Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3.52 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):
25
Dose descriptor starting point:
NOAEL
Value:
50 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
88.1 mg/m³
Explanation for the modification of the dose descriptor starting point:

No long-term inhalation toxicity studies are available for Amides, C12 -18 (even numbered),N-[3 (dimethyl amino)propyl], N'-oxides. However, data from a repeated dose toxicity study by the oral route could be used as a starting point for extrapolation to the inhalation route.

A 90-day oral repeated dose toxicity study was performed in Sprague-Dawley rats (Horne, 2014). The test material was administered by gavage to three groups, each consisting of ten males and ten females, for up to ninety consecutive days, at dose levels of 50, 150 and 500 mg/kg bw/day. A control group of ten males and ten females was dosed with the vehicle alone (distilled water). The NOAEL was considered to be 50 mg/kg/day. A 28 -day oral repeated dose toxicity study is also available (Jones, 2000). In this test, the test material was administered by gavage to three groups, each consisting of five males and five females, for up to twenty-eight consecutive days, at dose levels of 15, 150 and 1000 mg/kg bw/day. A control group of five males and five females was dosed with the vehicle alone (distilled water). The NOEL was considered to be 15 mg/kg/day. Although this repeated dose toxicity study yields the lowest NOEL/NOAEL value, this study is considered to be less sensitive compared to the 90 -day oral repeated dose study as the duration of exposure is shorter and less animals are used per group. In addition, the spacing between doses in the 28 -day study of 10 -fold (compared to 2 -3 fold in the 90 -day study) also increases the uncertainty about the derived NO(A)EL. Therefore, the oral 90 -day NOAEL value is considered more reliable than the 28 -day NOEL value and thus, the oral NOAEL of 50 mg/kg bw/day is used for deriving a DNEL for the inhalation route (systemic effects). There are no experimental data on inhalation or oral absorption.

Following the ECETOC Guidance on Assessment Factors to Derive a DNEL (Technical Report No. 110 of October 2010) a default factor of 1 is applied for route-to-route extrapolation (oral to inhalation). Therefore, the starting point (oral NOAEL = 50 mg/kg bw/day) does not need to be modified but corrected for units (corrected inhalation NOAEC is in mg/m³). For the route-to-route extrapolation from oral to inhalation, the dose descriptor starting point is 88.1 mg/ m³ = (50 mg/kg bw/day x 1/(0.38 m³/kg bw/day) x 6.7 m³/10 m³)

AF for dose response relationship:
1
Justification:
Starting point NOAEL
AF for differences in duration of exposure:
2
Justification:
Sub-chronic (90 days) to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
Covered by calculation for route-to-route extrapolation
AF for other interspecies differences:
2.5
Justification:
Remaining differences
AF for intraspecies differences:
5
Justification:
Default value for workers
AF for the quality of the whole database:
1
Justification:
Default value
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information
DNEL extrapolated from long term DNEL
Explanation for the modification of the dose descriptor starting point:

No reliable acute data is available for the inhalation route of exposure.

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:
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):
100
Dose descriptor starting point:
NOAEL
Value:
50 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
500 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

The NOAEL of 50 mg/kg/day established in the 90 -day oral repeated dose toxicity study was used to derive a DNEL longterm, systemic effects via dermal administration. There are no experimental data on dermal absorption and oral absorption. However, the substance was tested in an acute dermal toxicity study in rats (Sanders, 2000) at 2000 mg/kg, no mortality or systemic effects were reported. At the same dose level, mortality and clinical signs were reported in an acute oral toxicity study in rats (Sanders, 2000) but not at a dose level of 200 mg/kg. This 10 -fold difference is a rough indication of difference in absorption between oral and dermal route. It can therefore be expected that dermal absorption is about 10 -fold lower than oral absorption. After route-to-route extrapolation (oral to dermal) the dose descriptor starting point is 50 mg/kg/day x 10 = 500 mg/kg/day. A correction factor of 10 is applied as bioavailability after oral exposure is assumed to be 100% and the bioavailability after dermal exposure is assumed to be 10%.

AF for dose response relationship:
1
Justification:
Starting point NOAEL
AF for differences in duration of exposure:
2
Justification:
Sub-chronic (90 days) to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
Rat to humans
AF for other interspecies differences:
2.5
Justification:
Remaining differences
AF for intraspecies differences:
5
Justification:
Default value for workers
AF for the quality of the whole database:
1
Justification:
Default value
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information
DNEL extrapolated from long term DNEL

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:
low hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - workers

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.87 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
Dose descriptor starting point:
NOAEL
Value:
50 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
43.48 mg/m³
Explanation for the modification of the dose descriptor starting point:

