Litsea cubeba, ext.

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

9 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

other: ECETOC TR 110 (2010)

Overall assessment factor (AF):

12

Dose descriptor starting point:

NOAEC

Value:

215 mg/m³

Modified dose descriptor starting point:

NOAEC

Value:

108.04 mg/m³

Explanation for the modification of the dose descriptor starting point:

Route-to-route: 1 Inhalation was the original route of the study

Bioavailability differences between human and animal species: 1 No evidence for a difference between species for oral exposure to test substance 

Bioavailability differences between test and target substances: 1 Not applicable

Modification for exposure: 0.75 Conversion of the NOAEC from 6 hours/day in rats to 8 hours for human workers.

Modification for the respiratory volume: 0.67 ECHA Ch R.8, 2012, p 20: Respiratory volume light activity, standard conditions for worker - 8 hour (sRV human = 6,7 m3/kg/d) with relevant duration of 8 h - respiratory volume / exposure of 10 m3 (wRV). Applicable worker = 6.7/10 

AF for dose response relationship:

1

Justification:

No additional assessment factor for dose response is needed because the dosing was well spaced in the studies and a NOAEC was derived.

AF for differences in duration of exposure:

2

Justification:

sub-chronic to chronic = 2 ; sub-chronic’ usually refers to a 90 day study; (ECHA 2012, Chapter R8, p 29).

AF for interspecies differences (allometric scaling):

1

Justification:

An assessment factor of 1 has been used because the difference in metabolic rate between rat and humans,does not have to be corrected due to the nature of the exposure method (inhalation) as presented in ECHA’s guidance R.8 (November, 2012), figure R. 8-2 and APPENDIX R. 8-2 Bioavailability, route-to-route extrapolation and allometric scaling.

AF for other interspecies differences:

1

Justification:

An assessment factor of 1 has been applied because allometric differences has been accounted for and no other interspecies differences need to be adressed, which has been shown by ECETOC TR 110 (2010) after a review of the scientific literature. ECETOC concludes that adjusting animal dose by allometric scaling (if applicable) predicts reasonably well the appropriate dose in humans. The application the ‘remaining’ AF of 2.5 for interspecies variability would mean an unjustified compilation of AF. The ‘residual’ interspecies variability may remain following allometric scaling, but this is largely accounted for in the default AF proposed for intraspecies variability, i.e. reflecting the interdependency of inter- and intraspecies AF

AF for intraspecies differences:

3

Justification:

There is a major difference in the AF proposed by the REACH TGD and ECETOC for intraspecies extrapolation of systemic effects if the Point of Departure is derived from animal studies (worker: REACH TGD 5, ECETOC 3; general population: REACH TGD 10, ECETOC 5). The proposal of ECETOC is based on an evaluation of the scientific literature while the REACH guidance refers to standard default procedures. Therefore, for the evaluation of Litsea Cubeba Oil the ECETOC TR No. 110 (2010) is followed until the scientific basis for using an alternative approach has been established.

AF for the quality of the whole database:

2

Justification:

Based on the limit in detailed documentation of test results in this WoE

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties

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:

medium 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:

1.71 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other: ECETOC TR 110 (2010)

Overall assessment factor (AF):

63

Dose descriptor starting point:

LOAEL

Value:

60 mg/kg bw/day

Modified dose descriptor starting point:

LOAEL

Value:

108 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Route-to-route: 1.80 The available information on Litsea cubeba oil and its constituents (Neral, Geraniol) indicate that low to moderate dermal absorption of at least a part of its constituents is to be expected, though the high volatility of the constituents may limit its absorption. Therefore, for the derivation of the systemic dermal DNEL, a dermal penetration rate of 50% is assumed.Based on the available information for citral an expected oral absorption of 90% will be used. Therefore a modification factor of 90/50

Bioavailability differences between human and animal species: 1 No evidence for a difference between species for oral exposure to testsubstance

Bioavailability differences between test and target substances: 1 Not applicable

Modification for exposure(experiment in animal and human): 1 Not applicable

AF for dose response relationship:

3

Justification:

To convert a LOAEL to a NOAEL, the REACH TGD suggests an AF of 3 as a minimum for the majority of cases and going up to a default of 10 for exceptional cases (ECHA’s guidance, R.8.4.3.1, November, 2012). Higher AF have to be used if severe effects were observed at the LOAEL, in this case this is considered not applicable (the LOAEL was set based on reduced body weight effects). Furthermore, ECETOC TR 86 references the published literature showing that for most current well-designed studies a factor of 3 will account for the LOAEL/NOAEL difference.

AF for differences in duration of exposure:

1

Justification:

No additional assessment factor is required, since the LOAEL is derived from a chronic study; ‘chronic’ usually refers to a 1.5 - 2 year study (for rodents). (ECHA 2012, Chapter R8, p 29).

AF for interspecies differences (allometric scaling):

7

Justification:

Extrapolation from mouse to human.

