Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
14.8 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):
25
Dose descriptor starting point:
NOAEL
Value:
300 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
370 mg/m³
Explanation for the modification of the dose descriptor starting point:

Default (DNEL calculator)

AF for dose response relationship:
1
Justification:
Default (DNEL calculator)
AF for differences in duration of exposure:
2
Justification:
Default (DNEL calculator)
AF for interspecies differences (allometric scaling):
1
Justification:
Default (DNEL calculator)
AF for other interspecies differences:
2.5
Justification:
Default (DNEL calculator)
AF for intraspecies differences:
5
Justification:
Default (DNEL calculator)
AF for the quality of the whole database:
1
Justification:
Default (DNEL calculator)
AF for remaining uncertainties:
1
Justification:
no remaining uncertainties
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:
105 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:
300 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
10 500 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Default (DNEL calculator)

AF for dose response relationship:
1
Justification:
Default (DNEL calculator)
AF for differences in duration of exposure:
2
Justification:
Default (DNEL calculator)
AF for interspecies differences (allometric scaling):
4
Justification:
Default (DNEL calculator)
AF for other interspecies differences:
2.5
Justification:
Default (DNEL calculator)
AF for intraspecies differences:
5
Justification:
Default (DNEL calculator)
AF for the quality of the whole database:
1
Justification:
Default (DNEL calculator)
AF for remaining uncertainties:
1
Justification:
no remaining uncertainties
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

Selection of the relevant dose descriptor:


90 d NOAEL = 300 mg/kg bw/d (rat, OECD TG 408, oral study)


NOAEL(fertility) = 1000 mg/kg bw/d (rat, OECD TG 433, read across from MDEA-Esterquat C16-18 and C18 unsatd.), no adverse effects observed


NOAEL(development) = 1000 mg/kg bw/d (rat, OECD TG 414, read across from MDEA-Esterquat C16-18 and C18 unsatd.), no adverse effects observed


 


The hazard assessment concluded that long-term repeated exposure to the test substance have the potential to cause mild systemic effects on the urinary bladder such as enhanced desquamation and regressive epithelial changes. These are the only critical systemic substance induced effects identified and the relevance of the findings are somewhat hampered by the concurrent bacterial infection of the test animals. The effects have not been detected in the 28-day study up to the highest tested dose of 1000 mg/kg bw/d. No adverse effects were observed in the EOGRTS and the prenatal developmental toxicity study conducted with the structurally related source substance MDEA-Esterquat C16-18 and C18 unsatd. up to and including the limit dose of 1000 mg/kg bw/d. The relevant dose descriptor has been identified from the 90-day oral study on rats with a NOEL of 300 mg/kg bw/d.


 


 


Modification of the relevant dose descriptors to the correct starting point: 


Oral absorption


By default, 50% oral absorption is assumed in accordance with Guidance on Information Requirements and Chemical Safety Assessment, R8.


 


Dermal absorption


No studies have been undertaken by the dermal route to characterize the dose-response relationship for systemic effects therefore it will be necessary to obtain a long-term dermal DNEL by route-to-route extrapolation. Experimental data show an oral absorption of about 40 % for MTEA-I, the iodide form of the metabolite of a TEA-based Esterquat and somewhat higher absorption rates of 41% for males and 63% for female rats for DEEDMAC (HERA RAR 2009). As a realistic worst case a 50% oral absorption is assumed for TEA based Esterquats. A cut-off of 50% GI absorption is also recommended in the TGD R7c to reflect the intrinsic variability in the analysis of absorption studies. Thus, this cut-off level obviates the need to make comparatively small adjustments in the toxicity value that would otherwise impart on the process a level of accuracy that is not supported by the scientific literature (TGD on information requirements R7c). In the worst case (under occlusive conditions) only up to 2% absorption occurred for similar substances after dermal application (data taken from HERA RAR 2009).


 


Inhalation absorption


For chemical safety assessment an inhalation absorption rate of 100% is assumed as a worst case default value in accordance with Guidance on Information Requirements and Chemical Safety Assessment, R8.


 


DERIVATION OF DNELs


DNELs derived from the subchronic repeated dose toxicity NOAEL (OECD TG 408)


 


Worker-DNEL long-term for inhalation route (systemic): 14.8 mg/m³


Start value: 300 mg/kg bw/d


Route of original study: oral


Dose descriptor starting point after route-to-route extrapolation: 370 mg/m³


 


For workers the corrected inhalation NOEC is calculated according to the following equation:


corrected inhalation NOAEC = oral NOAEL x 1/sRVrat x ABSoral-rat/ ABSinh-human x sRVhuman/ wRV x correction for exposure conditions (7 d / 5 d)


                                             = 300 x 1/0.38 x 50/100 x 6.7/10 x 1.4


The corrected inhalation NOAECworker (8h) is therefore:


                                             = 370.3 mg/m³ (8h-TWA)


 


Overall AF: 1*2*1*2.5*5*1*1 = 25


 


 


Worker-DNEL long-term for dermal route (systemic):  105 mg/kg bw/d


Start value: 300 mg/kg bw/d


Route of original study: oral


Dose descriptor starting point after route-to-route extrapolation: 10500 mg/kg bw/d


 


corrected dermal NOAEL         = oral NOAEL x correction for exposure conditions (7 d / 5 d) x ABSoral/ ABSdermal


                                                 = 300 x 1.4 x 50/2


                                                  = 10500 mg/kg bw/d


 


Overall AF: 1*2*4*2.5*5*1*1 = 100

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.61 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:
300 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
131 mg/m³
Explanation for the modification of the dose descriptor starting point:

Default (DNEL calculator)

