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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
8.7 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
Modified dose descriptor starting point:
NOAEC
Value:
435.7 mg/m³
Explanation for the modification of the dose descriptor starting point:

The DNEL for systemic effects in workers after long-term inhalation exposure to the read-across substance, 4-methyl-4-phenylpentan-2-ol, was

derived via route-to-route extrapolation from the NOAEL obtained in the OECD Guideline 421 in rats (494.32 mg/kg bw/day). To convert the oral NOAEL in rats to an inhalation NOAEC in humans, a rat default respiratory volume was used corresponding to the daily duration of human exposure (sRVrat: 0.38m3/kg bw/8h). For workers a correction was added for the difference between respiratory rates under standard conditions (sRVhuman: 6.7 m3 for an 8h exposure period) and under conditions of light activity (wRV: 10 m3 for an 8h exposure period); extrapolation from 50% bioavailability oral to 100% bioavailability inhalation. Therefore, inhalatory NOAEC = oralNOAEL*(1/sRVrat 8h)*(ABSoral/ABSinh)*(sRVhuman/wRV) OR 494.32*(1/0.38)*(50/100)*(6.7/10) = 435.7.

AF for dose response relationship:
1
Justification:
not required as starting from a NOAEC
AF for differences in duration of exposure:
4
Justification:
The duration of exposure in the key study providing the point of departure NOAEL was at least 6 weeks for male rats and 7-8 weeks for female rats. These exposure durations fall between the descriptors for subchronic (90 days) and subacute (28 days) in the guidance document. That´s why a modification to the exposure duration AF was made from the conservative AF6 to AF4.
AF for interspecies differences (allometric scaling):
1
Justification:
Not required when route to route extrapolation conducted
AF for other interspecies differences:
2.5
Justification:
default factor for remaining differences
AF for intraspecies differences:
5
Justification:
default factor for worker exposure
AF for the quality of the whole database:
1
Justification:
not required
AF for remaining uncertainties:
1
Justification:
not required
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
Acute/short term exposure
Hazard assessment conclusion:
low 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:
2.47 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
Modified dose descriptor starting point:
NOAEL
Value:
494.32 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

The No Observed Adverse Effect Level (NOAEL) used to calculate the DNEL was taken from the findings for the read across substance 4-methyl-4-phenylpentan-2-ol in a reproductive toxicity study (OECD 421) in rats. The NOAEL (No Observed Adverse Effect Level) was, therefore, determined to be 494.32 mg/kg bw/day. Based on the REACH guidance R8 page 19, a default value of 50% is assumed for dermal absorption. As oral absorption was also set at 50%, no correction of dose descriptor starting point was done.

AF for dose response relationship:
1
Justification:
not required as stating from a NOAEL
AF for differences in duration of exposure:
4
Justification:
The duration of exposure in the key study providing the point of departure NOAEL was at least 6 weeks for male rats and 7-8 weeks for female rats. These exposure durations fall between the descriptors for subchronic (90 days) and subacute (28 days) in the guidance document. That´s why a modification to the exposure duration AF was made from the conservative AF6 to AF4.
AF for interspecies differences (allometric scaling):
4
Justification:
allometric scaling rat -human
AF for other interspecies differences:
2.5
Justification:
default factor
AF for intraspecies differences:
5
Justification:
factor for worker exposure
AF for the quality of the whole database:
1
Justification:
not required
AF for remaining uncertainties:
1
Justification:
not required
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

The basis for the inhalation and dermal DNELs for worker exposure comes from an oral OECD 421 with the read across substance 4-methyl-4-phenylpentan-2-ol , from which a NOAEL of 400 mg/kg bw/day was identified. The NOAEL (No Observed Adverse Effect Level) of 400 mg/kg bw/day was used (taking into account the molecular weight correction between source and target substance (178.27 vs. 220.31), the NOAEL for 1,3-Dimethyl-3-phenylbutyl acetate is 494.32 mg/kg) as the basis of the DNEL calculations using appropriate assessment factors for relevant indicators including route to route extrapolation, allometric scaling, exposure duration and study length.

