(-)-pin-2(10)-ene

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

5.69 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

25

Modified dose descriptor starting point:

NOAEC

Value:

142 mg/m³

Explanation for the modification of the dose descriptor starting point:

NOAEC mouse (mg/m3) = (NOAEC (ppm) x MW) / Vmol = (50 x 136.24) / 24.05 = 283.24 mg/m3; Modification for exposure (experiment to human): 6/8 (Mouse Exposure condition (6h) / Worker Exposure condition (8 h) ; Modification for respiratory volume: 6.7/10 (respiratory rate difference under standard conditions and under conditions of light activity for 8 hours) Thus, the corrected starting point for inhalation is : 283.24 mg/kg bw/d x (6 h/8 h) x (6.7 m3 for 8h exposure /10 m3 for 8h exposure) = 142 mg/m3

AF for dose response relationship:

1

Justification:

Starting point is a NOAEC

AF for differences in duration of exposure:

2

Justification:

Sub-chronic to chronic extrapolation

AF for interspecies differences (allometric scaling):

1

Justification:

AF not used for oral to inhalation extrapolation

AF for other interspecies differences:

2.5

Justification:

Toxicodynamic and toxicokinetic remaining differencies

AF for intraspecies differences:

5

Justification:

Default factor for workers

AF for the quality of the whole database:

1

Justification:

Appropriate database

AF for remaining uncertainties:

1

Justification:

None

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.8 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

175

Modified dose descriptor starting point:

NOAEL

Value:

142 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

NOAEC mouse (mg/m3) = (NOAEC (ppm) x MW) / Vmol = (50 x 136.24) / 24.05 = 283.24 mg/m3; Modification for exposure (experiment to human): 6/8 (Mouse Exposure condition (6h) / Worker Exposure condition (8 h) ; Standard respiratory volume for mice: Standard respiratory volume for humans x allometric scaling x duration of exposure = 0.2 L/min/kg x 7 x 60 min x 8 h = 0.672 m3/kg. Thus, the corrected starting point for inhalation is : 283.24 mg/kg bw/d x (6 h/8 h) x 0.2 L/min/kg x 7 x 60 min x 8 h= 142 mg/kg bw/d

AF for dose response relationship:

1

Justification:

Starting point is a NOAEC

AF for differences in duration of exposure:

2

Justification:

Sub-chronic to chronic extrapolation

AF for interspecies differences (allometric scaling):

7

Justification:

Allometric scaling from mouse to human

AF for other interspecies differences:

2.5

Justification:

Toxicodynamic and toxicokinetic remaining differencies

AF for intraspecies differences:

5

Justification:

Default factor for workers

AF for the quality of the whole database:

1

Justification:

Appropriate database

AF for remaining uncertainties:

1

Justification:

None

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

54 µg/cm²

Most sensitive endpoint:

sensitisation (skin)

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

135

Dose descriptor:

other: NOAEL

AF for dose response relationship:

1

Justification:

EC3 is considered as a NOEL

AF for differences in duration of exposure:

3

Justification:

Repeated (long term) exposure

AF for interspecies differences (allometric scaling):

3

Justification:

From all animal studies assessing skin sensitisation, the lowest concentration inducing a positive response was found in an LLNA with EC3=29%. In humans, the highest concentration without positive response was 10%; therefore, an AF of 3, corresponding to the difference of concentration without effect between animals and humans, was considered

AF for other interspecies differences:

1

Justification:

None

AF for intraspecies differences:

5

Justification:

Default factor for workers

AF for remaining uncertainties:

3

Justification:

Dermal integrity and exposure conditions (matrix effects)

Acute/short term exposure

Hazard assessment conclusion:

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

Most sensitive endpoint:

sensitisation (skin)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - workers

Justification for the selection of the key study (repeated dose toxicity study) for the calculation of systemic long-term DNELs

alpha-Pinene and beta-pinene are structurally similar compounds. They are bicyclic terpene hydrocarbons and are positional isomers. A great extent of similar patterns was demonstrated for physico-chemical properties, (eco)toxicological properties and environmental fate. Therefore the use of repeated dose toxicity studies on alpha-pinene for establishing the DNELs for beta-pinene is fully justified.

