Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.303 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):
12.5
Modified dose descriptor starting point:
NOAEC
DNEL value:
3.79 mg/m³
Explanation for the modification of the dose descriptor starting point:
No repeat-dose toxicity study by inhalation route is available.
AF for dose response relationship:
1
AF for differences in duration of exposure:
1
AF for interspecies differences (allometric scaling):
1
AF for other interspecies differences:
2.5
AF for intraspecies differences:
5
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
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:
3.33 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Dermal
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
300
Modified dose descriptor starting point:
NOAEL
DNEL value:
1 000 mg/kg bw/day
AF for dose response relationship:
1
AF for differences in duration of exposure:
6
AF for interspecies differences (allometric scaling):
4
AF for other interspecies differences:
2.5
AF for intraspecies differences:
5
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)
Acute/short term exposure
Hazard assessment conclusion:
no DNEL required: short term exposure controlled by conditions for long-term

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - workers

Discussion and details of derivation of several DNEL values (workers)

 

Reference(s):

GIRCSA R.8: Guidance on information requirements and chemical safety assessment, ECHA, Version 2.1, November 2010, Chapter R.8

 

GIRCSA Part E: Guidance on information requirements and chemical safety assessment, Part E: Risk Characterisation, ECHA, Version 2.0, November 2012

 

 

W1) Worker-DNEL long-term for inhalation route - systemic

 

W1a) Repeat-dose toxicity - rat (derivation from chronic data)

 

Dose-descriptor selection:

No repeat-dose toxicity study by inhalation route is available. Potential dose-descriptors are available resulting from a combined chronic toxicity/carcinogenicity study (NOAEL, rat, oral dietary, 24 month).

 

Assessment of mode of action:

The identified endpoint and the observed effects have a threshold mode of action.

 

Dose-descriptor modification:

The dose descriptor was modified according to GIRCSA R.8, R.8.4.2 and Appendix R.8-2 using extrapolation from the oral to the inhalation route (assumed no first-pass effect) and the following defaults: light-work respiratory volume of the worker, 50% oral absorption (ABSoral-rat), 100% inhalation absorption (ABSinh-human), assumed standard respiratory volume (sRV) of a rat for a given exposure period: 0.384 m3/kg bw for 8 h exposure (based on a standard respiratory volume of a rat of 0.8 L/min/kg bw corresponding to 0.2 L/min/rat and a body weight (bw) of a rat of 0.25 kg), assumed standard respiratory volume (sRV) of a human for a given exposure period: 6.72 m3/person for 8 h exposure (based on a standard respiratory volume of a human of 0.2 L/min/kg bw {derived from a standard respiratory volume of a rat of 0.8 L/min/kg bw, using an allometric scaling factor between rat and human of 4} and a body weight of 70 kg), assumed respiratory volume of a worker (wRV) for an 8 h exposure period at light activity: 10 m3/person.

 

NOAECcorr-inh-worker = NOAELoral-rat * (1/sRVrat) * (ABSoral-rat/ABSinh-rat) * (ABSinh-rat/ABSinh-human) * (sRVhuman/wRV) = NOAELoral-rat * (1/sRVrat) * (ABSoral-rat/ ABSinh-human) * (sRVhuman/wRV) = 4.33 mg/kg bw/day * (1/(0.384 m3/kg bw/day)) * (0.5/1) * ((6.72 m3/person)/(10 m3/person)) = 3.79 mg/m3

 

Assessment factors:

The assessment factors were applied as laid out in GIRCSA R.8, R.8.4.3, R.8.4.3.1 and R.8.4.3.3.

AF1 (interspecies differences due to differences in metabolic rate/body weight (allometric scaling)): 1 (inhalation DNEL: differences in the allometry are assumed to be compensated by differences in the respiration rate, thus an allometric scaling factor of 4 (rat/human) has been accounted for (implicitly) in the dose-descriptor modification)

AF2 (interspecies differences due to remaining differences): 2.5 (default)

AF3 (intraspecies differences): 5 (default for worker population)

AF4 (differences in duration of exposure): 1 (dose descriptor from chronic study, thus no extrapolation to chronic exposure needed)

AF5 (issues related to dose-response): 1 (dose descriptor is a NOAEL)

AF6 (quality of whole database): 1 (quality of database is appropriate)

Overall assessment factor: AF = AF1 * AF2 * AF3 * AF4 * AF5 * AF6 = 1*2.5*5*1*1*1 = 12.5

 

DNEL derivation:

DNEL = NOAECcorr-inh-worker / AF = 3.79 mg/m3 / 12.5 = 0.303 mg/m3

 

 

W1b) Repeat-dose toxicity - rat (alternative derivation from sub-chronic data, finally not used)

 

Dose-descriptor selection:

No repeat-dose toxicity study by inhalation route is available. Potential dose-descriptors are also available resulting from a sub-chronic study (rat, oral dietary, 13 week)

 

Assessment of mode of action:

The identified endpoint and the observed effects have a threshold mode of action.