AF for other interspecies differences:

1

Justification:

An assessment factor of 1 has been applied because besides allometric differences no other interspecies differences need to be accounted for which has been shown by ECETOC TR 110 (2010) after a review of the scientific literature. ECETOC concludes that adjusting animal dose by allometric scaling predicts reasonably well the appropriate dose in humans. The application the ‘remaining’ AF of 2.5 for interspecies variability would mean an unjustified compilation of AF. The ‘residual’ interspecies variability may remain following allometric scaling, but this is largely accounted for in the default AF proposed for intraspecies variability, i.e. reflecting the interdependency of inter- and intraspecies AF

AF for intraspecies differences:

3

Justification:

There is a major difference in the AF proposed by the REACH TGD and ECETOC for intraspecies extrapolation of systemic effects if the Point of Departure is derived from animal studies (worker: REACH TGD 5, ECETOC 3; general population: REACH TGD 10, ECETOC 5). The proposal of ECETOC is based on an evaluation of the scientific literature while the REACH guidance refers to standard default procedures. Therefore, for the evaluation of Litsea Cubeba Oil the ECETOC TR No. 110 (2010) is followed until the scientific basis for using an alternative approach has been established.

AF for the quality of the whole database:

1

Justification:

The LOAEL is derived from a reliable study performed similar to OECD TG 453 and may be considered sufficient for the calculation of a long term systemic DNEL.

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties

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)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.69 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

other: ECETOC TR 110 (2010)

Overall assessment factor (AF):

20

Dose descriptor starting point:

NOAEC

Value:

215 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

53.75 mg/m³

Explanation for the modification of the dose descriptor starting point:

Route-to-route: 1 Inhalation was the original route of the study

Bioavailability differences between  human and animal species:1 No evidence for a difference between species for oral exposure to test substance

Bioavailability differences between test and target substances: 1 Not applicable

Modification for exposure (experiment in animal and human): 0.25 Conversion of the NOAEC from 6 hours/day in rats to 24 hours in human.

Modification for the respiratory volume: 1

AF for dose response relationship:

1

Justification:

No additional assessment factor for dose response is needed because the dosing was well spaced in the studies and a NOAEC was derived.

AF for differences in duration of exposure:

2

Justification:

sub-chronic to chronic = 2 ; sub-chronic’ usually refers to a 90 day study (ECHA 2012, Chapter R8, p 29).

AF for interspecies differences (allometric scaling):

1

Justification:

An assessment factor of 1 has been used because the difference in metabolic rate between rat and humans,does not have to be corrected due to the nature of the exposure method (inhalation) as presented in ECHA’s guidance R.8 (November, 2012), figure R. 8-2 and APPENDIX R. 8-2 Bioavailability, route-to-route extrapolation and allometric scaling.

AF for other interspecies differences:

1

Justification:

An assessment factor of 1 has been applied because besides allometric differences no other interspecies differences need to be accounted for which has been shown by ECETOC TR 110 (2010) after a review of the scientific literature. ECETOC concludes that adjusting animal dose by allometric scaling predicts reasonably well the appropriate dose in humans. The application the ‘remaining’ AF of 2.5 for interspecies variability would mean an unjustified compilation of AF. The ‘residual’ interspecies variability may remain following allometric scaling, but this is largely accounted for in the default AF proposed for intraspecies variability, i.e. reflecting the interdependency of inter- and intraspecies AF

AF for intraspecies differences:

5

Justification:

There is a major difference in the AF proposed by the REACH TGD and ECETOC for intraspecies extrapolation of systemic effects if the Point of Departure is derived from animal studies (worker: REACH TGD 5, ECETOC 3; general population: REACH TGD 10, ECETOC 5). The proposal of ECETOC is based on an evaluation of the scientific literature while the REACH guidance refers to standard default procedures. Therefore, for the evaluation of Litsea Cubeba Oil the ECETOC TR No. 110 (2010) is followed until the scientific basis for using an alternative approach has been established.

AF for the quality of the whole database:

2

Justification:

Based on the limited detailed documentation of test results in this WoE

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties

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:

medium 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:

1.03 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other: ECETOC TR 110 (2010)

Overall assessment factor (AF):

105

Dose descriptor starting point:

LOAEL

Value:

60 mg/kg bw/day

Modified dose descriptor starting point:

LOAEL

Value:

108 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Route-to-route: 1.80 The available information on Litsea cubeba oil and its constituents (Neral, Geraniol) indicate that low to moderate dermal absorption of at least a part of its constituents is to be expected, though the high volatility of the constituents may limit its absorption. Therefore, for the derivation of the systemic dermal DNEL, a dermal penetration rate of 50% is assumed. Based on the available information for citral an expected oral absorption of 90% will be used. Therefore a modification factor of 90/50

Bioavailability differences between  human and animal species: 1 No evidence for a difference between species for oral  exposure to testsubstance

Bioavailability differences between test and target substances: 1 Not applicable

Modification for exposure (experiment in animal and human): 1 Not applicable

AF for dose response relationship:

3

Justification:

To convert a LOAEL to a NOAEL, the REACH TGD suggests an AF of 3 as a minimum for the majority of cases and going up to a default of 10 for exceptional cases (ECHA’s guidance, R.8.4.3.1, November, 2012). Higher AF have to be used if severe effects were observed at the LOAEL, in this case this is considered not applicable (the LOAEL was set based on reduced body weight effects). Furthermore, ECETOC TR 86 references the published literature showing that for most current well-designed studies a factor of 3 will account for the LOAEL/NOAEL difference.

