N-(carboxymethyl)-3-[(2Z)-docos-2-enoylamino]-N,N-dimethylpropan-1-aminium

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3.9 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):

225

Modified dose descriptor starting point:

LOAEC

Value:

881.6 mg/m³

Explanation for the modification of the dose descriptor starting point:

Assuming by default 100% absorption for the inhalation and 50% absorption for oral exposure routes, and standard respiratory volumes of 0.38 m3/kg over 8 hours for rats, 6.7 m3/person over 8 hours and 10 m3/person over 24 hours for humans

AF for dose response relationship:

3

Justification:

Use of LOAEL as a starting point

AF for differences in duration of exposure:

6

Justification:

Default value for subacute to chronic extrapolation

AF for interspecies differences (allometric scaling):

1

Justification:

Not applicable due to route-to-route extrapolation

AF for other interspecies differences:

2.5

Justification:

Default value

AF for intraspecies differences:

5

Justification:

Default value for workers

AF for the quality of the whole database:

1

Justification:

Klimisch 1 study used

AF for remaining uncertainties:

1

Justification:

Not applicable

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

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.1 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

900

Modified dose descriptor starting point:

LOAEL

Value:

1 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The starting point (oral LOAEL) was not modified to take account of the ratio between oral absorption in rats and dermal absorption in humans, which are both considered equal to 100% by default, in a worst-case hypothesis

AF for dose response relationship:

3

Justification:

Use of LOAEL as a starting point

AF for differences in duration of exposure:

6

Justification:

Default value for subacute to chronic extrapolation

AF for interspecies differences (allometric scaling):

4

Justification:

Default value for rats

AF for other interspecies differences:

2.5

Justification:

Default value

AF for intraspecies differences:

5

Justification:

Default value for workers

AF for the quality of the whole database:

1

Justification:

Klimisch 1 study used

AF for remaining uncertainties:

1

Justification:

Not applicable

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

DNEL derivation was performed according to the method proposed in the ECHA Guidance on information requirements and chemical safety assessment, Chapter R.8.

 

Acute / short-term or long-term exposure - local effects

 

For local effects, no sufficient information as to concentration-response relationship of irritation is available to enable DNEL derivation. The irritation effects observed, together with potential skin sensitization, should be considered as the most important hazard and a qualitative risk assessment performed for the local effects.

 

Long term exposure - systemic effects

 

Source study:

The 4-week oral repeat-dose toxicity study in rats was selected as the source study for DNEL derivation (Arrowsmith, 2003).

In this study, dose levels of 50, 150 or 1000 mg a.i./kg/day were administered by gavage to rats for 4 weeks. Following repeated dosing with the limit dose of 1000 mg a.i./kg/day, bodyweight gain was significantly reduced (-20% or -26%, for males or females, respectively), in association with lower mean food consumption (-14% or -11%, for males or females, respectively) and slightly lower efficiency of food utilisation, compared to respective controls. Minor changes occurred in clinical pathology parameters at 1000 mg a.i./kg/day. At necropsy, main observations consisted of inflammatory findings in the non-glandular region of the stomach and the mesenteric lymph nodes, which were attributed to the repeated gavage administration of a surfactant with irritating properties. These local toxicity findings were considered to be of limited relevance for the human situation, based on the route of administration, and the absence of any anatomical counterpart of the forestomach in the human species. The only other finding relevant to systemic toxicity at 1000 mg a.i./kg/day was a significantly lower mean absolute thymus weight compared to controls in males, correlating with a higher incidence of minimal thymic involution and atrophy at microscopic examination. These findings were observed in one gender only.

The dose of 150 mg a.i./kg/day was therefore considered as a NOAEL for systemic toxicity over 4 weeks of administration, and 1000 mg a.i./kg/day as a LOAEL for systemic toxicity, based on the amplitude and severity of the changes observed. These effects were considered to bear a threshold mode of action.

 

For oral route:

 

The oral route is considered not relevant to the worker situation.

 

For inhalation route:

 

-       Modification of the starting point:

The starting point is converted using an oral-to-inhalation route extrapolation (assuming by default100% absorption for the inhalation and 50% absorption for oral exposure routes, and standard respiratory volumes of 0.38 m³/kg over 8 hours for rats, 6.7 m³/person over 8 hours and 10 m³/person over 24 hours for humans):

 

Inhalation NAEC worker (8 h)= 1000 x (1 / 0.38) x (50/100) x (6.7 / 10)= 881.6 mg/m³

 

-       Assessment factors:

The following assessment factors were applied:

·      Interspecies differences: not applicable (route-to-route extrapolation)

·      Remaining interspecies TK differences (mainly toxicodynamic): 2.5 (default value)

·      Intraspecies differences: 5 (default value for workers)

·      Differences in duration of exposure: 6 (default value for subacute to chronic extrapolation)

·      Issues related to severity and dose-response: 3 (because of the use of LOAEL as a starting point)

·      Quality of whole database: 1 (reliability 1 study).

 

Global assessment factor= 2.5 x 5 x 6 x 3 x 1= 225

 

-         DNEL:

 

Worker-DNEL long-term for inhalation route-systemic= 881.6 / 225= 3.9 mg/m³

 

For dermal route:

 

-       Modification of the starting point:

The starting point (oral LOAEL) is not modified to take account of the ratio between oral absorption in rats and dermal absorption in humans, which are both considered equal to 100% by default, in a worst-case hypothesis.

 

Dermal LAEL worker=1000 mg/kg bw

 

-       Assessment factors:

The following assessment factors were applied:

·      Interspecies differences: 4 (default value for rats)

·      Remaining interspecies TK differences (mainly toxicodynamic): 2.5 (default value)

·      Intraspecies differences: 5 (default value for workers)

·      Differences in duration of exposure: 6 (default value for subacute to chronic extrapolation)

·      Issues related to severity and dose-response: 3 (because of the use of LOAEL as a starting point)

·      Quality of whole database: 1 (reliability 1 study).

 

Global assessment factor= 4 x 2.5 x 5 x 6 x 3 x 1= 900

 

-         DNEL:

 

Worker-DNEL long-term for dermal route-systemic= 1000 / 900= 1.1 mg/kg bw

 

 

Reference

 

·      Arrowsmith W. DV6850 Toxicity study by oral administration to CD rats for 4 weeks. Huntingdon Life Sciences study report RHI 011/032437, 2003 (see section 7.5.1 of the IUCLID).

General Population - Hazard via inhalation route

Systemic 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

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:

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

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

General Population - Hazard via oral route

Systemic 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 for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - General Population

Given its oilfield application, no significant exposure of the general population to DV6850, directly or via the environment, is expected.