Fatty acids, C18-22

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

17.632 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

Modified dose descriptor starting point:

NOAEC

Value:

881.6 mg/m³

Explanation for the modification of the dose descriptor starting point:

NOAEC(corr) = NOAEL(oral)*(1/0.38 m³/kg/d)*ABS(oral-rat)/ABS(inh-human)*(6.7 m³ (8h)/10 m³ (8 h)) = 1000 mg/kg bw/d*(1/0.38 m³/kg/d)*(0.5*1)*0.67 = 881.6 mg/m³. It is assumed, that the oral absorption rate is 50% of that of the inhalation absorption. ABS(oral-rat)=oral absorption rate in rats, ABS(inh-human)=inhalation absorption rate in humans.

AF for dose response relationship:

1

Justification:

The dose descriptor starting point is based on a NOAEL.

AF for differences in duration of exposure:

4

Justification:

DNEL is based on an OECD 422 study.

AF for interspecies differences (allometric scaling):

1

Justification:

AF not used for inhalation route.

AF for other interspecies differences:

2.5

Justification:

Default value according to ECHA REACH Guidance.

AF for intraspecies differences:

5

Justification:

Default value for workers according to ECHA REACH Guidance.

AF for the quality of the whole database:

1

Justification:

The data base is adequate and of good quality (taking into account reliability and consistency, across different studies and endpoints).

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties.

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

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:

10 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

Modified dose descriptor starting point:

NOAEL

Value:

2 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Dermal NOAEL = oral NOAEL*ABS(oral)/ABS(dermal) = 1000 mg/kg bw/day*(1/0.5) = 2000 mg/kg bw/day. Based on a moderate dermal absorption the absorption difference for the dermal route compared to the oral route is adjusted by the factor 0.5.

AF for dose response relationship:

1

Justification:

The dose descriptor starting point is based on a NOAEL.

AF for differences in duration of exposure:

4

Justification:

DNEL is based on an OECD 422 study.

AF for interspecies differences (allometric scaling):

4

Justification:

The experimental animal was the rat.

AF for other interspecies differences:

2.5

Justification:

Default value according to ECHA REACH Guidance.

AF for intraspecies differences:

5

Justification:

Default value for workers according to ECHA REACH Guidance.

AF for the quality of the whole database:

1

Justification:

The data base is adequate and of good quality (taking into account reliability and consistency, across different studies and endpoints).

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

Route of original study:

Dermal

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - workers

In general, the calculation of a DNEL is based on the observed effect level which has to be modified as described in “Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterisation of dose [concentration]-response for human health” (ECHA, May 2012).

Long-term dermal and inhalative intakes are the possible exposure routes for workers, whereas oral, dermal and inhalative intakes are the possible exposure routes for the general population. In regard to acute and long-term systemic effects no hazard was identified for the fatty acids category members based on the available data. Considering acute and long-term local effects, no local irritation on skin and/or mucous membranes are expected for fatty acids with a chain length > C12 with the exception of C22:1 (erucic acid).

 

As starting point for derivation of the DNEL, the NOAEL of 1000 mg/kg bw/day (for systemic effects) was used which was found in a study performed according to OECD 422 where the males were treated by gavage for 42 days with docosanoic acid and the females 14 days prior to mating until day 3 of lactation (Nagao et al., 2002).

A substance-specific adjustment of the NOAEL is not performed since the obtained value of 1000 mg/kg bw/day reflects the “worst case” among the available key studies for repeated dose toxicity and for toxicity on reproduction of fatty acids within the category.

 

Inhalation

For calculation of the DNEL for long-term inhalative systemic effects, the dose descriptor has to be converted into a corrected starting point by route-to-route extrapolation. The absorption difference for inhalation compared to the oral route is reflected by the factor 2 as suggested by the ECHA CSA Guidance Chapter R.8. Besides this, the interspecies difference between rat and human has to be taken into account. Therefore, the no observed effect level has to be corrected by the risk assessor 6.7 / 0.38*10 regarding breathing volume and frequency. Thus, the corrected starting point for workers was 881.6 mg/m³/d for inhalation.