No long-term inhalation toxicity studies are available for Amides, C12 -18 (even numbered),N-[3 (dimethyl amino)propyl], N'-oxides. However, data from a repeated dose toxicity study by the oral route could be used as a starting point for extrapolation to the inhalation route. A 90 -day oral repeated dose toxicity study was performed in Sprague-Dawley rats (Horne, 2014). The test material was administered by gavage to three groups, each consisting of ten males and ten females, for up to ninety consecutive days, at dose levels of 50, 150 and 500 mg/kg bw/day. A control group of ten males and ten females was dosed with the vehicle alone (distilled water). The NOAEL was considered to be 50 mg/kg/day. A 28 -day oral repeated dose toxicity study is also available (Jones, 2000). In this test, the test material was administered by gavage to three groups, each consisting of five males and five females, for up to twenty-eight consecutive days, at dose levels of 15, 150 and 1000 mg/kg bw/day. A control group of five males and five females was dosed with the vehicle alone (distilled water). The NOEL was considered to be 15 mg/kg/day. Although this repeated dose toxicity study yields the lowest NOEL/NOAEL value, this study is considered to be less sensitive compared to the 90 -day oral repeated dose study as the duration of exposure is shorter and less animals are used per group. In addition, the spacing between doses in the 28 -day study of 10 -fold (compared to 2 -3 fold in the 90 -day study) also increases the uncertainty about the derived NO(A)EL. Therefore, the oral 90 -day NOAEL value is considered more reliable than the 28 -day NOEL value and thus, the oral NOAEL of 50 mg/kg bw/day is used for deriving a DNEL for the inhalation route (systemic effects). There are no experimental data on inhalation or oral absorption. Following the ECETOC Guidance on Assessment Factors to Derive a DNEL (Technical Report No. 110 of October 2010) a default factor of 1 is applied for route-to-route extrapolation (oral to inhalation). Therefore, the starting point (oral NOAEL = 50 mg/kg bw/day) does not need to be modified but corrected for units (corrected inhalation NOAEC is in mg/m³). For the route-to-route extrapolation from oral to inhalation, the dose descriptor starting point is 43.48 mg/m³ = (50 mg/kg bw/day x 1/(1.15 m³/kg bw/day))

AF for dose response relationship:
1
Justification:
Starting point NOAEL
AF for differences in duration of exposure:
2
Justification:
Sub-chronic (90 days) to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
Covered by calculation for route-to-route extrapolation
AF for other interspecies differences:
2.5
Justification:
Remaining differences
AF for intraspecies differences:
10
Justification:
Default value for consumers
AF for the quality of the whole database:
1
Justification:
good quality of the database
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information
DNEL extrapolated from long term DNEL

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
DNEL extrapolated from long term DNEL

General Population - Hazard via dermal 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):
200
Dose descriptor starting point:
NOAEL
Value:
50 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
500 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

The NOAEL of 50 mg/kg/day established in the 90 -day oral repeated dose toxicity study was used to derive a DNEL longterm, systemic effects via dermal administration. There are no experimental data on dermal absorption and oral absorption. However, the substance was tested in an acute dermal toxicity study in rats (Sanders, 2000) at 2000 mg/kg, no mortality or systemic effects were reported. At the same dose level, mortality and clinical signs were reported in an acute oral toxicity study in rats (Sanders, 2000) but not at a dose level of 200 mg/kg. This 10 -fold difference is a rough indication of difference in absorption between oral and dermal route. It can therefore be expected that dermal absorption is about 10 -fold lower than oral absorption. After route-to-route extrapolation (oral to dermal) the dose descriptor starting point is 50 mg/kg/day x 10 = 500 mg/kg/day. A correction factor of 10 is applied as bioavailability after oral exposure is assumed to be 100% and the bioavailability after dermal exposure is assumed to be 10%.

AF for dose response relationship:
1
Justification:
Starting point NOAEL
AF for differences in duration of exposure:
2
Justification:
Sub-chronic (90 days) to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
Rat to humans
AF for other interspecies differences:
2.5
Justification:
Remaining differences
AF for intraspecies differences:
10
Justification:
Default value for consumers
AF for the quality of the whole database:
1
Justification:
Default value
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information
DNEL extrapolated from long term DNEL

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:
low hazard (no threshold derived)

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.25 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
Dose descriptor starting point:
NOAEL
Value:
50 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
50 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

No route-to-route extrapolation required as a 90 -day repeated dose toxicity study via oral gavage is available.

AF for dose response relationship:
1
Justification:
Starting point NOAEL/NOAEC
AF for differences in duration of exposure:
2
Justification:
Sub-chronic (90 days) to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
Rat to humans
AF for other interspecies differences:
2.5
Justification:
Remaining differences
AF for intraspecies differences:
10
Justification:
Default value for consumers
AF for the quality of the whole database:
1
Justification:
Default value
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information
Explanation for the modification of the dose descriptor starting point:

An acute oral toxicity test has been performed in rats (Sanders, 2000). The acute oral LD50 of the test substance was estimated as being in the range of 500 - 1000 mg/kg of pure test substance. Other acute oral toxicity studies are also available. Applying a weight of evidence approach, the LD50 was determined to be 1000 mg/kg bw. Therefore the substance is classified as R22 according to the DSD Regulation and as acute oral toxicant category 4 in accordance with the criteria of the CLP Regulation (EC) 1272/2008. According to the ECHA Guidance ‘Characterisation of dose [concentration] - response for human health’ (Chapter R8), 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 for high peak exposures. As no high peak exposure is anticipated for this substance, no acute DNEL has been derived.

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - General Population