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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
23 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):
75
Modified dose descriptor starting point:
NOAEC
Value:
1 730 mg/m³
Explanation for the modification of the dose descriptor starting point:
Correction for absorption is 0.2 as oral absorption is expected to be 5 times respiratory absorption
AF for dose response relationship:
1
Justification:
Default value according to Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health
AF for differences in duration of exposure:
6
Justification:
Default value according to Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health
AF for interspecies differences (allometric scaling):
2.5
Justification:
Default value according to Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health
AF for other interspecies differences:
1
Justification:
Default value according to Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health
AF for intraspecies differences:
5
Justification:
Default value according to Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health
AF for the quality of the whole database:
1
Justification:
key study based on metabolite of the substance, the oral absorption of the metabolite is expected to be much higher than that of the test substanceThis metabolite is present at maximum 50% of the administrated dose
AF for remaining uncertainties:
1
Justification:
Default value according to Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health
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:
3.3 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):
300
Modified dose descriptor starting point:
NOAEL
Value:
980 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
correction for absorption is 0.2 as oral absorption is expected to be 5 times dermal absorption
AF for dose response relationship:
1
Justification:
Default value according to Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health
AF for differences in duration of exposure:
6
Justification:
Default value according to Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health
AF for interspecies differences (allometric scaling):
2.5
Justification:
Default value according to Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health
AF for other interspecies differences:
4
Justification:
Default value according to Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health
AF for intraspecies differences:
5
Justification:
Default value according to Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health
AF for the quality of the whole database:
1
Justification:
key study based on metabolite of the substance, the oral absorption of the metabolite is expected to be much higher than that of the test substanceThis metabolite is present at maximum 50% of the administrated dose
AF for remaining uncertainties:
1
Justification:
Default value according to Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health
Acute/short term exposure
Hazard assessment conclusion:
no DNEL required: short term exposure controlled by conditions for long-term
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
31.6 µg/cm²
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
15
Dose descriptor:
other: EC3
AF for dose response relationship:
3
Justification:
extrapolation fromLOAEL to NOAEL
AF for differences in duration of exposure:
1
Justification:
local effects
AF for interspecies differences (allometric scaling):
1
Justification:
local effects
AF for intraspecies differences:
5
Justification:
extrapolation to worker
AF for the quality of the whole database:
1
Justification:
study based on analogue that is the most likely candidate for absorption
AF for remaining uncertainties:
1
Justification:
no effect of matrix expected
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

Acute toxicity

ECHA Guidance R.8 (Chapter R.8.1.2.5) indicates that DNELs for acute toxicity are not required if no acute toxicity hazard leading to classification has been identified.Resin acids and rosin acids, fumarated, compds. with triethanolamineis not found to be acutely toxic following oral or dermal exposure (LD50 >2000 mg/kg bw) while a low vapour pressure precludes inhalation exposure indicating a low of concern for this route of exposure. No DNELs for acute toxicity are therefore necessary.

 Irritation

Corrosive and irritant effects on the eyes are local, concentration-dependent phenomena. However while test results indicate that resin acids and rosin acids, fumarated, compds. with triethanolamineis irritating to eye (but not to skin), the nature of the data is such that no conclusion can be drawn with regard to any dose-response relationship present. No DNEL for irritation can therefore be derived.

 Sensitisation

The sensitisation potential of the resin acids and rosin acids, fumarated, compds. with triethanolamine was evaluated by use of data from the suspected hydrolysis product rosin, fumarated. As this substances shows positive results in a local lymph node assay, resin acids and rosin acids, fumarated, compds. with triethanolamine is also regarded to have a potential to induce skin sensitisation.

ECHA Guidance R.8, Appendix R.8-10, (ECHA, 2010) states that while skin sensitisation is generally regarded as a threshold effect it may be very difficult to derive a threshold and to set a DNEL. Thus the general approach for sensitisers involves a qualitative approach where a DNEL is used to judge any remaining/residual risks after the implementation of appropriate risk management measures (RMM) and occupational controls (OC). In the risk assessment for resin acids and rosin acids, fumarated, compds. with triethanolamine both approaches will be run in parallel.

The extent of the RMM and OC required is dependent on the intrinsic sensitising potency of the substance.

Based on the EC3 value of 1.9% Rosin, fumarated is regarded to have a strong potential to cause skin sensitisation (ECHA (2010), Appendix R.8 -10).

