Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.954 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
10
Modified dose descriptor starting point:
LOAEC
DNEL value:
9.54 mg/m³
Explanation for the modification of the dose descriptor starting point:
APPENDIX R. 8-2 Bioavailability, route-to-route extrapolation and allometric scaling of Chapter R.8: Characterisation of dose [concentration]-response for human health provides for modification of the dose descriptor in calculating DNEL for repeat dose inhalation toxicity.
AF for dose response relationship:
1
Justification:
Chapter R.8: Characterisation of dose [concentration]-response for human health
AF for differences in duration of exposure:
2
Justification:
sub-chronic to chronic
AF for interspecies differences (allometric scaling):
5
Justification:
intraspecies – workers
Justification:
None
AF for intraspecies differences:
0.5
Justification:
For workers (in case of 8 hour exposure / day) Corrected LOAEL (inhalation) = LOAEL (inhalation rat) / AS * srv / Hrv x test time / default working hours. Where: LOAEL: 19 mg/m3 (from 90-day inhalation toxicity study); Srv = 6.7 mg/m3 Hrv = Human respiration rate = 10 m3 / person x 6/8 hours = 19 * 6.7/10 *6/8= 9.54 mg/m3.
AF for the quality of the whole database:
1
Justification:
Chapter R.8: Characterisation of dose [concentration]-response for human health
Justification:
it is considered that there is sufficient safety factors built into the extrapolations utilised to justify omission of this “uncertain” assessment factor
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
896 mg/m³
Most sensitive endpoint:
acute toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
5
Modified dose descriptor starting point:
NOAEC
DNEL value:
4 480 mg/m³
Explanation for the modification of the dose descriptor starting point:
NOAEC: derived from LD50 Inhalation Toxicity with appropriate allometric scaling applied. LD50 Inhalation Toxicity = 2.56 mg/l (4 hours) = 2560 mg/m3. APPENDIX R. 8-8 Acute toxicity of Chapter R.8: Characterisation of dose [concentration]-response for human health states in Figure R. 8-5 Decision tree for setting an acute inhalation toxicity DNEL provides for modification of the dose descriptor in calculating DNEL for acute inhalation toxicity. Given a 4-hour exposure is available, it is considered appropriate to scale this value to provide a 4-hour DNEL; the principle that any brief exposure would be below this DNEL
AF for dose response relationship:
1
Justification:
Chapter R.8: Characterisation of dose [concentration]-response for human health
AF for interspecies differences (allometric scaling):
5
Justification:
Chapter R.8: Characterisation of dose [concentration]-response for human health
Justification:
None
AF for intraspecies differences:
1.8
Justification:
Allometric scaling factor: 4; BW(human) = 70 kg, Hrv = Human respiration rate = 10 m3 / person. = 2560 / 4 * 70/10 = 4480 mg/m
AF for the quality of the whole database:
1
Justification:
Chapter R.8: Characterisation of dose [concentration]-response for human health
Justification:
it is considered that there is sufficient safety factors built into the extrapolations utilised to justify omission of this “uncertain” assessment factor

Local effects

Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
8.26 mg/m³
Most sensitive endpoint:
acute toxicity
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
5
Dose descriptor starting point:
LOAEC
AF for dose response relationship:
1
Justification:
Chapter R.8: Characterisation of dose [concentration]-response for human health
AF for interspecies differences (allometric scaling):
1.8
Justification:
Allometric scaling factor: 4; BW(human) = 70 kg, Hrv = Human respiration rate = 10 m3 / person. = 23.6 / 4 * 70/10 = 41.3 mg/m3
Justification:
None
AF for intraspecies differences:
5
Justification:
Chapter R.8: Characterisation of dose [concentration]-response for human health
AF for the quality of the whole database:
1
Justification:
Chapter R.8: Characterisation of dose [concentration]-response for human health
Justification:
it is considered that there is sufficient safety factors built into the extrapolations utilised to justify omission of this “uncertain” assessment factor