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.15 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):
100
Modified dose descriptor starting point:
NOAEC
Value:
215 mg/m³
Explanation for the modification of the dose descriptor starting point:

The DNEL for systemic effects in general population after long-term inhalation exposure to the read-across substance, 4-methyl-4-phenylpentan-2-ol, was derived via route-to-route extrapolation from the NOAEL obtained in the OECD 421 oral repeated dose toxicity study in rats (494.32 mg/kg bw/day). To convert oral rat NOAEL into inhalatory NOAEC in humans, a rat default respiratory volume was used corresponding to the daily duration of human exposure (sRVrat: 1.15 m3/kg bw/24h); extrapolation from 50% bioavailability oral to 100% bioavailability inhalation. Therefore, the corrected inhalation NOAEC for general population is oral NOAEL*(1/sRVrat 24h)*(ABSoral/ABSinh) or 494.32*(1/1.15)*(50/100) = 215 mg/m3.

AF for dose response relationship:
1
Justification:
Not requiredas starting point is NOAEC
AF for differences in duration of exposure:
4
Justification:
The duration of exposure in the key study providing the point of departure NOAEL was at least 6 weeks for male rats and 7-8 weeks for female rats. These exposure durations fall between the descriptors for subchronic (90 days) and subacute (28 days) in the guidance document. That´s why a modification to the exposure duration AF was made from the conservative AF6 to AF4.
AF for interspecies differences (allometric scaling):
1
Justification:
Not required for concentrations
AF for other interspecies differences:
2.5
Justification:
Default factor for remaining differences
AF for intraspecies differences:
10
Justification:
Default factor for general population
AF for the quality of the whole database:
1
Justification:
Not required
AF for remaining uncertainties:
1
Justification:
Not required
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
Acute/short term exposure
Hazard assessment conclusion:
low 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:
1.23 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):
400
Modified dose descriptor starting point:
NOAEL
Value:
494.32 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

The DNEL for systemic effects in the general population after long-term dermal exposure to the read-across substance, 4-methyl-4-phenylpentan-2-ol, was derived via route-to-route extrapolation from the NOAEL of 494.32 mg/kg bw/day obtained in the OECD 421 in rats with the read-across substance. Based on the REACH guidance R8 page 19, a default value of 50% is assumed for dermal absorption. As oral absorption was also set at 50%, no correction of dose descriptor starting point was done.

AF for dose response relationship:
1
Justification:
Not required with a starting point of NOAEL
AF for differences in duration of exposure:
4
Justification:
The duration of exposure in the key study providing the point of departure NOAEL was at least 6 weeks for male rats and 7-8 weeks for female rats. These exposure durations fall between the descriptors for subchronic (90 days) and subacute (28 days) in the guidance document. That´s why a modification to the exposure duration AF was made from the conservative AF6 to AF4.
AF for interspecies differences (allometric scaling):
4
Justification:
Allometric scaling rat to human
AF for other interspecies differences:
2.5
Justification:
Default factor for remaining differences
AF for intraspecies differences:
10
Justification:
Default factor for general population
AF for the quality of the whole database:
1
Justification:
Not required
AF for remaining uncertainties:
1
Justification:
Not required
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
Acute/short term exposure
Hazard assessment conclusion:
low 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:
1.23 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):
400
Dose descriptor starting point:
NOAEL
Value:
494.32 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

As the NOAEL was taken from an oral study, no modification of the dose descriptor was performed.

AF for dose response relationship:
1
Justification:
Not required as starting point is NOAEL
AF for differences in duration of exposure:
4
Justification:
The duration of exposure in the key study providing the point of departure NOAEL was at least 6 weeks for male rats and 7-8 weeks for female rats. These exposure durations fall between the descriptors for subchronic (90 days) and subacute (28 days) in the guidance document. That´s why a modification to the exposure duration AF was made from the conservative AF6 to AF4.
AF for interspecies differences (allometric scaling):
4
Justification:
Allometric scaling rat to human
AF for other interspecies differences:
2.5
Justification:
Default factor for remaining differences
AF for intraspecies differences:
10
Justification:
Default factor for general population
AF for the quality of the whole database:
1
Justification:
Not required
AF for remaining uncertainties:
1
Justification:
Not required
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

The basis for the inhalation, dermal and oral DNELs for general population exposure comes from an oral OECD 421 with the read across substance 4-methyl-4-phenylpentan-2-ol , from which a NOAEL of 400 mg/kg bw/day was identified. The NOAEL (No Observed Adverse Effect Level) of 400 mg/kg bw/day was used (taking into account the molecular weight correction between source and target substance (178.27 vs. 220.31), the NOAEL for 1,3-Dimethyl-3-phenylbutyl acetate is 494.32 mg/kg) as the basis of the DNEL calculations using appropriate assessment factors for relevant indicators including route to route extrapolation, allometric scaling, exposure duration and study length.