Salts of phosphoric acid, 2-ethylhexyl esters with C16-18 (even numbered) and C18-unsaturated-alkylamines

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

6.83 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):

18

Dose descriptor starting point:

NOAEL

Value:

50 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

123 mg/m³

Explanation for the modification of the dose descriptor starting point:

Kinetics (metabolism, distribution and excretion) are considered to be similar for oral and inhalation intake in the absence of evidence of the opposite.

Starting point:

NOAEL of 50 mg/kg bw/day in a 28-day repeated dose toxicity study in rat.

An additional factor was included in the modification calculation to take into account correction for differences between human and experimental exposure conditions. When correcting an oral NOAEL to inhalation NOAEC the correction factor for worker population would be: 7 day/week (experimental animal exposure, check study) / 5 days/week (worker exposure conditions) = 1.4.

 

Conversion of an oral NOAEL into a corrected NOAEC:

For workers (8h exposure/day), the corrected inhalatory NOAEC = oral NOAEL * 1/sRVrat * ABSoral-rat /ABSinhal-human * sRVhuman/wRV

= 50 mg/kg bw/day * 1/0.38 m³/kg/8h * ABSoral-rat /ABSinhal-human * 6.7 m³ (8h)/10 m³ (8h) *1.4

= 50 mg/kg bw/day * 1/0.38 m³/kg/8h * 1 * 6.7 m3 (8h)/10 m³ (8h) *1.4

= 50 /0.38 * 1* (6.7/10) *1.4 = 123 mg/m³.

AF for dose response relationship:

1

Justification:

Value is a NOAEL

AF for differences in duration of exposure:

6

Justification:

Extrapolation from subacute study to chronic exposure

AF for interspecies differences (allometric scaling):

1

Justification:

No correction for caloric demand for inhalation; is included in dose descriptor starting point

AF for other interspecies differences:

1

Justification:

Additional assessment factors for interspecies differences are not needed as has been derived in the ECETOC report (TR 110, 2010) based on a review of the scientific literature. The concept of adjusting animal dose by allometric scaling predicts reasonably well the appropriate dose in humans. A Geometric Standard Deviation (GSD) of 2.5-2.6 suggests the likelihood of some variability or additional uncertainty around the predicted NOAEL in humans. This analysis is based on a comparison of animal to actual human data that per se includes intraspecies variability in humans (see below at intraspecies differences).

AF for intraspecies differences:

3

Justification:

An assessment factor of 3 has been used to account for the intraspecies differences. This factor has been retrieved by ECETOC (TR110, 2010). The ECETOC analysis has been based on a comparison between animal and actual human data that per se includes intraspecies variability in humans. In addition, the human population under investigation comprised cancer patients; this represents a very sensitive subpopulation. A Geometric Standard Deviation (GSD) of 2.5-2.6 suggests the likelihood of some variability or additional uncertainty around the predicted NOAEL in humans. Thus, this standard deviation represented by the GSD of 2.5-2.6 is probably due to potential differences in biological sensitivity between species and includes intraspecies differences.

AF for the quality of the whole database:

1

Justification:

Reliable studies used

AF for remaining uncertainties:

1

Justification:

An assessment factor of 1 is applicable, because there are no remaining uncertainties, which have not already been accounted for.

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.347 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):

72

Dose descriptor starting point:

NOAEL

Value:

50 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

25 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Kinetics (metabolism, distribution and excretion) are considered to be similar for oral and dermal intake in the absence of evidence of the opposite. Correction dermal NOAEL: 50 mg/kg bw/day x 50/100^a = 25 mg/kg bw/day (^a % oral/dermal absorption)

AF for dose response relationship:

1

Justification:

Value is a NOAEL

AF for differences in duration of exposure:

6

Justification:

Extrapolation from subacute study to chronic exposure

AF for interspecies differences (allometric scaling):

4

Justification:

Correction for caloric demand from rat to human

AF for other interspecies differences:

1

Justification:

Additional assessment factors for interspecies differences are not needed as has been derived in the ECETOC report (TR 110, 2010) based on a review of the scientific literature. The concept of adjusting animal dose by allometric scaling predicts reasonably well the appropriate dose in humans. A Geometric Standard Deviation (GSD) of 2.5-2.6 suggests the likelihood of some variability or additional uncertainty around the predicted NOAEL in humans. This analysis is based on a comparison of animal to actual human data that per se includes intraspecies variability in humans (see below at intraspecies differences).

AF for intraspecies differences:

3

Justification:

An assessment factor of 3 has been used to account for the intraspecies differences. This factor has been retrieved by ECETOC (TR110, 2010). The ECETOC analysis has been based on a comparison between animal and actual human data that per se includes intraspecies variability in humans. In addition, the human population under investigation comprised cancer patients; this represents a very sensitive subpopulation. A Geometric Standard Deviation (GSD) of 2.5-2.6 suggests the likelihood of some variability or additional uncertainty around the predicted NOAEL in humans. Thus, this standard deviation represented by the GSD of 2.5-2.6 is probably due to potential differences in biological sensitivity between species and includes intraspecies differences.