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.19 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
40
Modified dose descriptor starting point:
LOAEL
DNEL value:
7.6 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
APPENDIX R. 8-2 Bioavailability, route-to-route extrapolation and allometric scaling of Chapter R.8: Characterisation of dose [concentration]-response for human health Example B. 4 Oral# exposure; inhalatory N(L)OAEC rat provides for modification of the dose descriptor in calculating DNEL for repeat dose dermal toxicity (where # denotes similar situation with dermal exposure) Corrected LOAEL (dermal) = inhalatory LOAEC x srv - rat x ABSinh-rat / ABSderm-human Where srv-rat = 0.2 l/min No values exist for ABS. As as a worst case assume ABS inh-rat rat = 100%/ ABSderm-human 50%])
AF for dose response relationship:
1
Justification:
Chapter R.8: Characterisation of dose [concentration]-response for human health
AF for differences in duration of exposure:
2
Justification:
Chapter R.8: Characterisation of dose [concentration]-response for human health; subchronic to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
Chapter R.8: Characterisation of dose [concentration]-response for human health
AF for other interspecies differences:
0.4
Justification:
Corrected LOAEL (dermal) = inhalatory LOAEC x srv - rat x ABSinh-rat / ABSderm-human Where srv-rat = 0.2 l/min No values exist for ABS. As as a worst case assume ABS inh-rat rat = 100%/ ABSderm-human 50%]) Therefore, corrected LOAEL (dermal) = 19 x 0.2 x (100/50) = 7.6 mg/kg/day
Justification:
None
AF for the quality of the whole database:
1
Justification:
Chapter R.8: Characterisation of dose [concentration]-response for human health
Justification:
it is considered that there is sufficient safety factors built into the extrapolations utilised to justify omission of this “uncertain” assessment factor
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
127.5 mg/kg bw/day
Most sensitive endpoint:
acute toxicity
Route of original study:
Dermal
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
20
Modified dose descriptor starting point:
NOAEL
DNEL value:
2 550 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
APPENDIX R. 8-8 Acute toxicity of Chapter R.8: Characterisation of dose [concentration]-response for human health states that although, peak exposures in theory may also occur for the dermal and oral routes, these are not normally assessed, so the establishment of acute toxicity DNELs for dermal and oral peak exposures appears superfluous. However, on a case-by-case basis an ‘acute’ dermal or oral DNEL can be set for comparison with single exposure events. No detailed guidance is given for setting oral or dermal acute toxicity DNELs, but the principles are the same as those described below for setting inhalation acute toxicity DNELs. In the case of the substance effects where seen at above the limit dose used for classification within the EU. However, as the substance is classified as GHS Acute Class 5 for dermal, it is considered appropriate to assess the substance for DNEL. Part B: Hazard Assessment, Section B 6.2 Human health endpoints states that when a limit test has been conducted, and no adverse effects on health have been observed, then the limit dose can be regarded as the dose descriptor in setting the DNEL. In the absence of other information is considered appropriate in this case to utilise the LD50 Dermal toxicity as the DNEL and apply a suitable scaling factor as follows:
AF for dose response relationship:
1
Justification:
Chapter R.8: Characterisation of dose [concentration]-response for human health
AF for interspecies differences (allometric scaling):
4
Justification:
Chapter R.8: Characterisation of dose [concentration]-response for human health
Justification:
None
AF for intraspecies differences:
5
Justification:
Chapter R.8: Characterisation of dose [concentration]-response for human health
AF for the quality of the whole database:
1
Justification:
Chapter R.8: Characterisation of dose [concentration]-response for human health
Justification:
it is considered that there is sufficient safety factors built into the extrapolations utilised to justify omission of this “uncertain” assessment factor

Local effects

Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
high hazard (no threshold derived)

Additional information - workers

Taking account of the data from the carcinogenicity studies into consideration, the biological significance of three neoplasms observed in the respiratory tract in male rats could not be assessed due to the lack of historical control data in this strain. The number of tumors in mice is limited, but the rarity of the neoplasms seen in this species and the presence of preneoplastic lesions at the site of the tumors suggests carcinogenic potential. While there is some uncertainty about the mechanism of tumor induction, it is likely that the genotoxic and irritant properties of this substance may play a role in tumourgenesis.

