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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
DNEL related information
Overall assessment factor (AF):
12.5
Modified dose descriptor starting point:
NOAEC
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
Acute/short term exposure
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
DNEL related information
Overall assessment factor (AF):
75
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
Most sensitive endpoint:
sensitisation (skin)

Workers - Hazard for the eyes

Additional information - workers

Long-term – inhalation, systemic

Repeat-dose Toxicity - rat

Dose-descriptor selection

Potential dose-descriptors are available resulting from a chronic study (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 by the following defaults as laid out in Guidance on Information Requirements and Chemical Safety Assessment, December 2010, R.8.4.2 and Appendix R.8-2: extrapolation from the oral-to-inhalation route, light-work respiratory volume in the worker, 50% oral absorption, 100% inhalation absorption, assumed no first-pass effect.

NOAELcorr (worker) = NOAEL*(1/rat respiratory volume)*(human/worker respiratory volume)*(Oral absorption/Inhalation absorption)

NOAELcorr (worker) = 4.33 mg/kg*(1/0.38 m3/kg)*(6.7 m3/10 m3)*(1/2) = 3.8 mg/m3

Assessment factors

The default assessment factors were applied as laid out in Guidance on Information Requirements and Chemical Safety Assessment, December 2010, R.8.4.3.3. Allometric scaling has been accounted for (implicitly) in the dose-descriptor modification.

 

Assessment factor = (Interspecies) * (Intraspecies) * (Exposure Duration) * (Dose-response) * (Quality of whole database)

Assessment factor (worker) = 2.5 * 5 * 1* 1 * 1 = 12.5

DNEL derivation

DNEL = NOAELcorr / Assessment factor

DNEL = 3.8 mg/m3/ 12.5 = 0.303 mg/m3

 

Repeat-dose Toxicity - rat

Dose-descriptor selection

Potential dose-descriptors are also available resulting from a subchronic 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 by the following defaults as laid out in Guidance on Information Requirements and Chemical Safety Assessment, December 2010, R.8.4.2 and Appendix R.8-2: extrapolation from the oral-to-inhalation route, light-work respiratory volume in the worker, 50% oral absorption, 100% inhalation absorption, assumed no first-pass effect.

NOAELcorr (worker) = NOAEL*(1/rat respiratory volume)*(human/worker respiratory volume)*(Oral absorption/Inhalation absorption)

NOAELcorr (worker) = 9.66 mg/kg*(1/0.38m3/kg)*(6.7m3/10m3)*(1/2) = 8.5 mg/m3

Assessment factors

The default assessment factors were applied as laid out in Guidance on Information Requirements and Chemical Safety Assessment, December 2010, R.8.4.3.3. Allometric scaling has been accounted for (implicitly) in the dose-descriptor modification.

 

Assessment factor = (Interspecies) * (Intraspecies) * (Exposure Duration) * (Dose-response) * (Quality of whole database)

Assessment factor (worker) = 2.5 * 5 * 2* 1 * 1 = 25

DNEL derivation

DNEL = NOAELcorr / Assessment factor

DNEL = 8.5 mg/m3/ 25 = 0.339 mg/m3

 

The lower value i.e. 0.303 mg/m3is selected as long term (systemic) inhalation DNEL for workers.

 

 

Long-term – dermal, systemic

Repeat-dose Toxicity - rat

Dose-descriptor selection

Potential dose-descriptors are also available resulting from a subacute 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 by the following defaults as laid out in Guidance on Information Requirements and Chemical Safety Assessment, December 2010, R.8.4.2 and Appendix R.8-2: dermal absorption rat = dermal absorption human, allometric scaling (AS) = 4 (rat).

NOAELcorr = NOAEL*(1/AS)*(Dermal absorption rat/Dermal absorption human)

NOAELcorr (worker) = 1000 mg/kg/day*(1/4)*(1) = 250 mg/kg/day

Assessment factors

The default assessment factors were applied as laid out in Guidance on Information Requirements and Chemical Safety Assessment, December 2010, R.8.4.3.3. Allometric scaling has been accounted for (explicitly) in the dose-descriptor modification.

 

Assessment factor = (Interspecies) * (Intraspecies) * (Exposure Duration) * (Dose-response) * (Quality of whole database)

Assessment factor (worker) = 2.5 * 5 * 6* 1 * 1 = 75

(remark: the assessment factor including allometric scaling is 300)

DNEL derivation

DNEL = NOAELcorr / Assessment factor

DNEL = 250 mg/kg/day / 75 = 3.33 mg/kg/day

 

 

Long-term – dermal, 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

Associated Effect

Remarks on Study

Local Effect

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 the ECHA Guidance, Chapter R.8,December 2010, 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 the Guidance, Part E: Risk Characterisation, May 2008, 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.

General Population - Hazard via inhalation route

Systemic effects

Acute/short term exposure
DNEL related information

Local effects

Acute/short term exposure
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Acute/short term exposure
DNEL related information

General Population - Hazard via oral route

Systemic effects

Acute/short term exposure
DNEL related information

General Population - Hazard for the eyes

Additional information - General Population

According to Guidance on Information Requirements and Chemical Safety Assessment, December 2010, 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 Guidance on Information Requirements and Chemical Safety Assessment, May 2010, R.16.6.8.3).

As a consequence the derivation of DNELs for the general population is not required.