 

Dose-descriptor modification:

The dose descriptor was modified according to GIRCSA R.8, R.8.4.2 and Appendix R.8-2 using extrapolation from the oral to the inhalation route (assumed no first-pass effect) and the following defaults: light-work respiratory volume of the worker, 50% oral absorption (ABSoral-rat), 100% inhalation absorption (ABSinh-human), assumed standard respiratory volume (sRV) of a rat for a given exposure period: 0.384 m3/kg bw for 8 h exposure (based on a standard respiratory volume of a rat of 0.8 L/min/kg bw corresponding to 0.2 L/min/rat and a body weight (bw) of a rat of 0.25 kg), assumed standard respiratory volume (sRV) of a human for a given exposure period: 6.72 m3/person for 8 h exposure (based on a standard respiratory volume of a human of 0.2 L/min/kg bw {derived from a standard respiratory volume of a rat of 0.8 L/min/kg bw, using an allometric scaling factor between rat and human of 4} and a body weight of 70 kg), assumed respiratory volume of a worker (wRV) for an 8 h exposure period at light activity: 10 m3/person.

 

NOAECcorr-inh-worker = NOAELoral-rat * (1/sRVrat) * (ABSoral-rat/ABSinh-rat) * (ABSinh-rat/ABSinh-human) * (sRVhuman/wRV) = NOAELoral-rat * (1/sRVrat) * (ABSoral-rat/ ABSinh-human) * (sRVhuman/wRV) = 9.66 mg/kg bw/day * (1/(0.384 m3/kg bw/day)) * (0.5/1) * ((6.72 m3/person)/(10 m3/person)) = 8.45 mg/m3

 

Assessment factors:

The assessment factors were applied as laid out in GIRCSA R.8, R.8.4.3, R.8.4.3.1 and R.8.4.3.3.

AF1 (interspecies differences due to differences in metabolic rate/body weight (allometric scaling)): 1 (inhalation DNEL: differences in the allometry are assumed to be compensated by differences in the respiration rate, thus an allometric scaling factor of 4 (rat/human) has been accounted for (implicitly) in the dose-descriptor modification)

AF2 (interspecies differences due to remaining differences): 2.5 (default)

AF3 (intraspecies differences): 5 (default for worker population)

AF4 (differences in duration of exposure): 2 (extrapolation from sub-chronic to chronic)

AF5 (issues related to dose-response): 1 (dose descriptor is a NOAEL)

AF6 (quality of whole database): 1 (quality of database is appropriate)

Overall assessment factor: AF = AF1 * AF2 * AF3 * AF4 * AF5 * AF6 = 1*2.5*5*2*1*1 = 25

 

DNEL derivation:

DNEL = NOAECcorr-inh-worker / AF = 8.45 mg/m3 / 25 = 0.338 mg/m3

 

The lower value i.e. 0.303 mg/m3 is selected as long term (systemic) inhalation DNEL for workers.

worker-DNEL long-term for inhalation route-systemic = 0.303 mg/m3

 

 

W2) Worker-DNEL long-term for dermal route - systemic

 

Repeat-dose toxicity - rat

 

Dose-descriptor selection:

Potential dose-descriptors are available resulting from a sub-acute study (rat, dermal, 28 day).

 

Assessment of mode of action:

The identified endpoint and the observed effects have a threshold mode of action.

 

Dose-descriptor modification:

The dose descriptor was modified according to GIRCSA R.8, R.8.4.2 and Appendix R.8-2 using the following defaults: dermal absorption rat (ABSdermal-rat) = dermal absorption human (ABSdermal-human).

NOAELcorr-dermal-human = NOAELdermal-rat * (ABSdermal-rat/ABSdermal-human) = 1000 mg/kg bw/day * (1) = 1000 mg/kg bw/day

 

Assessment factors:

The assessment factors were applied as laid out in GIRCSA R.8, R.8.4.3, R.8.4.3.1 and R.8.4.3.3.