AF for differences in duration of exposure:

1

Justification:

No additional assessment factor is required, since the LOAEL is derived from a chronic study; ‘chronic’ usually refers to a 1.5 - 2 year study (for rodents) (ECHA 2012, Chapter R8, p 29).

AF for interspecies differences (allometric scaling):

7

Justification:

Extrapolation from Mouse to Humans.

AF for other interspecies differences:

1

Justification:

An assessment factor of 1 has been applied because besides allometric differences no other interspecies differences need to be accounted for which has been shown by ECETOC TR 110 (2010) after a review of the scientific literature. ECETOC concludes that adjusting animal dose by allometric scaling predicts reasonably well the appropriate dose in humans. The application the ‘remaining’ AF of 2.5 for interspecies variability would mean an unjustified compilation of AF. The ‘residual’ interspecies variability may remain following allometric scaling, but this is largely accounted for in the default AF proposed for intraspecies variability, i.e. reflecting the interdependency of inter- and intraspecies AF.

AF for intraspecies differences:

5

Justification:

There is a major difference in the AF proposed by the REACH TGD and ECETOC for intraspecies extrapolation of systemic effects if the Point of Departure is derived from animal studies (worker: REACH TGD 5, ECETOC 3; general population: REACH TGD 10, ECETOC 5). The proposal of ECETOC is based on an evaluation of the scientific literature while the REACH guidance refers to standard default procedures. Therefore, for the evaluation of Litsea Cubeba Oil the ECETOC TR No. 110 (2010) is followed until the scientific basis for using an alternative approach has been established.

AF for the quality of the whole database:

1

Justification:

The LOAEL is derived from a reliable study performed similar to OECD TG 453 and may be considered sufficient for the calculation of a long term systemic DNEL.

AF for remaining uncertainties:

1

Justification:

no remaining uncertainties

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:

0.57 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other: ECETOC TR 110 (2010)

Overall assessment factor (AF):

105

Dose descriptor starting point:

LOAEL

Value:

60 mg/kg bw/day

Modified dose descriptor starting point:

LOAEL

Value:

60 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Route-to-route: 1 Oral-Oral  (90% oral absorption is expected, based on toxicokinetic data of citral)

Bioavailability differences between  human and animal species: 1 No evidence for a difference between species for oral  exposure to testsubstance

Bioavailability differences between test and target substances: 1 Not applicable

Modification for exposure (experiment in animal and human): 1 Not applicable

AF for dose response relationship:

3

Justification:

To convert a LOAEL to a NOAEL, the REACH TGD suggests an AF of 3 as a minimum for the majority of cases and going up to a default of 10 for exceptional cases (ECHA’s guidance, R.8.4.3.1, November, 2012). Higher AF have to be used if severe effects were observed at the LOAEL, in this case this is considered not applicable (the LOAEL was set based on reduced body weight effects). Furthermore, ECETOC TR 86 references the published literature showing that for most current well-designed studies a factor of 3 will account for the LOAEL/NOAEL difference.

AF for differences in duration of exposure:

1

Justification:

No additional assessment factor is required, since the LOAEL is derived from a chronic study; ‘chronic’ usually refers to a 1.5 - 2 year study (for rodents) (ECHA 2012, Chapter R8, p 29).

AF for interspecies differences (allometric scaling):

7

Justification:

Extrapolation from mouse to humans.

AF for other interspecies differences:

1

Justification:

An assessment factor of 1 has been applied because besides allometric differences no other interspecies differences need to be accounted for which has been shown by ECETOC TR 110 (2010) after a review of the scientific literature. ECETOC concludes that adjusting animal dose by allometric scaling predicts reasonably well the appropriate dose in humans. The application the ‘remaining’ AF of 2.5 for interspecies variability would mean an unjustified compilation of AF. The ‘residual’ interspecies variability may remain following allometric scaling, but this is largely accounted for in the default AF proposed for intraspecies variability, i.e. reflecting the interdependency of inter- and intraspecies AF.

AF for intraspecies differences:

5

Justification:

There is a major difference in the AF proposed by the REACH TGD and ECETOC for intraspecies extrapolation of systemic effects if the Point of Departure is derived from animal studies (worker: REACH TGD 5, ECETOC 3; general population: REACH TGD 10, ECETOC 5). The proposal of ECETOC is based on an evaluation of the scientific literature while the REACH guidance refers to standard default procedures. Therefore, for the evaluation of Litsea Cubeba Oil the ECETOC TR No. 110 (2010) is followed until the scientific basis for using an alternative approach has been established.

AF for the quality of the whole database:

1

Justification:

The LOAEL is derived from a reliable study performed similar to OECD TG 453 and may be considered sufficient for the calculation of a long term systemic DNEL.

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)