Octadecanoic acid, reaction products with diethylenetriamine and urea, acetates

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

11.8 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):

75

Modified dose descriptor starting point:

NOAEC

Value:

881.6 mg/m³

Explanation for the modification of the dose descriptor starting point:

The REACH Guidance on information requirements and chemical safety assessment (R.8.4.2) prescribes a default factor of 2 in case of oral to inhalation extrapolation. Standard respiratory volume of a rat, corrected for 8 h exposure, as proposed in the REACH Guidance on information requirements and chemical safety assessment (R.8.4.2) is considered to be 0.38 m3/kg bw. Correction for activity driven differences of respiratory volumes in workers compared to workers in rest was considered to be 6.7 m3/10 m³. Therefore, the modified dose descriptor starting point is 881.6 mg/m³ (= 1000 / 2 / 0.38 x (6.7/10)).

AF for differences in duration of exposure:

6

Justification:

Subacute to chronic duration extrapolation.

AF for other interspecies differences:

2.5

Justification:

Default value used.

AF for intraspecies differences:

5

Justification:

Worker default value used.

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:

3.33 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):

300

Modified dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

On the assumption that, in general, dermal absorption will not be higher than oral absorption, no default factor is introduced for the oral to dermal extrapolation. The REACH Guidance on information requirements and chemical safety assessment (R.8.4.2) prescribes a default factor of 1 in case of oral to dermal extrapolation.

AF for differences in duration of exposure:

6

Justification:

Subacute to chronic duration extrapolation.

AF for interspecies differences (allometric scaling):

4

Justification:

Rats are used in the study selected as starting endpoint.

AF for other interspecies differences:

2.5

Justification:

Default value used.

AF for intraspecies differences:

5

Justification:

Worker default value used.

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

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - workers

According to the REACH Guidance on information requirements and chemical safety assessment, a leading DN(M)EL needs to be derived for every relevant human population and every relevant route, duration and frequency of exposure, if feasible.

Short-term toxicity

According to the REACH guideline (R8, Appendix R 8-8), a DNEL for acute toxicity should be derived if an acute toxicity hazard (leading to C&L) has been identified and there is a potential risk for high peak exposures. Since the substance is not classified for acute dermal, inhalation, and oral toxicity, no short-term DNELs needs to be derived for these routes of exposure. The substance is also not classified as irritating to the skin and not sensitizing. Therefore no derivation of the DNEL for local dermal effects and for sensitization is needed. No data is available whether the test substance could cause irritation to the respiratory track and therefore no DNEL could be derived.

Long-term toxicity

A subacute (28-days) oral toxicity study is available in rats. In this study a NOAEL of 1000 mg/kg bw/day was established. This NOAEL is based on the absence of treatment related effects on mortality, clinical signs, food consumption, grip strength, body weight, and locomotor activity. Some effects in clinical laboratory investigations, macroscopic and microscopic findings were observed, but these test-item related changes were considered to be non-adverse.Since only a sub-acute oral toxicity study is available a route-to-route extrapolation is needed to derive the DNELs for dermal and inhalation route.

According to Chapter R.8 of REACH Guidance on information requirements and chemical safety assessment, it is proposed in the absence of route-specific information on the starting route, to include a default factor of 2 in the case of oral-to-inhalation extrapolation and a default factor of 1 in case of oral-to-dermal extrapolation. This approach will be taken forward to DNEL derivation.

Workers DNEL

 

Long-term – inhalation, systemic effects (based on sub-acute oral toxicity study with rats)

Step 1) Relevant dose-descriptor	NOAEL: 1000 mg/kg bw/day	No adverse effects observed at any dose level.
Step 2) Modification of starting point	2         0.38 m^3/kg bw         6.7 m^3/10 m^3	The REACH Guidance on information requirements and chemical safety assessment (R.8.4.2) prescribes a default factor of 2 in case of oral to inhalation extrapolation.   Standard respiratory volume of a rat, corrected for 8 h exposure, as proposed in the REACH Guidance on information requirements and chemical safety assessment (R.8.4.2).   Correction for activity driven differences of respiratory volumes in workers compared to workers in rest.
Modified dose-descriptor	1000 / 2 / 0.38 x (6.7/10) = 881.6 mg/m^3
Step 3) Assessment factors
Interspecies	2.5	For inhalation studies only a factor 2.5 is used, and no correction is made for differences in body size, because extrapolation is based on toxicological equivalence of a concentration of a chemical in the air of experimental animals and humans; animals and humans breathe at a rate depending on their caloric requirements.
Intraspecies	5	Default assessment factor for workers
Exposure duration	6	Extrapolation to chronic exposure based on a sub-acute toxicity study
Dose response	1
Quality of database	1
DNEL	Value
	881.6 / (2.5 x 5 x 6 x 1 x 1) =11.8 mg/m^3