AF1 (interspecies differences due to differences in metabolic rate/body weight (allometric scaling)): 4 (default, between rat and human)

AF2 (interspecies differences due to remaining differences): 2.5 (default)

AF3 (intraspecies differences): 5 (default for worker population)

AF4 (differences in duration of exposure): 6 (extrapolation from sub-acute to chronic)

AF5 (issues related to dose-response): 1 (dose descriptor is a NOAEL)

AF6 (quality of whole database): 1 (quality of database is appropriate)

Overall assessment factor: AF = AF1 * AF2 * AF3 * AF4 * AF5 * AF6 = 4*2.5*5*6*1*1 = 300

 

DNEL derivation:

DNEL = NOAELcorr-dermal-human / AF = 1000 mg/kg bw/day / 300 = 3.33 mg/kg bw/day

worker-DNEL long-term for dermal route-systemic = 3.33 mg/kg bw/day

 

 

W3) Worker - long-term for dermal route - local

 

Identification of relevant endpoints :

Relevant long-term dermal-route data for local effects are available.

 

Available dose-descriptors per endpoint as a result of hazard assessment:

Endpoint

Qualitative dose-descriptor / Local Effect

Associated Effect

Remarks on Study

Skin sensitisation - Dermal

Sensitising

Sensitisation observed

GPMT. All 20 treated guinea pigs showed positive skin reactions to the test material after epicutaneous challenge.

 

Skin Sensitisation

1. Dose-descriptor selection

A single study is available which gives information on skin sensitisation potential. The test substance was found to be sensitising on the basis of an OECD 406 guideline study. The substance was classified based on the clearly positive result.

 

2. Assessment of mode of action

The identified endpoint, and the observed effects, have a threshold mode of action. However, no quantitative dose-response information for this endpoint is available and as such no DNEL can be derived. As a result, a qualitative risk assessment is required.

 

3. Semi-quantitative risk assessment

The intradermal concentration of the test material during induction phase was 0.1% in 20% propylene glycol and 80% physiological saline. Epicutaneous challenge was with 1% substance in Vaseline.

 

On the basis of ECETOC Technical Report No. 87, Contact Sensitisation: Classification According to Potency, April 2003, 2.2.1, Table 3, the test substance could be categorised as a “moderate sensitiser”, using the 1% concentration used in topical administration during induction, and the subsequent 100% elicitation incidence in the challenge.

 

However, the recommendations in GIRCSA R.8, Appendix R.8-10, Table R.8-24, based on the EU Working Group on Skin Sensitisation, suggest that with an induction concentration of 0.1%, and >=60% observed sensitisation, the potency is “extreme”.

 

A qualitative risk assessment approach based on the “extreme sensitiser” potency categorisation is undertaken.The potency categorisation of the test substance, in combination with the Hazard Categories given in GIRCSA Part E, Table E.3-1, results in a “high hazard” categorisation for the purposes of risk assessment. This categorisation is carried forward to Risk Charaterisation.

 

Selection of leading health effect and DNEL

Information relevant to long-term dermal, local effects, is available from one endpoint – skin sensitization. The result of the qualitative assessment of potency “high hazard” is taken forward to Risk Characterisation.

 

 

Reference(s):

GIRCSA R.8: Guidance on information requirements and chemical safety assessment, ECHA, Version 2.1, November 2010, Chapter R.8

 

GIRCSA Part E: Guidance on information requirements and chemical safety assessment, Part E: Risk Characterisation, ECHA, Version 2.0, November 2012

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.075 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
Modified dose descriptor starting point:
NOAEC
DNEL value:
1.88 mg/m³
Explanation for the modification of the dose descriptor starting point:
No repeat-dose toxicity study by inhalation route is available.
AF for dose response relationship:
1
AF for differences in duration of exposure:
1
AF for interspecies differences (allometric scaling):
1
AF for other interspecies differences:
2.5
AF for intraspecies differences:
10
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
Acute/short term exposure
DNEL related information

Local effects

Acute/short term exposure
DNEL related information

General Population - Hazard via dermal 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:
Dermal
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
600
Modified dose descriptor starting point:
NOAEL
DNEL value:
1 000 mg/kg bw/day
AF for dose response relationship:
1
AF for differences in duration of exposure:
6
AF for interspecies differences (allometric scaling):
4
AF for other interspecies differences:
2.5
AF for intraspecies differences:
10
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
Acute/short term exposure
DNEL related information

