Farnesol

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.85 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

Dose descriptor starting point:

NOAEL

Value:

105 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

92.57 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 2,6,10-Dodecatrien-1-ol, 3,7,11-trimethyl- was derived via route-to-route extrapolation from the lowest NOAEL obtained in the sub acute repeated dose toxicity and reproductive toxicity screening study in rats (105 mg/kg bw/day) with dosing over a prolonged period (approximately 36 days in males and 57 days in females) with the read-across substance, Nerolidol. 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 105*(1/0.38)*(50/100)*(6.7/10) = 92.57. This Therefore, DNEL = Corrected inhalation NOAEC (92.57 mg/m3)*(1/50{Overall AF}) = 1.85 mg/m3.

AF for dose response relationship:

1

Justification:

Not required as the starting point is 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 36 days for male rats and 57 days for female rats. These exposure durations fall between the descriptors for subchronic (90 days) and subacute (28 days) in the guidance document. Since adaptive hepatotoxicity was observed in animals from this study, a modification to the exposure duration AF was made fro 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 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:

no hazard identified

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:

1.32 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

Dose descriptor starting point:

NOAEL

Value:

105 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 2,6,10-Dodecatrien-1-ol, 3,7,11-trimethyl- was derived via route-to-route extrapolation from the lowest NOAEL of 105 mg/kg bw/day obtained in the sub acute oral repeated dose toxicity and reproductive toxicity screening study in rats with the read-across substance, Nerolidol. Therefore, DNEL = 105 mg/kg bw/day*(1/4{modified exposure duration sub acute to chronic}*4{allometric scaling rat-human}*2.5{interspecies differences}*5{intraspecies differences-worker population}) = 0.525 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, however, dermal absorption has been determined to be 39.8% of the applied dose in a key dermal absorption study with radiolabelled 3,7,11-trimethyldodeca-2,6,10-trien-1-ol in guinea pigs. Therefore, the DNEL should be adjusted by a factor of 100/39.8 to allow for this absorption profile i.e. adjusted DNEL = 0.35*(100/39.8) = 1.32 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:

4

Justification:

The duration of exposure in the key study providing the point of departure NOAEL was 36 days for male rats and 57 days for female rats. These exposure durations fall between the descriptors for subchronic (90 days) and subacute (28 days) in the guidance document. Since adaptive hepatotoxicity was observed in animals from this study, a modification to the exposure duration AF was made fro 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:

5

Justification:

Default factor for 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 hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Acute/short term exposure

Hazard assessment conclusion:

medium 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 systemic DNELs for worker exposure to 2,6,10-Dodecatrien-1-ol, 3,7,11-trimethyl- is an oral subacute repeated dose toxicity study and reproductive toxicity screening study with the read-across substance, Nerolidol , from which the lowest NOAEL of 1500 ppm (equivalent to 105 mg/kg bw/day for F0 parental females) was identified. The NOAEL in parental males was identified as 4000 ppm (equivalent to 266 mg/kg/day). This study was of a prolonged duration (approximately 36 days in males and 57 days in females) and resulted in reduced body weight gains, reduced food intake and hepatotoxicity in males and females at the high dietary inclusion level of 12000 ppm and also in females treated with 4000 ppm. The lowest NOAEL (No Observed Adverse Effect Level) of 105 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. For local effects it is considered that the systemic DNEL for inhalation exposure would be protective for this exposure in the absence of specific data. For dermal exposure the combination of acute dermal data and dermal absorption studies would indicate only a medium hazard.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.457 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

Dose descriptor starting point:

NOAEL

Value:

105 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

45.7 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 2,6,10-Dodecatrien-1-ol, 3,7,11-trimethyl- was derived via route-to-route extrapolation from the NOAEL obtained in the sub acute oral repeated dose toxicity and reproductive toxicity screening study in rats (105 mg/kg bw/day) with dosing over a prolonged period (approximately 36 days in males and 57 days in females) with the read-across substance, Nerolidol. 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 105*(1/1.15)*(50/100) = 45.7 mg/m3. Therefore, DNEL = Corrected inhalation NOAEC (45.7 mg/m3)*(1/100{Overall AF}) = 0.457 mg/m3.

AF for dose response relationship:

1

Justification:

Not required as the starting point is 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 36 days for male rats and 57 days for female rats. These exposure durations fall between the descriptors for subchronic (90 days) and subacute (28 days) in the guidance document. Since adaptive hepatotoxicity was observed in animals from this study, a modification to the exposure duration AF was made fro the conservative AF6 to AF4

AF for interspecies differences (allometric scaling):

1

Justification:

Not required when route to route extrapolation is conducted

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)

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:

0.66 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:

105 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 2,6,10-Dodecatrien-1-ol, 3,7,11-trimethyl- was derived via route-to-route extrapolation from the lowest NOAEL of 105 mg/kg bw/day obtained in the sub acute oral repeated dose toxicity and reproductive toxicity screening study in rats with the read-across substance, Nerolidol. Therefore, DNEL = 105 mg/kg bw/day*(1/4{modified exposure duration sub acute to chronic}*4{allometric scaling rat-human}*2.5{interspecies differences}*10{intraspecies differences-general population}) = 0.263 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, however, dermal absorption has been determined to be 39.8% of the applied dose in a key dermal absorption study with radiolabelled 3,7,11-trimethyldodeca-2,6,10-trien-1-ol in guinea pigs. Therefore, the DNEL should be adjusted by a factor of 100/39.8 to allow for this absorption profile i.e. adjusted DNEL = 0.263*(100/39.8) = 0.44 mg/kg bw/day.

AF for dose response relationship:

1

Justification:

Notrequired as the starting point is 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 36 days for male rats and 57 days for female rats. These exposure durations fall between the descriptors for subchronic (90 days) and subacute (28 days) in the guidance document. Since adaptive hepatotoxicity was observed in animals from this study, a modification to the exposure duration AF was made fro 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:

medium hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.263 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:

105 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Not applicable.

AF for dose response relationship:

1

Justification:

Not required as the starting point is 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 36 days for male rats and 57 days for female rats. These exposure durations fall between the descriptors for subchronic (90 days) and subacute (28 days) in the guidance document. Since adaptive hepatotoxicity was observed in animals from this study, a modification to the exposure duration AF was made fro 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

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - General Population

The basis for the inhalation and dermal systemic DNELs for worker exposure to 2,6,10-Dodecatrien-1-ol, 3,7,11-trimethyl- is an oral subacute repeated dose toxicity study and reproductive toxicity screening study with the read-across substance, Nerolidol , from which the lowest NOAEL of 1500 ppm (equivalent to 105 mg/kg bw/day for F0 parental females) was identified. The NOAEL in parental males was identified as 4000 ppm (equivalent to 266 mg/kg/day). This study was of a prolonged duration (approximately 36 days in males and 57 days in females) and resulted in reduced body weight gains, reduced food intake and hepatotoxicity in males and females at the high dietary inclusion level of 12000 ppm and also in females treated with 4000 ppm. The lowest NOAEL (No Observed Adverse Effect Level) of 105 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. For local effects it is considered that the systemic DNEL for inhalation exposure would be protective for this exposure in the absence of specific data. For dermal exposure the combination of acute dermal data and dermal absorption studies would indicate only a medium hazard.