DNELs were derived for local effects after short term or after long term inhalative exposure, as the substance exhibits no hazardous potential in terms of these endpoints and the conservatively derived long term inhalative DNEL for systemic effects covers putative local effects. No DNELs were derived for systemic effects after short term dermal or inhalative exposure, as the substance exhibits no hazardous potential in terms of these endpoints and the conservatively derived respective long term DNELs for systemic effects sufficiently covers such putative effects.

No DNEL for local effects after short term/ long term dermal exposure was derived. Data for skin sensitization identify prenyl acetat as not skin sensiziting in a weight of evidence and do not fulfill the respective classification and labeling criteria. Furtherrmore prenyl acetate was found to be not irritating to skin.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.42 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

Overall assessment factor (AF):

20

Modified dose descriptor starting point:

NOAEC

Value:

28.43 mg/m³

Explanation for the modification of the dose descriptor starting point:

see discussion

Acute/short term exposure

DNEL related information

Local effects

Acute/short term exposure

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3.27 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

Overall assessment factor (AF):

20

Modified dose descriptor starting point:

NOAEL

Value:

65.4 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

see discussion

Acute/short term exposure

DNEL related information

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3.27 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

Overall assessment factor (AF):

20

Modified dose descriptor starting point:

NOAEL

Value:

65.4 mg/kg bw/day

Acute/short term exposure

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - General Population

No data on repeated dose toxicity are available for prenyl acetate. However, repeated dose toxicity data on the structurally and metabolically related prenol (3-methylbut-2-en-1-ol; CAS No. 556-82-1) are taken into account for assessment via read across. This read across is justified, based on the high likelihood that prenyl acetate would rapidly be hydrolized to prenol and acetate in the GIT and liver, and/or show a similar GIT / liver metabolism profile as prenol.

 

In the subchronic oral (drinking water) repeated dose toxicity study in Wistar rats (BASF AG, 2002), major adverse test substance related effects were reduced food and water consumption, leading to significantly decreased body weights/ body weight gains, decreased urinary volume and increased urinary specific gravity. The NOAEL has been set at 1000 ppm (65.4 mg/kg bw/day in males, 82.1 mg/kg bw/day in females).

 

In the prenatal developmental toxicity study in Wistar rats (BASF AG, 2002), oral (gavage) administration of prenol (600 mg/kg bw/day) resulted in adverse clinical findings (salivation, lacrimation, abdominal position and piloerection), reduced food consumption, reduced body weight / body weight gain of the dams. The test substance administration evoked no signs of developmental toxicity. The NOAEL for maternal toxicity has been set at 200 mg/kg bw/day and >= 600 mg/kg bw/day (the highest dose tested) for developmental toxicity.

 

The respective NOAEL of 65.4 mg/kg bw/day for male rats (82.1 mg/kg bw/day for female rats) has been taken as conservative point of departure for the systemic DNELs derived, which covers findings observed in the subchronic repeated dose and developmental toxicity study. 

 

Route to route extrapolation:

No experimental data on absorption of prenyl acetate are available. Based on the physicochemical properties prenyl acetate is considered to show good bioavailability via the dermal and oral route. On the basis of the low vapour pressure, the exposure with prenyl acetate via inhalation as a vapour is low. According to Chapter R.8 of REACH Guidance on information requirements and chemical safety assessment, it is proposed in the absence of route-specific information to include a default factor in the case of inhalation-to-oral extrapolation, assuming 50% oral and 100% inhalation absorption. Due to the lack of experimental data a default factor of 1 for oral-to-dermal extrapolation is used for the DNEL derivation.

 

For the general population, the following DNELs were derived:

For derivation of the long-term systemic inhalative DNEL for prenyl acetate, the oral NOAEL of 65.4 mg/kg bw/d was taken as a basis and converted into a corrected inhalative NOAEC of 28.43 mg/m³according to the procedure, recommended in the current guidance document (R8, ECHA 2008). Applying all assessment factors, the inhalative long-term systemic DNEL was set at 1.42 mg/m³for the general population.

 

Long-term – inhalation, systemic effects

Description	Value	Remark
Step 1) Relevant dose-descriptor	NOAEL: 65.4 mg/kg bw/day
Step 2) Modification of starting point	50%/100%   1.15 m^3/kg bw	Ratio of oral (rat) to inhalation (human) absorption (default value, as proposed in the REACH guidance (R.8.4.2)   Standard respiratory volume of a rat, corrected for 24 h exposure, as proposed in the REACH Guidance (R.8.4.2)
Modified dose-descriptor	NOAEC corrected inhalative = 65.4 * (50/100) * (1/1.15) = 28.43 mg/m^3
Step 3) Assessment factors
Allometric scaling	1	No allometric scaling has to be applied in case of oral to inhalation route to route extrapolation according to R8 ECHA 2008.
Remaining differences	1	Substance specific assessment factor: Besides unspecific general effects such as clinical signs, impaired body weights and changes in urine, predominantly as secondary consequence of reduced water and food consumption, no specific test substance related organ toxicity has been observed. The intensive taste and odor of the test substance solutions used is likely to be the cause of the major adverse effects observed after oral application. On the basis of these findings, no toxicodynamic and/or additional toxicokinetic differences between test animals and humans is to be expected. Overall, no additional AF for remaining differences is considered mandatory.
Intraspecies	10	Default assessment factor according to R8 ECHA 2008 was used as worst case to cover uncertainties due to the read across made.
Exposure duration	2	Use of a subchronic study as starting point forlong-term systemic DNEL derivation (default assessment factor according to R8 ECHA 2008).
Dose response	1	according to R8 ECHA 2008
Quality of database	1	according to R8 ECHA 2008 (GLP guideline Study)
DNEL	Value
	28.43 / (1 x 1 x 10 x 2 x 1 x 1) = 1.42 mg/m^3

 

For derivation of the long-term systemic dermal DNEL of prenyl acetate, the oral NOAEL of 65.4 mg/kg bw/d was taken as a basis and was converted into a corrected dermal NOAEL of 65.4 mg/kg bw/d according to the procedure, recommended in the current guidance document (R8, ECHA 2008). Applying all assessment factors, the dermal long-term systemic DNEL derived was 3.27 mg/kg bw/d for the general population.