Subsequently assessment factors are listed, which have to be taken into account for the final DNEL calculation: remaining interspecies-differences (2.5), intraspecies differences (5), exposure duration (4). An assessment factor of (4) for duration extrapolation was chosen, since in the combined repeated dose and reproductive/developmental toxicity screening test (Nagao et al., 2002) from which the NOAEL was taken as starting point, the exposure duration exceeds a subacute exposure duration of 28 days. Thus the mean value (4) of the default assessment factor (6) for an extrapolation subacute - chronic and the default assessment factor (2) for an extrapolation subchronic – chronic was considered appropriate.

The DNEL is calculated according to the equation: DNEL = (corrected starting point)/(overall AF). Thus, the resulting DNEL for long-term inhalative systemic effects is 17.632 mg/m³ for workers.

 

Dermal

For calculation of the DNEL for long-term dermal systemic effects, the dose descriptor has to be converted into a corrected starting point by route-to-route extrapolation. The absorption difference for the dermal route compared to the oral route is adjusted by the factor 0.5 due to the skin absorption classification as moderate based on the QSAR result for hexanoic acid (Danish EPA Database, 2004). This fatty acid has the highest absorption rate among all members of the category with 0.047 mg/cm²/h reflecting the worst case for all category members. Thus the corrected starting point for workers was 2000 mg/kg bw for the dermal route.

Subsequently, following assessment factors are taken into account for the final DNEL calculation: interspecies differences (4), remaining interspecies-differences (2.5), intraspecies differences (5), exposure duration (4).

As a consequence, the resulting DNEL for long-term dermal systemic effects is 10.0 mg/kg bw/day for workers.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

4.348 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

Modified dose descriptor starting point:

NOAEC

Value:

434.8 mg/m³

Explanation for the modification of the dose descriptor starting point:

NOAEC(corr) = NOAEL(oral)*(1/1.15 m³/kg/d)*ABS(oral-rat)/ABS(inh-human) = 1000 mg/kg bw/d*(1/1.15 m³/kg/d)*(0.5*1) = 434.8 mg/m³. It is assumed, that the oral absorption rate is 50% of that of the inhalation absorption. ABS(oral-rat)=oral absorption rate in rats, ABS(inh-human)=inhalation absorption rate in humans.

AF for dose response relationship:

1

Justification:

The dose descriptor starting point is based on a NOAEL.

AF for differences in duration of exposure:

4

Justification:

DNEL is based on an OECD 422 study.

AF for interspecies differences (allometric scaling):

1

Justification:

AF not used for inhalation route.

AF for other interspecies differences:

2.5

Justification:

Default value according to ECHA REACH Guidance.

AF for intraspecies differences:

10

Justification:

Default value for general population according to ECHA REACH Guidance.

AF for the quality of the whole database:

1

Justification:

The data base is adequate and of good quality (taking into account reliability and consistency, across different studies and endpoints).

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties.

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

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:

5 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

Modified dose descriptor starting point:

NOAEL

Value:

2 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Dermal NOAEL=oral NOAEL*ABS(oral)/ABS(dermal). Based on a moderate dermal absorption the absorption difference for the dermal route compared to the oral route is adjusted by the factor 0.5.

AF for dose response relationship:

1

Justification:

The dose descriptor starting point is based on a NOAEL.

AF for differences in duration of exposure:

4

Justification:

DNEL is based on an OECD 422 study.

AF for interspecies differences (allometric scaling):

4

Justification:

The experimental animal was the rat.

AF for other interspecies differences:

2.5

Justification:

Default value according to ECHA REACH Guidance.

AF for intraspecies differences:

10

Justification:

Default value for general population according to ECHA REACH Guidance.

AF for the quality of the whole database:

1

Justification:

The data base is adequate and of good quality (taking into account reliability and consistency, across different studies and endpoints).

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

Route of original study:

Dermal

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

skin irritation/corrosion

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.5 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

Modified dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No route-to-route extrapolation required.

AF for dose response relationship:

1

Justification:

The dose descriptor starting point is based on a NOAEL.

AF for differences in duration of exposure:

4

Justification:

DNEL is based on an OECD 422 study.

AF for interspecies differences (allometric scaling):

4

Justification:

The experimental animal was the rat.

