4-methyl-4-phenylpentan-2-ol

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

4.7 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):

75

Modified dose descriptor starting point:

NOAEC

Value:

352.6 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 4-methyl-4-phenylpentan-2-ol was derived via route-to-route extrapolation from the NOAEL obtained in the sub acute (28-day) oral repeated dose toxicity study in rats (400 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 = oral NOAEL*(1/sRVrat 8h)*(ABSoral/ABSinh)*(sRVhuman/wRV) OR 400*(1/0.38)*(50/100)*(6.7/10) = 352.6. Therefore, DNEL = Corrected inhalation NOAEC (352.6 mg/m3)*(1/75{Overall AF}) = 4.7 mg/m3.

AF for dose response relationship:

1

Justification:

Not required as starting point is NOAEC

AF for differences in duration of exposure:

6

Justification:

subacute to chronic study

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:

5

Justification:

default factor for workers

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:

low hazard (no threshold derived)

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

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:

1.33 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:

400 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The DNEL for systemic effects in workers after long-term dermal exposure to 4-methyl-4-phenylpentan-2-ol was derived via route-to-route extrapolation from the NOAEL of 400 mg/kg bw/d obtained in the sub acute (28-day) oral repeated dose toxicity study in rats. Therefore, DNEL = 400 mg/kg bw/day*(1/6{exposure duration sub acute to chronic}*4{allometric scaling rat-human}*2.5{interspecies differences}*5{intraspecies differences-worker population}) = 1.33 mg/kg bw/day. This is considered to be the worst-case scenario assuming 100% dermal absorption hence 100% bioavailability and systemic exposure at this level.

AF for dose response relationship:

1

Justification:

Not required as starting point is NOAEL

AF for differences in duration of exposure:

6

Justification:

sub acute to a chronic study

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:

intraspecies differences-worker 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 DNEL required: short term exposure controlled by conditions for long-term

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:

no DNEL required: short term exposure controlled by conditions for long-term

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - workers

The basis for the inhalation and dermal DNEL for worker exposure is an oral 28 day toxicity study with 4-methyl-4 - phenylpentan-2-ol , from which a NOEL of 100 mg/kg bw/day and a NOAEL of 400 mg/kg bw/day were identified. There were also no adverse effects observed at 400 mg/kg bw/day in a reproductive toxicity study of a longer duration period (approximately 42 days in males and 49 days in females). In the 28-day toxicity study some mild and transient effects were observed at the highest dose of 400mg/kg bw/day and so the NOEL (No Observed Effect Level) was determined to be the lower dose of 100 mg/kg bw/day. However, the increase of kidney weights at 400 mg/kg is considered to be the result of a hyperplasia caused by an increased metabolic activity for the metabolism and/or elimination of the test item. A cytotoxic effect on the kidney is excluded because an elevation of appropriate systemic enzyme activities was not observed and there were also no macroscopic pathological or histological findings in this tissue. The other findings at 400 mg/kg/day including short term transient neurological effects in a few animals immediately post dosing, were not seen in the longer duration reproductive toxicity study and so were not considered to be toxicologically significant. The NOAEL (No Observed Adverse Effect Level) of 400 mg/kg bw/day was used 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:

1.2 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):

150

Modified dose descriptor starting point:

NOAEC

Value:

173.9 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 4-methyl-4-phenylpentan-2-ol was derived via route-to-route extrapolation from the NOAEL obtained in the sub acute (28-day) oral repeated dose toxicity study in rats (400 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 400*(1/1.15)*(50/100) = 173.9 mg/m3. Therefore, DNEL = Corrected inhalation NOAEC (173.9 mg/m3)*(1/150{Overall AF}) = 1.2 mg/m3.

AF for dose response relationship:

1

Justification:

Not required as starting point is NOAEC

AF for differences in duration of exposure:

6

Justification:

Subacute to chronic study

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:

low hazard (no threshold derived)

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

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:

0.67 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):

600

Modified dose descriptor starting point:

NOAEL

Value:

400 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 4-methyl-4-phenylpentan-2-ol was derived via route-to-route extrapolation from the NOAEL of 400 mg/kg bw/day obtained in the sub acute (28-day) oral repeated dose toxicity study in rats. Therefore, DNEL = 400 mg/kg bw/day*(1/6{exposure duration sub acute to chronic}*4{allometric scaling rat-human}*2.5{interspecies differences}*10{intraspecies differences-general population}) = 0.67 mg/kg bw/day. This is considered to be the worst-case scenario assuming 100% dermal absorption hence 100% bioavailability and systemic exposure at this level.

AF for dose response relationship:

1

Justification:

Not required as starting point is NOAEL

AF for differences in duration of exposure:

6

Justification:

Subacute to chronic study

AF for interspecies differences (allometric scaling):

4

Justification:

Allometric scaling rat to human

AF for other interspecies differences:

2.5

Justification:

Default value 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 DNEL required: short term exposure controlled by conditions for long-term

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:

no DNEL required: short term exposure controlled by conditions for long-term

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.67 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):

600

Modified dose descriptor starting point:

NOAEL

Value:

400 mg/kg bw/day

AF for dose response relationship:

1

Justification:

Not required as starting point is NOAEL

AF for differences in duration of exposure:

6

Justification:

Subacute to chronic study

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:

low hazard (no threshold derived)

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - General Population

The basis for the inhalation and dermal DNEL for general population exposure is an oral 28 day toxicity study with 4-methyl-4 - phenylpentan-2-ol , from which a NOEL of 100 mg/kg bw/day and a NOAEL of 400 mg/kg bw/day were identified. There were also no adverse effects observed at 400 mg/kg bw/day in a reproductive toxicity study of a longer duration period (approximately 42 days in males and 49 days in females). In the 28-day toxicity study some mild and transient effects were observed at the highest dose of 400 mg/kg bw/day and so the NOEL (No Observed Effect Level) was determined to be the lower dose of 100 mg/kg bw/day. However, the increase of kidney weights at 400 mg/kg is considered to be the result of a hyperplasia caused by an increased metabolic activity for the metabolism and/or elimination of the test item. A cytotoxic effect on the kidney is excluded because an elevation of appropriate systemic enzyme activities was not observed and there were also no macroscopic pathological or histological findings in this tissue. The other findings at 400 mg/kg/day including short term transient neurological effects in a few animals immediately post dosing, were not seen in the longer duration reproductive toxicity study and so were not considered to be toxicologically significant. The NOAEL (No Observed Adverse Effect Level) of 400 mg/kg bw/day was used 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.