 

Long-term – dermal, systemic effects 

Description	Value	Remark
Step 1) Relevant dose-descriptor	NOAEL: 65.4 mg/kg bw/day
Step 2) Modification of starting point	1	Default assessment factor for oral to dermal extrapolation according to R8 ECHA 2008 was used due to lack of experimental data on dermal penetration rate
Modified dose-descriptor	NOAEL corrected dermal = 65.4 * 1 = 65.4 mg/kg bw/d
Step 3) Assessment factors
Allometric scaling	1	Substance specific assessment factor: Adverse effects observed were unspecific general effects such as clinical signs, impaired body weights and changes in urine, predominantly as secondary consequence of reduced water and food consumption. The intensive taste and odor of the test substance solutions used is likely to be the cause of the major adverse effects observed after oral application. These findings are not expected to depend on a systemic toxic parent compound/metabolite being excreted dependent of caloric demand. Therefore, use of AF >1 for allometric scaling is not considered necessary based on the nature of effects observed.
Remaining differences	1	Substance specific assessment factor: Besides unspecific general effects such as clinical signs, impaired body weights and changes in urine, predominantly as secondary consequence of reduced water and food consumption, no specific test substance related organ toxicity has been observed. The intensive taste and odor of the test substance solutions used is likely to be the cause of the major adverse effects observed after oral application. On the basis of these findings, no toxicodynamic and/or additional toxicokinetic differences between test animals and humans is to be expected. Overall, no additional AF for remaining differences is considered mandatory.
Intraspecies	10	Default assessment factor according to R8 ECHA 2008 was used as worst case to cover uncertainties due to the read across made.
Exposure duration	2	Use of a subchronic study as starting point forlong-term systemic DNEL derivation (default assessment factor according to R8 ECHA 2008)
Dose response	1	according to R8 ECHA 2008
Quality of database	1	according to R8 ECHA 2008 (GLP guideline Study)
DNEL	Value
	65.4 / (1 x 1 x 10 x 2 x 1 x 1) = 3.27 mg/kg bw/day

 

For derivation of the long-term systemic oral DNELof prenyl acetate,the NOAEL 65.4 mg/kg bw/d was used. After applying the assessment factors, the oral long-term systemic DNEL was set at 3.27 mg/ kg bw/day for the general population.

 

Long-term – oral, systemic effects

Description	Value	Remark
Step 1) Relevant dose-descriptor	NOAEL: 65.4 mg/kg bw/day
Step 2) Modification of starting point	-	-
Step 3) Assessment factors
Allometric scaling	1	Substance specific assessment factor: Adverse effects observed were unspecific general effects such as clinical signs, impaired body weights and changes in urine, predominantly as secondary consequence of reduced water and food consumption. The intensive taste and odor of the test substance solutions used is likely to be the cause of the major adverse effects observed after oral application. These findings are not expected to depend on a systemic toxic parent compound/metabolite being excreted dependent of caloric demand. Therefore, use of AF >1 for allometric scaling is not considered necessary based on the nature of effects observed.
Remaining differences	1	Substance specific assessment factor: Besides unspecific general effects such as clinical signs, impaired body weights and changes in urine, predominantly as secondary consequence of reduced water and food consumption, no specific test substance related organ toxicity has been observed. The intensive taste and odor of the test substance solutions used is likely to be the cause of the major adverse effects observed after oral application. On the basis of these findings, no toxicodynamic and/or additional toxicokinetic differences between test animals and humans is to be expected. Overall, no additional AF for remaining differences is considered mandatory.
Intraspecies	10	Default assessment factor according to R8 ECHA 2008 was used as worst case to cover uncertainties due to the read across made.
Exposure duration	2	use of a subchronic study as starting point forlong-term systemic DNEL derivation (default assessment factor according to R8 ECHA 2008)
Dose response	1	according to R8 ECHA 2008
Quality of database	1	according to R8 ECHA 2008 (GLP guideline Study)
DNEL	Value
	65.4 / (1 x 1 x 10 x 2 x 1 x 1) = 3.27 mg/kg bw/day

 

No DNELs were derived for local effects after short term or after long term inhalative exposure, as the substance exhibits no hazardous potential in terms of these endpoints and the conservatively derived long term inhalative DNEL for systemic effects covers putative local effects. No DNELs were derived for systemic effects after short term oral, dermal or inhalative exposure, as the substance exhibits no hazardous potential in terms of these endpoints and the conservatively derived respective long term DNELs for systemic effects sufficiently covers such putative effects.

No DNEL for local effects after short term/ long term dermal exposure was derived. Data for skin sensitization identify prenyl acetat as not skin sensiziting in a weight of evidence and do not fulfill the respective classification and labeling criteria. Furtherrmore prenyl acetate was found to be not irritating to skin.