 

A NOAEL is proposed for carcinogenicity; however, there is insufficient data listed in the report to allow for calculation of DMEL utilisingdose-descriptors T25 and BMD10. Therefore it is proposed that risk characterisation can proceed using a DNEL based on the assumption of a threshold mechanism. The lowest threshold mechanism provided is that for a 90-day inhalation study with a givenLOAEC of 19 mg/m³ (sub chronic; rat) – this value is lower than the NOAEL value proposed from the carcinogenicity study. This data is utilised for the purposes of hazard assessment, with suitable extrapolations.

 

The “remaining differences” assessment factor is not applied, as it is considered that there is sufficient safety factors built into the extrapolations utilised to justify omission of this “uncertain” assessment factor.


General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.477 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
20
Modified dose descriptor starting point:
NOAEC
DNEL value:
9.54 mg/m³
Explanation for the modification of the dose descriptor starting point:
APPENDIX R. 8-2 Bioavailability, route-to-route extrapolation and allometric scaling of Chapter R.8: Characterisation of dose [concentration]-response for human health provides for modification of the dose descriptor in calculating DNEL for repeat dose inhalation toxicity.
AF for dose response relationship:
1
Justification:
Chapter R.8: Characterisation of dose [concentration]-response for human health
AF for differences in duration of exposure:
2
Justification:
sub-chronic to chronic
AF for interspecies differences (allometric scaling):
0.5
Justification:
For the general public (in case of 8 hour exposure / day) Corrected LOAEL (inhalation) = LOAEL (inhalation rat) / AS * srv / Hrv x test time / default working hours. This is considered appropriate, as the substance is not available to the general public. Where: LOAEL: 19 mg/m3 (from 90-day inhalation toxicity study); Srv = 6.7 mg/m3 Hrv = Human respiration rate = 10 m3 / person x 6/8 hours = 19 * 6.7/10 *6/8= 9.54 mg/m3.
Justification:
None
AF for intraspecies differences:
10
Justification:
Intraspecies - general population.
AF for the quality of the whole database:
1
Justification:
Chapter R.8: Characterisation of dose [concentration]-response for human health
Justification:
it is considered that there is sufficient safety factors built into the extrapolations utilised to justify omission of this “uncertain” assessment factor
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
448 mg/m³
Most sensitive endpoint:
acute toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
10
Modified dose descriptor starting point:
NOAEC
DNEL value:
4 480 mg/m³
Explanation for the modification of the dose descriptor starting point:
APPENDIX R. 8-8 Acute toxicity of Chapter R.8: Characterisation of dose [concentration]-response for human health states in Figure R. 8-5 Decision tree for setting an acute inhalation toxicity DNEL provides for modification of the dose descriptor in calculating DNEL for acute inhalation toxicity. Given a 4-hour exposure is available, it is considered appropriate to scale this value to provide a 4-hour DNEL; the principle that any brief exposure would be below this DNEL. The following factors are applied: Allometric scaling factor: 4; BW(human) = 70 kg, Hrv = Human respiration rate = 10 m3 / person. = 2560 / 4 * 70/10 = 4480 mg/m3. AF = 10 [10 (intraspecies – general population) x 1 (dose-response) x 1 (quality of data base)].
AF for dose response relationship:
1
Justification:
Chapter R.8: Characterisation of dose [concentration]-response for human health
Justification:
None - addresssed in AF for interspecies differences
AF for other interspecies differences:
1.8
Justification:
Allometric scaling factor: 4; BW(human) = 70 kg, Hrv = Human respiration rate = 10 m3 / person. = 2560 / 4 * 70/10 = 4480 mg/m
AF for intraspecies differences:
10
Justification:
intraspecies – general population
AF for the quality of the whole database:
1
Justification:
Chapter R.8: Characterisation of dose [concentration]-response for human health
Justification:
It is considered that there is sufficient safety factors built into the extrapolations utilised to justify omission of this “uncertain” assessment factor

