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Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1 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):
17.5
Modified dose descriptor starting point:
NOAEC
DNEL value:
17.5 mg/m³
Explanation for the modification of the dose descriptor starting point:
In the absence of a repeated dose toxicity study via the inhalation it is deemed appropriate to use a reliable chronic oral repeated dose toxicity study conducted with dogs.
AF for dose response relationship:
1
Justification:
The starting point for the derivation is a chronic NOAEL
AF for differences in duration of exposure:
1
Justification:
The starting point for the derivation is a chronic NOAEL
AF for interspecies differences (allometric scaling):
1.4
Justification:
This is the assessment factor for allometric scaling from dog to human as given in ECHA guidance R.8, Table R.8-3
AF for other interspecies differences:
2.5
Justification:
This is the additional assessment factor for remaining uncertainties due to other interspecies differences
AF for intraspecies differences:
5
Justification:
This is the standard assessment factor for intraspecies differences for workers
AF for the quality of the whole database:
1
Justification:
No additional assessment factor is applied since the quality of the whole database is considered high
AF for remaining uncertainties:
1
Justification:
No additional assessment factor is applied since the quality of the whole database is considered high
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:
2.8 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):
360
Modified dose descriptor starting point:
NOAEL
DNEL value:
1 010 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
A sub-acute dermal repeated dose toxicity study is available and no route-to-route extrapolation is applied.
AF for dose response relationship:
1
Justification:
The starting point for the derivation is a sub-acute NOAEL
AF for differences in duration of exposure:
6
Justification:
This is the standard factor for extrapolation from sub-acute to chronic effects
AF for interspecies differences (allometric scaling):
2.4
Justification:
This is the assessment factor for allometric scaling from rabbit to human as given in ECHA guidance R.8, Table R.8-3
AF for other interspecies differences:
2.5
Justification:
This is the additional assessment factor for remaining uncertainties due to other interspecies differences
AF for intraspecies differences:
5
Justification:
This is the standard assessment factor for intraspecies differences for workers
AF for the quality of the whole database:
2
Justification:
No additional assessment factor is applied since the quality of the whole database is considered limited
AF for remaining uncertainties:
1
Justification:
No additional assessment factor is applied since the quality of the whole database is considered high
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

Long-term – dermal, systemic

Identification of relevant endpoints

Relevant long-term dermal data are only available for the endpoint repeat-dose toxicity. In addition, relevant long-term oral data are available for the endpoints repeat-dose and reproduction toxicity.

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

Endpoint

Quantitative dose descriptor, system effects

Associated effects

Remarks on study

Repeat-dose toxicity

Oral

NOAEL: 5 mg/kg bw/day

Reduced body weight gain; minor disturbance of blood clinical pathology parameters; increases in liver and kidney weights with pigment deposition in the kidney at higher doses

Dog, oral gavage, 52 weeks

Oral

NOEL: 3.3 mg/kg bw/day

Reduced body weight gain and food consumption; slightly increase liver weights

Rat, oral dietary, 52 weeks

Derm.

NOEL: 1010 mg/kg bw/day

No relevant toxicological effects observed

Rabbit, dermal-occlusive, 21 days

Inhal.

No data

 

 

Reproduction toxicity

Oral

NOEL: 4 mg/kg bw/day

No adverse effects on fertility; reduced body weights and food consumption at higher doses

Rat, oral dietary, fertility

Derm.

No data

 

 

Inh.

No data

 

 

 

Repeat-dose Toxicity - rabbit

Dose-descriptor selection

Potential dose-descriptors are available resulting from a 21 day repeat dose dermal study in rabbits.

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, R.8, November 2012.

NOELworker=NOELrabbit*AllometricScaling=1010*1/2.4=421mg/kg

Assessment factors

The default assessment factors were applied as laid out in Guidance on Information Requirements and Chemical Safety Assessment, November 2012, R.8.4.3.3. 

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

AF=inter*intra*duration*DatabaseQuality=2.5*5*6*2=150

DNEL derivation

DNEL = NOAELcorr / Assessment factor

DNEL = 421 mg/kg / 150 = 2.8 mg/kg

Long-term – inhalation, systemic

Identification of relevant endpoints

No relevant long-term inhalation data are available. Relevant long-term oral data are available for the endpoint repeat-dose toxicity and reproduction toxicity.