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.043 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
Modified dose descriptor starting point:
NOAEL
DNEL value:
4.33 mg/kg bw/day
AF for dose response relationship:
1
AF for differences in duration of exposure:
1
AF for interspecies differences (allometric scaling):
4
AF for other interspecies differences:
2.5
AF for intraspecies differences:
10
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
Acute/short term exposure
DNEL related information

General Population - Hazard for the eyes

Additional information - General Population

Discussion and details of derivation of several DNEL values (General Population)

 

According to GIRCSA R.8, R.8.1.2.3: "DNELs may have to be derived for workers and the general population. The general population includes consumers, and humans exposed via the environment, with the DNEL usually being identical for consumers and human via the environment."

The substance is, during its whole life-cycle, used only by workers/professionals, thus never by consumers. The assessment of indirect exposure of humans via the environment is not considered to be required for this substance (based on tonnage band and classification, see GIRCSA R.16, R.16.6.8.3).

As a consequence the derivation of DNELs for the general population is not required. Nevertheless some DNELs have been derived.

 

Reference(s):

GIRCSA R.8: Guidance on information requirements and chemical safety assessment, ECHA, Version 2.1, November 2010, Chapter R.8

 

GIRCSA R.16: Guidance on information requirements and chemical safety assessment, ECHA,Version: 2.1, October 2012, Chapter R.16

 

 

GP1) General Population-DNEL long-term for inhalation route - systemic

 

Repeat-dose toxicity - rat (derivation from chronic data)

 

Dose-descriptor selection:

No repeat-dose toxicity study by inhalation route is available. Potential dose-descriptors are available resulting from a combined chronic toxicity/carcinogenicity study (NOAEL, rat, oral dietary, 24 month).

 

Assessment of mode of action:

The identified endpoint and the observed effects have a threshold mode of action.

 

Dose-descriptor modification:

The dose descriptor was modified according to GIRCSA R.8, R.8.4.2 and Appendix R.8-2 using extrapolation from the oral to the inhalation route (assumed no first-pass effect) and the following defaults: light-work respiratory volume of the worker, 50% oral absorption (ABSoral-rat), 100% inhalation absorption (ABSinh-human), assumed standard respiratory volume (sRV) of a rat for a given exposure period: 1.152 m3/kg bw for 24 h exposure (based on a standard respiratory volume of a rat of 0.8 L/min/kg bw corresponding to 0.2 L/min/rat and a body weight (bw) of a rat of 0.25 kg), assumed standard respiratory volume (sRV) of a human for a given exposure period: 20.16 m3/person for 24 h exposure (based on a standard respiratory volume of a human of 0.2 L/min/kg bw {derived from a standard respiratory volume of a rat of 0.8 L/min/kg bw, using an allometric scaling factor between rat and human of 4} and a body weight of 70 kg).

 

NOAECcorr-inh-worker = NOAELoral-rat * (1/sRVrat) * (ABSoral-rat/ABSinh-rat) * (ABSinh-rat/ABSinh-human) = NOAELoral-rat * (1/sRVrat) * (ABSoral-rat/ ABSinh-human) = 4.33 mg/kg bw/day * (1/(1.152 m3/kg bw/day)) * (0.5/1) = 1.88 mg/m3

 

Assessment factors:

The assessment factors were applied as laid out in GIRCSA R.8, R.8.4.3, R.8.4.3.1 and R.8.4.3.3.

AF1 (interspecies differences due to differences in metabolic rate/body weight (allometric scaling)): 1 (inhalation DNEL: differences in the allometry are assumed to be compensated by differences in the respiration rate, thus an allometric scaling factor of 4 (rat/human) has been accounted for (implicitly) in the dose-descriptor modification)

AF2 (interspecies differences due to remaining differences): 2.5 (default)

AF3 (intraspecies differences): 10 (default for general population)

AF4 (differences in duration of exposure): 1 (dose descriptor from chronic study, thus no extrapolation to chronic exposure needed)

AF5 (issues related to dose-response): 1 (dose descriptor is a NOAEL)

AF6 (quality of whole database): 1 (quality of database is appropriate)

Overall assessment factor: AF = AF1 * AF2 * AF3 * AF4 * AF5 * AF6 = 1*2.5*10*1*1*1 = 25

 

DNEL derivation:

DNEL = NOAECcorr-inh-worker / AF = 1.88 mg/m3 / 25 = 0.075 mg/m3

Gneral Population-DNEL long-term for inhalation route-systemic = 0.075 mg/m3

 

 

GP2) General Population-DNEL long-term for dermal route - systemic

 

Repeat-dose toxicity - rat

 

Dose-descriptor selection:

Potential dose-descriptors are available resulting from a sub-acute study (rat, dermal, 28 day).