AF for dose response relationship:
1
Justification:
Default (DNEL calculator)
AF for differences in duration of exposure:
2
Justification:
Default (DNEL calculator)
AF for interspecies differences (allometric scaling):
1
Justification:
Default (DNEL calculator)
AF for other interspecies differences:
2.5
Justification:
Default (DNEL calculator)
AF for intraspecies differences:
10
Justification:
Default (DNEL calculator)
AF for the quality of the whole database:
1
Justification:
Default (DNEL calculator)
AF for remaining uncertainties:
1
Justification:
no remaining uncertainties
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

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
37.5 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:
300 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
7 500 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Default (DNEL calculator)

AF for dose response relationship:
1
Justification:
Default (DNEL calculator)
AF for differences in duration of exposure:
2
Justification:
Default (DNEL calculator)
AF for interspecies differences (allometric scaling):
4
Justification:
Default (DNEL calculator)
AF for other interspecies differences:
2.5
Justification:
Default (DNEL calculator)
AF for intraspecies differences:
10
Justification:
Default (DNEL calculator)
AF for the quality of the whole database:
1
Justification:
Default (DNEL calculator)
AF for remaining uncertainties:
1
Justification:
no remaining uncertainties
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:
1.5 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:
300 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
300 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Default (DNEL calculator)

AF for dose response relationship:
1
Justification:
Default (DNEL calculator)
AF for differences in duration of exposure:
2
Justification:
Default (DNEL calculator)
AF for interspecies differences (allometric scaling):
4
Justification:
Default (DNEL calculator)
AF for other interspecies differences:
2.5
Justification:
Default (DNEL calculator)
AF for intraspecies differences:
10
Justification:
Default (DNEL calculator)
AF for the quality of the whole database:
1
Justification:
Default (DNEL calculator)
AF for remaining uncertainties:
1
Justification:
no remaining uncertainties
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

Selection of the relevant dose descriptor:


90 d NOAEL = 300 mg/kg bw/d (rat, OECD TG 408, oral study)


NOAEL(fertility) = 1000 mg/kg bw/d (rat, OECD TG 433, read across from MDEA-Esterquat C16-18 and C18 unsatd.), no adverse effects observed


NOAEL(development) = 1000 mg/kg bw/d (rat, OECD TG 414, read across from MDEA-Esterquat C16-18 and C18 unsatd.), no adverse effects observed


 


The hazard assessment concluded that long-term repeated exposure to the test substance have the potential to cause mild systemic effects on the urinary bladder such as enhanced desquamation and regressive epithelial changes. These are the only critical systemic substance induced effects identified and the relevance of the findings are somewhat hampered by the concurrent bacterial infection of the test animals. The effects have not been detected in the 28-day study up to the highest tested dose of 1000 mg/kg bw/d. No adverse effects were observed in the EOGRTS and the prenatal developmental toxicity study conducted with the structurally related source substance MDEA-Esterquat C16-18 and C18 unsatd. up to and including the limit dose of 1000 mg/kg bw/d. The relevant dose descriptor has been identified from the 90-day oral study on rats with a NOEL of 300 mg/kg bw/d.


 


 


Modification of the relevant dose descriptors to the correct starting point: 


Oral absorption


By default, 50% oral absorption is assumed in accordance with Guidance on Information Requirements and Chemical Safety Assessment, R8.


 


Dermal absorption


No studies have been undertaken by the dermal route to characterize the dose-response relationship for systemic effects therefore it will be necessary to obtain a long-term dermal DNEL by route-to-route extrapolation. Experimental data show an oral absorption of about 40 % for MTEA-I, the iodide form of the metabolite of a TEA-based Esterquat and somewhat higher absorption rates of 41% for males and 63% for female rats for DEEDMAC (HERA RAR 2009). As a realistic worst case a 50% oral absorption is assumed for TEA based Esterquats. A cut-off of 50% GI absorption is also recommended in the TGD R7c to reflect the intrinsic variability in the analysis of absorption studies. Thus, this cut-off level obviates the need to make comparatively small adjustments in the toxicity value that would otherwise impart on the process a level of accuracy that is not supported by the scientific literature (TGD on information requirements R7c). In the worst case (under occlusive conditions) only up to 2% absorption occurred for similar substances after dermal application (data taken from HERA RAR 2009).


 


Inhalation absorption


For chemical safety assessment an inhalation absorption rate of 100% is assumed as a worst case default value in accordance with Guidance on Information Requirements and Chemical Safety Assessment, R8.


 


 


DERIVATION OF DNELs


DNELs derived from the subchronic repeated dose toxicity NOAEL (OECD TG 408)


 


General population-DNEL long-term for inhalation route (systemic): 2.61 mg/m³


Start value: 300 mg/kg bw/d


Route of original study: oral


Dose descriptor starting point after route-to-route extrapolation: 131 mg/m³


 


For general population the corrected inhalation NOEC is calculated according to the following equation:


corrected inhalation NOAEC  = oral NOAEL x 1/sRVrat x ABSoral-rat/ ABSinh-human


                                             = 300 x 1/1.15 x 50/100


 


The corrected inhalation NOAECgeneral population (24 h) is therefore:


                                             = 131 mg/m³ (24 h)


Overall AF: 1*2*1*2.5*10*1*1 = 50


 


 


general population-DNEL long-term for dermal route (systemic):  37.5 mg/kg bw/d


Start value: 300 mg/kg bw/d


Route of original study: oral


Dose descriptor starting point after route-to-route extrapolation: 7500 mg/kg bw/d


Overall AF: 1*2*4*2.5*10*1*1 = 200


 


general population-DNEL long-term for oral route (systemic):  1.5 mg/kg bw/d


Start value: 300 mg/kg bw/d


Route of original study: oral


Overall AF: 1*2*4*2.5*10*1*1 = 200