Local effects

Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4.13 mg/m³
Most sensitive endpoint:
acute toxicity
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
10
Dose descriptor starting point:
NOAEC
AF for dose response relationship:
1
Justification:
Chapter R.8: Characterisation of dose [concentration]-response for human health
Justification:
None - addresssed in AF for interspecies differences
AF for other interspecies differences:
1.8
Justification:
Allometric scaling factor: 4; BW(human) = 70 kg, Hrv = Human respiration rate = 10 m3 / person. = 23.6 / 4 * 70/10 = 41.3 mg/m3.
AF for intraspecies differences:
10
Justification:
intraspecies – general population
AF for the quality of the whole database:
1
Justification:
Chapter R.8: Characterisation of dose [concentration]-response for human health
Justification:
It is considered that there is sufficient safety factors built into the extrapolations utilised to justify omission of this “uncertain” assessment factor

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.095 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
80
Modified dose descriptor starting point:
NOAEL
DNEL value:
7.6 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
APPENDIX R. 8-2 Bioavailability, route-to-route extrapolation and allometric scaling of Chapter R.8: Characterisation of dose [concentration]-response for human health Example B. 4 Oral# exposure; inhalatory N(L)OAEC rat provides for modification of the dose descriptor in calculating DNEL for repeat dose dermal toxicity (where # denotes similar situation with dermal exposure) Corrected LOAEL (dermal) = inhalatory LOAEC x srv - rat x ABSinh-rat / ABSderm-human Where srv-rat = 0.2 l/min No values exist for ABS. As as a worst case assume ABS inh-rat rat = 100%/ ABSderm-human 50%]) Therefore, corrected LOAEL (dermal) = 19 x 0.2 x (100/50) = 7.6 mg/kg/day
AF for dose response relationship:
1
Justification:
Chapter R.8: Characterisation of dose [concentration]-response for human health
AF for differences in duration of exposure:
2
Justification:
subchronic to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
Chapter R.8: Characterisation of dose [concentration]-response for human health
AF for other interspecies differences:
1.8
Justification:
Corrected LOAEL (dermal) = inhalatory LOAEC x srv - rat x ABSinh-rat / ABSderm-human
AF for intraspecies differences:
10
Justification:
intraspecies – general population
AF for the quality of the whole database:
1
Justification:
Chapter R.8: Characterisation of dose [concentration]-response for human health
Justification:
It is considered that there is sufficient safety factors built into the extrapolations utilised to justify omission of this “uncertain” assessment factor
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
63.75 mg/kg bw/day
Most sensitive endpoint:
acute toxicity
Route of original study:
Dermal
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
40
Modified dose descriptor starting point:
NOAEL
DNEL value:
2 550 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
APPENDIX R. 8-8 Acute toxicity of Chapter R.8: Characterisation of dose [concentration]-response for human health states that although, peak exposures in theory may also occur for the dermal and oral routes, these are not normally assessed, so the establishment of acute toxicity DNELs for dermal and oral peak exposures appears superfluous. However, on a case-by-case basis an ‘acute’ dermal or oral DNEL can be set for comparison with single exposure events. No detailed guidance is given for setting oral or dermal acute toxicity DNELs, but the principles are the same as those described below for setting inhalation acute toxicity DNELs. In the case of the substance effects where seen at above the limit dose used for classification within the EU. However, as the substance is classified as GHS Acute Class 5 for dermal, it is considered appropriate to assess the substance for DNEL.
AF for dose response relationship:
1
Justification:
Chapter R.8: Characterisation of dose [concentration]-response for human health
AF for interspecies differences (allometric scaling):
4
Justification:
Chapter R.8: Characterisation of dose [concentration]-response for human health
Justification:
None
AF for intraspecies differences:
10
Justification:
intraspecies – general population
AF for the quality of the whole database:
1
Justification:
Chapter R.8: Characterisation of dose [concentration]-response for human health
Justification:
It is considered that there is sufficient safety factors built into the extrapolations utilised to justify omission of this “uncertain” assessment factor