 

Assessment of mode of action:

The identified endpoint and the observed effects have a threshold mode of action.

 

Dose-descriptor modification:

The dose descriptor was modified according to GIRCSA R.8, R.8.4.2 and Appendix R.8-2 using the following defaults: dermal absorption rat (ABSdermal-rat) = dermal absorption human (ABSdermal-human).

NOAELcorr-dermal-human = NOAELdermal-rat * (ABSdermal-rat/ABSdermal-human) = 1000 mg/kg bw/day * (1) = 1000 mg/kg bw/day

 

Assessment factors:

The assessment factors were applied as laid out in GIRCSA R.8, R.8.4.3, R.8.4.3.1 and R.8.4.3.3.

AF1 (interspecies differences due to differences in metabolic rate/body weight (allometric scaling)): 4 (default, between rat and human)

AF2 (interspecies differences due to remaining differences): 2.5 (default)

AF3 (intraspecies differences): 10 (default for general population)

AF4 (differences in duration of exposure): 6 (extrapolation from sub-acute to chronic)

AF5 (issues related to dose-response): 1 (dose descriptor is a NOAEL)

AF6 (quality of whole database): 1 (quality of database is appropriate)

Overall assessment factor: AF = AF1 * AF2 * AF3 * AF4 * AF5 * AF6 = 4*2.5*10*6*1*1 = 600

 

DNEL derivation:

DNEL = NOAELcorr-dermal-human / AF = 1000 mg/kg bw/day / 600 = 1.67 mg/kg bw/day

General Population-DNEL long-term for dermal route-systemic = 1.67 mg/kg bw/day

 

 

GP3) General Population-DNEL long-term for oral route - systemic

 

Repeat-dose toxicity - rat

 

Dose-descriptor selection:

Potential dose-descriptors are available resulting from a combined chronic toxicity/carcinogenicity study (NOAEL, rat, oral dietary, 24 month).

 

Assessment of mode of action:

The identified endpoint and the observed effects have a threshold mode of action.

 

Dose-descriptor modification:

The dose descriptor was modified according to GIRCSA R.8, R.8.4.2 and Appendix R.8-2 using the following defaults: oral absorption rat (ABSoral-rat) = oral absorption human (ABSoral-human).

NOAELcorr-oral-human = NOAELoral-rat * (ABSoral-rat/ABSoral-human) = 4.33 mg/kg bw/day * (1) = 4.33 mg/kg bw/day

 

Assessment factors:

The assessment factors were applied as laid out in GIRCSA R.8, R.8.4.3, R.8.4.3.1 and R.8.4.3.3.

AF1 (interspecies differences due to differences in metabolic rate/body weight (allometric scaling)): 4 (default, between rat and human)

AF2 (interspecies differences due to remaining differences): 2.5 (default)

AF3 (intraspecies differences): 10 (default for general population)

AF4 (differences in duration of exposure): 1 (dose descriptor from chronic study, thus no extrapolation to chronic exposure needed)

AF5 (issues related to dose-response): 1 (dose descriptor is a NOAEL)

AF6 (quality of whole database): 1 (quality of database is appropriate)

Overall assessment factor: AF = AF1 * AF2 * AF3 * AF4 * AF5 * AF6 = 4*2.5*10*1*1*1 = 100

 

DNEL derivation:

DNEL = NOAELcorr-oral-human / AF = 4.33 mg/kg bw/day / 100 = 0.0433 mg/kg bw/day

General Population-DNEL long-term for oral route-systemic = 0.0433 mg/kg bw/day

 

 

Reference(s):

GIRCSA R.8: Guidance on information requirements and chemical safety assessment, ECHA, Version 2.1, November 2010, Chapter R.8

 

GIRCSA R.16: Guidance on information requirements and chemical safety assessment, ECHA,Version: 2.1, October 2012, Chapter R.16