Two 90-day inhalation studies were conducted by NTP (National Toxicological Program) with alpha-pinene, one in rats, the other in mice. Mortality was observed in female rats in the high dose group. As no specific target organ was sufficiently impaired by the treatment to cause mortality, it may be concluded that these deaths have a general systemic toxicity origin (NOAEL 200 ppm). The lowest NOAEL was found in male and female mice (50 ppm) based on minimal to moderate hyperplasia in the transitional epithelium of the urinary bladder from 100 ppm. Although the relevance of this effect for humans is uncertain, this study is selected for calculating the systemic long-term DNELs for (-)-beta-pinene, in a conservative approach.

Justification for the selection of the key study (LLNA assay) for the calculation of local long-term DNELs

Skin sensitisation is the most critical local effect of (-)-beta-pinene.

Among all available animal studies, a recent LLNA assay conducted according to GLP guidelines is the most reliable (Pelcot, 2010).

According to the EC3 value (29%) observed in this experiment, (-)-beta-pinene is considered as a weak sensitiser.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

50

Modified dose descriptor starting point:

NOAEC

Value:

50.6 mg/m³

Explanation for the modification of the dose descriptor starting point:

NOAEC mouse (mg/m3) = (NOAEC (ppm) x MW) / Vmol = (50 x 136.24) / 24.05 = 283.24 mg/m3; Modification for exposure (experiment to human): (6/24)*(5/7) (Mouse Exposure condition (6h – 5/7 days) / General population Exposure condition (24 h – 7/7 days). Thus, the corrected starting point for inhalation is : 283.24 mg/kg bw/d x (6 h/24 h) x (5 d / 7 d) = 50.6 mg/m3

AF for dose response relationship:

1

Justification:

Starting point is a NOAEC

AF for differences in duration of exposure:

2

Justification:

Subchronic to chronic extrapolation

AF for interspecies differences (allometric scaling):

1

Justification:

AF not used for oral to inhalation route extrapolation

AF for other interspecies differences:

2.5

Justification:

Toxicodynamic and toxicokinetic remaining differencies

AF for intraspecies differences:

10

Justification:

Default factor for general population

AF for the quality of the whole database:

1

Justification:

Appropriate database

AF for remaining uncertainties:

1

Justification:

None

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.3 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

350

Modified dose descriptor starting point:

NOAEL

Value:

102 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

NOAEC mouse (mg/m3) = (NOAEC (ppm) x MW) / Vmol = (50 x 136.24) / 24.05 = 283.24 mg/m3; Modification for exposure (experiment to human): (6/24)*(5/7) (Mouse Exposure condition (6h – 5/7 days) / General population Exposure condition (24 h – 7/7 days) ; Standard respiratory volume for mice: Standard respiratory volume for humans * allometric scaling * duration of exposure = 0.2 L/min/kg * 7 * 60 min * 24 h = 2.02 m3/kg. Thus, the corrected starting point for inhalation is : 283.24 mg/kg bw/d x (6 h/24 h) x (5 j/7j) x 0.2 L/min/kg x 7 x 60 min x 24 h= 102 mg/kg bw/d

AF for dose response relationship:

1

Justification:

Starting point is a NOAEC

AF for differences in duration of exposure:

2

Justification:

Subchronic to chronic extrapolation

AF for interspecies differences (allometric scaling):

7

Justification:

Allometric scaling from mouse to human

AF for other interspecies differences:

2.5

Justification:

Toxicodynamic and toxicokinetic remaining differencies

AF for intraspecies differences:

10

Justification:

Default factor for general population

AF for the quality of the whole database:

1

Justification:

Appropriate database

AF for remaining uncertainties:

1

Justification:

None

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

27 µg/cm²

Most sensitive endpoint:

sensitisation (skin)

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

270

Dose descriptor:

other: NOAEL

AF for dose response relationship:

1

Justification:

EC3 is considerd as a NOEL

AF for differences in duration of exposure:

3

Justification:

Repeated (long term) exposure

AF for interspecies differences (allometric scaling):

3

Justification:

From all animal studies assessing skin sensitisation, the lowest concentration inducing a positive response was found in an LLNA with EC3=29%. In humans, the highest concentration without positive response was 10%; therefore, an AF of 3, corresponding to the difference of concentration without effect between animals and humans, was considered

AF for other interspecies differences:

1

Justification:

None

AF for intraspecies differences:

10

Justification:

Default factor for general population

AF for remaining uncertainties:

3

Justification:

Dermal integrity and exposure conditions (matrix)

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:

0.3 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

350

Modified dose descriptor starting point:

NOAEL

Value:

102 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

NOAEC mouse (mg/m3) = (NOAEC (ppm) x MW) / Vmol = (50 x 136.24) / 24.05 = 283.24 mg/m3; Modification for exposure (experiment to human): (6/24)*(5/7) (Mouse Exposure condition (6h – 5/7 days) / General population Exposure condition (24 h – 7/7 days) ; Standard respiratory volume for mice: Standard respiratory volume for humans * allometric scaling * duration of exposure = 0.2 L/min/kg * 7 * 60 min * 24 h = 2.02 m3/kg. Thus, the corrected starting point for inhalation is : 283.24 mg/kg bw/d x (6 h/24 h) x (5 j/7j) x 0.2 L/min/kg x 7 x 60 min x 24 h= 102 mg/kg bw/d

AF for dose response relationship:

1

Justification:

Starting point is a NOAEL

AF for differences in duration of exposure:

2

Justification:

Subchronic to chronic extrapolation

AF for interspecies differences (allometric scaling):

7

Justification:

Allometric scaling from mouse to human

AF for other interspecies differences:

2.5

Justification:

Toxicodynamic and toxicokinetic remaining differencies

AF for intraspecies differences:

10

Justification:

Default factor for general population

AF for the quality of the whole database:

1

Justification:

Appropriate database

AF for remaining uncertainties:

1

Justification:

None

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

Justification for the selection of the key study (repeated dose toxicity study) for the calculation of systemic long-term DNELs

alpha-Pinene and beta-pinene are structurally similar compounds. They are bicyclic terpene hydrocarbons and are positional isomers. A great extent of similar patterns was demonstrated for physico-chemical properties, (eco)toxicological properties and environmental fate. Therefore the use of repeated dose toxicity studies on alpha-pinene for establishing the DNELs for beta-pinene is fully justified.

Two 90-day inhalation studies were conducted by NTP (National Toxicological Program) with alpha-pinene, one in rats, the other in mice. Mortality was observed in female rats in the high dose group. As no specific target organ was sufficiently impaired by the treatment to cause mortality, it may be concluded that these deaths have a general systemic toxicity origin (NOAEL 200 ppm). The lowest NOAEL was found in male and female mice (50 ppm) based on minimal to moderate hyperplasia in the transitional epithelium of the urinary bladder from 100 ppm. Although the relevance of this effect for humans is uncertain, this study is selected for calculating the systemic long-term DNELs for (-)-beta-pinene, in a conservative approach.

Justification for the selection of the key study (LLNA assay) for the calculation of local longterm DNELs

Skin sensitisation is the most critical local effect of (-)-beta-pinene.

Among all available animal studies, a recent LLNA assay conducted according to GLP guidelines is the most reliable (Pelcot, 2010).

According to the EC3 value (29%) observed in this experiment, (-)-beta-pinene is considered as a weak sensitiser.