Hydrocarbons, terpene processing by-products

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.9 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):

75

Modified dose descriptor starting point:

NOAEC

Value:

220 mg/m³

Explanation for the modification of the dose descriptor starting point:

In the absence of data on absorption, it was assumed that 50% absorption occurs by the oral route. To secure a conservative external NOAEL a maximum absorption should be assumed for the inhalation route (i.e.; 100%). To convert the oral NOAEL into inhalatory NOAEC, a rat default respiratory volume was used corresponding to the daily duration of human exposure (sRVrat: 0.38 m3/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). Thus, the corrected starting point for inhalation is : 250 mg/kg bw/d x 0.5 x (1/0.38 m3/kg bw/8h) x (6.7 m3 for 8h exposure /10 m3 for 8h exposure) = 220 mg/m3 for workers.

AF for dose response relationship:

1

Justification:

Starting point is a NOAEC

AF for differences in duration of exposure:

6

Justification:

Sub-acute 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:

medium hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

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:

low hazard (no threshold derived)

Additional information - workers

The DNELs relevant to the susbtance could be calculated from three different starting points:

- a 90-day inhalation study in mice exposed to alpha pinene (NOAEC = 283.24 mg/m3/day)

- an OECD guideline 422 and GLP compliant study in rats exposed to Terpinolene multiconstituent by diet (NOAEL = 435.8 mg/kg bw/day)

- an OECD guideline 407 and GLP compliant study in rats exposed to camphene by oral gavage (NOAEL = 250 mg/kg bw/day)

DNEL were calculated for each of the three starting points and the most conservative (ie. the lowest) DNEL value was selected for risk assessment. See details on DNEL calculation in the file attached.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.7 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):

150

Modified dose descriptor starting point:

NOAEC

Value:

109 mg/m³

Explanation for the modification of the dose descriptor starting point:

In the absence of data on absorption, it was assumed that 50% absorption occurs by the oral route.To secure a conservative external NOAEL a maximum absorption should be assumed for the inhalation route (i.e.; 100%). To convert the oral NOAEL into inhalatory NOAEC, a rat default respiratory volume was used corresponding to the daily duration of human exposure (sRVrat: 1.15 m3/kg bw/d). Thus, the corrected starting point for inhalation is : 250 mg/kg bw/d x 50%/100% x (1/1.15 m3/kg bw/d) = 109 mg/m3

AF for dose response relationship:

1

Justification:

Starting point is a NOAEC

AF for differences in duration of exposure:

6

Justification:

Sub-acute 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)

Most sensitive endpoint:

sensitisation (skin)

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

Most sensitive endpoint:

sensitisation (skin)

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:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

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

The DNEL relevant to the registered susbtance could be calculated from three different starting points:

- a 90-day inhalation study in mice exposed to Alpha-pinene (NOAEC = 283.24 mg/m3/day)

- an OECD guideline 422 and GLP compliant study in rats exposed to Terpinolene multiconstituent by diet (NOAEL = 435.8 mg/kg bw/day)

- an OECD guideline 407 and GLP compliant study in rats exposed to camphene by oral gavage (NOAEL = 250 mg/kg bw/day)

DNEL were calculated for each of the three starting points and the most conservative (ie. the lowest) DNEL value was selected for risk assessment. See details on DNEL calculation in the file attached.