AF for the quality of the whole database:

1

Justification:

Reliable study used

AF for remaining uncertainties:

1

Justification:

An assessment factor of 1 is applicable, because there are no remaining uncertainties, which have not already been accounted for.

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.08 mg/kg bw/day

DNEL related information

DNEL extrapolated from long term DNEL

Local effects

Long term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.45 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):

30

Dose descriptor starting point:

NOAEL

Value:

50 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

43.5 mg/m³

Explanation for the modification of the dose descriptor starting point:

Kinetics (metabolism, distribution and excretion) are considered to be similar for oral and inhalation intake in the absence of evidence of the opposite.

For the general population (24h exposure/day), the corrected inhalatory NOAEC = oral NOAEL * 1/sRVrat * ABSoral-rat /ABSinhal-human

 

            = 50 mg/kg bw/day * 1/1.15 m³/kg * ABSoral-rat /ABSinhal-human

 

            = 50 mg/kg bw/day * 1/1.15 m³/kg * 1 =  43.5 mg/m³

 

With ABS: Absorption, sRV: Standard Respiratory Volume;

ABSoral-rat /ABSinhal-human= 50/50= 1, assuming no differences in inhalation absorption between rats and humans.

AF for dose response relationship:

1

Justification:

Value is a NOAEL

AF for differences in duration of exposure:

6

Justification:

Extrapolation from subacute study to chronic exposure

AF for interspecies differences (allometric scaling):

1

Justification:

No correction for caloric demand for inhalation; is included in dose descriptor starting point

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:

An assessment factor of 5 has been used to account for the intraspecies differences as has been derived by ECETOC (TR110, 2010) based on a review of the scientific literature. The ECETOC analysis has been based on a comparison between animal and actual human data that per se includes intraspecies variability in humans. In addition, the human population under investigation comprised cancer patients, this represents a very sensitive subpopulation. A Geometric Standard Deviation (GSD) of 2.5-2.6 suggests the likelihood of some variability or additional uncertainty around the predicted NOAEL in humans. Thus, this standard deviation represented by the GSD of 2.5-2.6 is probably due to potential differences in biological sensitivity between species but includes intraspecies differences.

AF for the quality of the whole database:

1

Justification:

Reliable study used

AF for remaining uncertainties:

1

Justification:

An assessment factor of 1 is applicable, because there are no remaining uncertainties, which have not already been accounted for.

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.208 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):

120

Dose descriptor starting point:

NOAEL

Value:

50 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

25 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Kinetics (metabolism, distribution and excretion) are considered to be similar for oral and dermal intake in the absence of evidence of the opposite. Correction dermal NOAEL: 50 mg/kg bw/day x 50/100^a = 25 mg/kg bw/day (^a % oral/dermal absorption).

AF for dose response relationship:

1

Justification:

Value is a NOAEL

AF for differences in duration of exposure:

6

Justification:

Extrapolation from subacute study to chronic exposure

AF for interspecies differences (allometric scaling):

4

Justification:

Correction for caloric demand from rat 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:

5

Justification:

An assessment factor of 5 has been used to account for the intraspecies differences as has been derived by ECETOC (TR110, 2010) based on a review of the scientific literature. The ECETOC analysis has been based on a comparison between animal and actual human data that per se includes intraspecies variability in humans. In addition, the human population under investigation comprised cancer patients, this represents a very sensitive subpopulation. A Geometric Standard Deviation (GSD) of 2.5-2.6 suggests the likelihood of some variability or additional uncertainty around the predicted NOAEL in humans. Thus, this standard deviation represented by the GSD of 2.5-2.6 is probably due to potential differences in biological sensitivity between species but includes intraspecies differences.

AF for the quality of the whole database:

1

Justification:

Reliable study used

AF for remaining uncertainties:

1

Justification:

An assessment factor of 1 is applicable, because there are no remaining uncertainties, which have not already been accounted for.

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.25 mg/kg bw/day

DNEL related information

DNEL extrapolated from long term DNEL

Local effects

Long term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

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:

0.416 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):

120

Dose descriptor starting point:

NOAEL

Value:

50 mg/kg bw/day

AF for dose response relationship:

1

Justification:

Value is a NOAEL

AF for differences in duration of exposure:

6

Justification:

Extrapolation from subacute study to chronic exposure worker

AF for interspecies differences (allometric scaling):

4

Justification:

Correction for caloric demand from rat 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:

5

Justification:

An assessment factor of 5 has been used to account for the intraspecies differences as has been derived by ECETOC (TR110, 2010) based on a review of the scientific literature. The ECETOC analysis has been based on a comparison between animal and actual human data that per se includes intraspecies variability in humans. In addition, the human population under investigation comprised cancer patients, this represents a very sensitive subpopulation. A Geometric Standard Deviation (GSD) of 2.5-2.6 suggests the likelihood of some variability or additional uncertainty around the predicted NOAEL in humans. Thus, this standard deviation represented by the GSD of 2.5-2.6 is probably due to potential differences in biological sensitivity between species but includes intraspecies differences.

AF for the quality of the whole database:

1

Justification:

Reliable study used

AF for remaining uncertainties:

1

Justification:

An assessment factor of 1 is applicable, because there are no remaining uncertainties, which have not already been accounted for.

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