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

Endpoint

Quantitative dose descriptor, system effects

Associated effects

Remarks on study

Repeat-dose toxicity

Oral

NOAEL: 5 mg/kg bw/day

Reduced body weight gain; minor disturbance of blood clinical pathology parameters; increases in liver and kidney weights with pigment deposition in the kidney at higher doses

Dog, oral gavage, 52 weeks

Oral

NOEL: 3.3 mg/kg bw/day

Reduced body weight gain and food consumption; slightly increase liver weights

Rat, oral dietary, 52 weeks

Derm.

NOEL: 1010 mg/kg bw/day

No relevant toxicological effects observed

Rabbit, dermal-occlusive, 21 days

Inhal.

No data

 

 

Reproduction toxicity

Oral

NOEL: 4 mg/kg bw/day

No adverse effects on fertility; reduced body weights and food consumption at higher doses

Rat, oral dietary, fertility

Derm.

No data

 

 

Inh.

No data

 

 

 

Repeat-dose Toxicity - rat

Dose-descriptor selection

Potential dose-descriptors are available resulting from a chronic study.

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, November 2012, R.8.4.2: 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 = NOAEL*1/rat respiratory volume*human/worker respiratory volume*Oral absorption/Inhalation absorption

NOAELcorr (worker) = 3.3 mg/kg*1/0.38m3/kg*6.7m3/10m3*1/2 = 2.9 mg/m3

Assessment factors

The default assessment factors were applied as laid out in Guidance on Information Requirements and Chemical Safety Assessment, November 2012, R.8.4.3.3. While an additional assessment factor could be applied for use of repeat-dose toxicity data to meet a reproductive toxicity endpoint (Appendix R.8-12), this endpoint only addresses repeat-dose toxicity and as such a further factor is not warrant. Allometric scaling has been accounted for 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 = 2.9 mg/m3/ 12.5 = 0.23 mg/m3

 

Repeat-dose Toxicity - dog

Dose-descriptor selection

Potential dose-descriptors are available resulting from a chronic study.

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, November 2012, R.8.4.2 (and following example R.8-2 workers): 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 = NOAEL*1/allometric scaling*bodyweight/worker respiratory volume*Oral absorption/Inhalation absorption

NOAELcorr (worker) = 5 mg/kg*1/1.4/kg*70kg/10 m3/2 = 12.5 mg/m3

Assessment factors

The default assessment factors were applied as laid out in Guidance on Information Requirements and Chemical Safety Assessment, November 2012, R.8.4.3.3. While an additional assessment factor could be applied for use of repeat-dose toxicity data to meet a reproductive toxicity endpoint (Appendix R.8-12), this endpoint only addresses repeat-dose toxicity and as such a further factor is not warrant. Allometric scaling has been accounted for 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 = 12.5 mg/m3/ 12.5 = 1 mg/m3

 

Looking at the NOAELs not in isolation, there is a 10-fold difference between the NOAEL and the LOAEL in rat chronic study, and the dog NOAEL fits within this range. The toxicity profiles are comparable, and the dog NOAEL was used for the DNEL derivation. As a result, the worker long-term inhalation DNEL for systemic effects is 1 mg/cubic metre based on the dog study.

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 the hazard assessment

Endpoint

Qualitative dose descriptor, systemic effects

Associated effects

Remarks on study

Skin sensitisation

Dermal

Sensitising, “moderate hazard”

Sensitisation observed

Variant on the Buehler test. All 10 treated guinea pigs showed positive skin reactions to the test material after challenge on day 36.

 

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 EPAOPP 81-6 (similar to the occluded Buehler test). 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 application concentration of the test material during induction phase was 0.5 g in 0.5 mL of water, equating to ca. 50wt%. It should be noted the water solubility is 38 mg/L at 25 °C.

On the basis of ECETOC Technical Report No. 87, Contact Sensitisation: Classification According to Potency, April 2003, 2.2.1, Table 5, the test substance could be categorised as a “weak sensitiser”, using the 50wt% concentration used in topical administration during induction, and the subsequent 100% elicitation incidence in the 50wt% challenge.

However, the recommendations in the ECHA Guidance, Chapter R.8, November 2012, Appendix R.8-10, Table R.8-25, based on the EU Working Group on Skin Sensitisation, suggest that with an induction concentration of >20%, and >=60% observed sensitisation, the potency is “moderate” with a high degree of uncertainty.

As a result, a qualitative risk assessment approach based on the “moderate 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, November 2012, Table E.3-1, results in a “moderate hazard” categorisation for the purposes of risk assessment. This categorisation is carried forward to Risk Characterisation.

 

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 “moderate hazard” is taken forward to Risk Characterisation.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
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:
no hazard identified
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:
no hazard identified
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

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, October 2012, R.16.6.8.3). As a consequence the derivation of DNELs for the general population is not required.