AF for other interspecies differences:

2.5

Justification:

Default value according to ECHA REACH Guidance.

AF for intraspecies differences:

10

Justification:

Default value for general population according to ECHA REACH Guidance.

AF for the quality of the whole database:

1

Justification:

The data base is adequate and of good quality (taking into account reliability and consistency, across different studies and endpoints).

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

Route of original study:

Oral

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - General Population

In general, the calculation of a DNEL is based on the observed effect level which has to be modified as described in “Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterisation of dose [concentration]-response for human health” (ECHA, May 2012).

Long-term dermal and inhalative intakes are the possible exposure routes for workers, whereas oral, dermal and inhalative intakes are the possible exposure routes for the general population. In regard to acute and long-term systemic effects no hazard was identified for the fatty acids category members based on the available data. Considering acute and long-term local effects, no local irritation on skin and/or mucous membranes are expected for fatty acids with a chain length > C12 with the exception of C22:1 (erucic acid).

 

As starting point for derivation of the DNEL, the NOAEL of 1000 mg/kg bw/day (for systemic effects) was used which was found in a study performed according to OECD 422 where the males were treated by gavage for 42 days with docosanoic acid and the females 14 days prior to mating until day 3 of lactation (Nagao et al., 2002).

A substance-specific adjustment of the NOAEL is not performed since the obtained value of 1000 mg/kg bw/day reflects the “worst case” among the available key studies for repeated dose toxicity and for toxicity on reproduction of fatty acids within the category.

 

Inhalation

For calculation of the DNEL for long-term inhalative systemic effects, the dose descriptor has to be converted into a corrected starting point by route-to-route extrapolation. The absorption difference for inhalation compared to the oral route is reflected by the factor 2 as suggested by the ECHA CSA Guidance Chapter R.8. Besides this, the interspecies difference between rat and human has to be taken into account. Therefore, the no observed effect level has to be corrected by the risk assessor 1/1.15 regarding breathing volume and frequency. Thus, the corrected starting point for the general population is 434.8 mg/m³/day for inhalation.

Subsequently assessment factors are listed, which have to be taken into account for the final DNEL calculation: remaining interspecies-differences (2.5), intraspecies differences (10), exposure duration (4). An assessment factor of (4) for duration extrapolation was chosen, since in the combined repeated dose and reproductive/developmental toxicity screening test (Nagao et al., 2002) from which the NOAEL was taken as starting point, the exposure duration exceeds a subacute exposure duration of 28 days. Thus a mean value of the default assessment factor (6) for an extrapolation subacute - chronic and the default assessment factor (2) for an extrapolation subchronic – chronic was considered appropriate.

The DNEL is calculated according to the equation: DNEL = (corrected starting point)/(overall AF). Thus, the resulting DNEL for long-term inhalative systemic effects is 4.348 mg/m³ for the general population.

Oral

For the DNEL of systemic oral effects a correction of the starting point is not required, since the observed effect level was derived in oral repeated dose toxicity study (Nagao et al., 2002).

Subsequently, following assessment factors are taken into account for the final DNEL calculation: interspecies differences (4), remaining interspecies-differences (2.5), intraspecies differences (10), exposure duration (4). The resulting DNEL for long-term oral systemic effects is 2.5 mg/kg bw/day for the general population.

Dermal

For calculation of the DNEL for long-term dermal systemic effects, the dose descriptor has to be converted into a corrected starting point by route-to-route extrapolation. The absorption difference for the dermal route compared to the oral route is adjusted by the factor 0.5 due to the skin absorption classification as moderate based on the QSAR result for hexanoic acid (Danish EPA Database, 2004). This fatty acid has the highest absorption rate among all members of the category with 0.047 mg/cm²/h reflecting the worst case for all category members. Thus the corrected starting point for workers was 2000 mg/kg bw for the dermal route.

Subsequently, following assessment factors are taken into account for the final DNEL calculation: interspecies differences (4), remaining interspecies-differences (2.5), intraspecies differences (10), exposure duration (4). The resulting DNEL for long-term dermal systemic effects is 5.0 mg/kg bw/day for the general population.