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.095 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
80
Modified dose descriptor starting point:
NOAEL
DNEL value:
7.6 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
APPENDIX R. 8-2 Bioavailability, route-to-route extrapolation and allometric scaling of Chapter R.8: Characterisation of dose [concentration]-response for human health Example B. 4 Oral exposure; inhalatory N(L)OAEC rat provides for modification of the dose descriptor in calculating DNEL for repeat dose oral toxicity. Corrected LOAEL (oral) = inhalatory LOAEC x srv - rat x ABSinh-rat / ABSoral-human Where srv-rat = 0.2 l/min No values exist for ABS. As as a worst case assume ABS inh-rat rat = 100%/ ABSoral-human 50%]) Therefore, corrected LOAEL (dermal) = 19 x 0.2 x (100/50) = 7.6 mg/kg/day
AF for dose response relationship:
1
Justification:
Chapter R.8: Characterisation of dose [concentration]-response for human health
AF for differences in duration of exposure:
2
Justification:
subchronic to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
Chapter R.8: Characterisation of dose [concentration]-response for human health
AF for other interspecies differences:
0.4
Justification:
See above justification
AF for intraspecies differences:
10
Justification:
intraspecies – general population
AF for the quality of the whole database:
1
Justification:
Chapter R.8: Characterisation of dose [concentration]-response for human health
Justification:
It is considered that there is sufficient safety factors built into the extrapolations utilised to justify omission of this “uncertain” assessment factor
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.285 mg/kg bw/day
Most sensitive endpoint:
acute toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
80
Modified dose descriptor starting point:
NOAEL
DNEL value:
22.8 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
APPENDIX R. 8-8 Acute toxicity of Chapter R.8: Characterisation of dose [concentration]-response for human health states that dependant on the steepness of the dose-response curve for the repeated dose effects, the DNEL for acute toxicity could be set for a reference period of 15 minutes at 1-5 times the value (default 3) of the long-term DNEL. The steeper the dose-response relationship, the smaller the multiplying factor. This approach can be used to derive an indicative acute toxicity DNEL for substances NOAEL:7.6 mg/kg bw/day (see long term oral – systemic below for calculations) Default assessment factor: 3 Corrected NOAEL (oral, acute) = 22.8 mg/kg bw/day
AF for dose response relationship:
1
Justification:
Chapter R.8: Characterisation of dose [concentration]-response for human health
AF for interspecies differences (allometric scaling):
4
Justification:
Chapter R.8: Characterisation of dose [concentration]-response for human health
AF for other interspecies differences:
0.3
Justification:
NOAEL:7.6 mg/kg bw/day (see long term oral – systemic below for calculations) Default assessment factor: 3 Corrected NOAEL (oral, acute) = 22.8 mg/kg bw/day
AF for intraspecies differences:
10
Justification:
intraspecies – general population
AF for the quality of the whole database:
1
Justification:
Chapter R.8: Characterisation of dose [concentration]-response for human health
Justification:
It is considered that there is sufficient safety factors built into the extrapolations utilised to justify omission of this “uncertain” assessment factor

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
high hazard (no threshold derived)

Additional information - General Population

It should be noted that the substance will not be available to the general population in its given form; hence this section is essentially redundant. It is included here for completeness purposes.