Long-term – dermal, systemic effects (based on sub-acute oral toxicity study with rats)

Description	Value	Remark
Step 1) Relevant dose-descriptor	NOAEL: 1000 mg/kg bw/day	No adverse effects observed at any dose level.
Step 2) Modification of starting point	1	Based on low log Kow and very high water solubility, dermal absorption is expected to be low. A ratio of 0.1% for dermal to oral absorption is therefore provisionally suggested for DNEL derivation.
Modified dose-descriptor	1000 / 1 = 1000 mg/kg bw/day
Step 3) Assessment factors
Interspecies	4 x 2.5	Assessment factor for allometric scaling.
Intraspecies	5	Default assessment factor for workers
Exposure duration	6	Extrapolation to chronic exposure based on a sub-acute toxicity study
Dose response	1
Quality of database	1
DNEL	Value
	1000 / (4 x 2.5 x 5 x 6 x 1 x 1) =3.33 mg/kg bw/day

General Population - 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:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

150

Modified dose descriptor starting point:

NOAEC

Value:

434.8 mg/m³

Explanation for the modification of the dose descriptor starting point:

The REACH Guidance on information requirements and chemical safety assessment (R.8.4.2) prescribes a default factor of 2 in case of oral to inhalation extrapolation. Standard respiratory volume of a rat, corrected for 24 h exposure, as proposed in the REACH Guidance on information requirements and chemical safety assessment (R.8.4.2) is considered to be 1.15 m³/kg bw. Therefore the modified dose descriptor starting point is 434.8 mg/m³ (= 1000 / 2 / 1.15).

AF for differences in duration of exposure:

6

Justification:

Subacute to chronic duration extrapolation.

AF for other interspecies differences:

2.5

Justification:

Default value used.

AF for intraspecies differences:

10

Justification:

Default value used.

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:

1.66 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):

600

Modified dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

On the assumption that, in general, dermal absorption will not be higher than oral absorption, no default factor is introduced for the oral to dermal extrapolation. The REACH Guidance on information requirements and chemical safety assessment (R.8.4.2) prescribes a default factor of 1 in case of oral to dermal extrapolation.

AF for differences in duration of exposure:

6

Justification:

Subacute to chronic duration extrapolation.

AF for interspecies differences (allometric scaling):

4

Justification:

Default value.

AF for other interspecies differences:

2.5

Justification:

Default value used.

AF for intraspecies differences:

10

Justification:

Default value used.

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:

1.67 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):

600

Modified dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

AF for differences in duration of exposure:

6

Justification:

Subacute to chronic duration extrapolation.

AF for interspecies differences (allometric scaling):

4

Justification:

Default value.

AF for other interspecies differences:

2.5

Justification:

Default value.

AF for intraspecies differences:

10

Justification:

Default value.

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

According to the REACH Guidance on information requirements and chemical safety assessment, a leading DN(M)EL needs to be derived for every relevant human population and every relevant route, duration and frequency of exposure, if feasible.

Short-term toxicity

According to the REACH guideline (R8, Appendix R 8-8), a DNEL for acute toxicity should be derived if an acute toxicity hazard (leading to C&L) has been identified and there is a potential risk for high peak exposures. Since the substance is not classified for acute dermal, inhalation, and oral toxicity, no short-term DNELs needs to be derived for these routes of exposure. The substance is also not classified as irritating to the skin and not sensitizing. Therefore no derivation of the DNEL for local dermal effects and for sensitization is needed. No data is available whether the test substance could cause irritation to the respiratory track and therefore no DNEL could be derived.

Long-term toxicity

A subacute (28-days) oral toxicity study is available in rats. In this study a NOAEL of 1000 mg/kg bw/day was established. This NOAEL is based on the absence of treatment related effects on mortality, clinical signs, food consumption, grip strength, body weight, and locomotor activity. Some effects in clinical laboratory investigations, macroscopic and microscopic findings were observed, but these test-item related changes were considered to be non-adverse.Since only a sub-acute oral toxicity study is available a route-to-route extrapolation is needed to derive the DNELs for dermal and inhalation route.

According to Chapter R.8 of REACH Guidance on information requirements and chemical safety assessment, it is proposed in the absence of route-specific information on the starting route, to include a default factor of 2 in the case of oral-to-inhalation extrapolation and a default factor of 1 in case of oral-to-dermal extrapolation. This approach will be taken forward to DNEL derivation.