Derivation of a DNEL for sensitisation

ECHA Guidance R.8, Appendix R.8-10 (ECHA, 2010), indicates that the EC3 concentration from a LLNA test can be taken as a LOAEL for the induction of skin sensitisation (ECHA, 2010) after conversion into an equivalent dose per unit area of skin (ug/cm2). Assuming

(i)              a dose volume of 25 ul (according to the standard LLNA protocol);

(ii)            an estimated treatment area of 1 cm2for the mouse ear; and

(iii)          an assumed density of is 1, the conversion is performed as follows: EC3[%]*250 [ug/cm2/% ] = EC3[ug/cm2]

 The equivalent EC3 [μg/cm2] is therefore: 0.19%*250 = 475 μg/cm2

The EC3 of 475 μg/cm2will be used to assess the magnitude of any remaining/residual risks after the use of RMMs and OCs recommended in the Qualitative Risk Assessment. Assessment Factors will be applied for LOAEL to NOAEL extrapolation and intra species extrapolation (3*5). As the analogue tested in the LLNA test is the most likely component to be absorbed from the substance under evaluation, no additional safety factor is used for the quality of the database. The capacity of the substance to induce skin sensitisation may be enhanced in the LLNA test by the deliberate use of a solvent system that is not present in an occupational or consumer setting. No additional correction factor was applied for this effect in a worst case assumption

Repeated dose toxicity

Inhalation

The NOAEL for oral repeated dose toxicity of analogue and expected hydrolysis product of resin acids and rosin acids, fumarated, compds. with triethanolamine, rosin, fumarated was found to be 221-228 mg/kg bw/d for males and 196-292 mg/kg bw/d for females. A NOAEL of 196 mg/kg bw/d is therefore used for the purposes of DNEL derivation for the inhalation route in a route-to-route exptrapolation

Relevant dose descriptors have been developed for the different endpoints and routes of exposure (see Guidance Document, Chapter R.8, Appendix R.8-2). The values are provided below. For potential inhalation exposures, route-to-route extrapolations from the oral NOAEL value is performed. This extrapolation takes into account the difference in absorption between the oral and inhalation route (50% versus 10% due to hydrolysis of the esterbonds after oral dosing)

To convert oral NOAEL into inhalator in NOAEC, a rat default respiratory volume was used corresponding to the daily duration of human exposure (sRVrat: 0.38 m3/kg bw/8 h).

For workers a correction was added for the difference between respiratory rates under standard conditions (sRVhuman: 6.7 m3for an 8-h exposure period) and under conditions of light activity (wRV: 10 m3for an 8-h exposure period).

The corrected inhalation NOAEC for workers is:

inhalation NOAEC = oral NOAEL * (1/ sRV rat 8h) * (ABS oral / ABS inh) * (sRV human / wRV)

inhalation NOAEC= 196 * (1/0.38) * (100/100) * (6.7 / 10)

inhalation NOAEC = 345.58 mg/m3corrected for absorption 1727.9 mg/m3.

Dermal

The NOAEL for systemic effects after repeated dermal application is based on the study with rosin, fumarated. The NOAEL was found to be 221-228 mg/kg bw/d for males and 196-292 mg/kg bw/d for females. The dermal absorption of esin acids and rosin acids, fumarated, compds. with triethanolamineis however expected to be lower than the oral absorption of the tested substance and therefore a correction factor of 0.2 is applied for route-to-route extrapolation.

Application of Assessment Factors to the Corrected Dose Descriptors

Endpoint-specific DNEL values were derived from the corrected dose descriptors after application of assessment factors (AF). The AFs were based on the procedures described ECHA Guidance R.8

Long-term DNEL Assessment Factors (Inhalation)

Assessment Factor

Worker

Differences in metabolic rate per b. w. (allometric scaling)

2.5

Interspecies remaining differences (toxicodynamic and toxicokinetic)

-

Intraspecies differences

5

Duration extrapolation

(sub-acute/sub-chronic/chronic)

6 (sub-acute)

Issues related to dose-response

1

Quality of whole database

1

Overall AF

75

 

Long-term DNEL Assessment Factors (Dermal)

Assessment Factor

Worker

Differences in metabolic rate per b. w. (allometric scaling)

2.5

Interspecies remaining differences (toxicodynamic and toxicokinetic)

4

Intraspecies differences

5

Duration extrapolation

(sub-acute/sub-chronic/chronic)

2 (subchronic)

Issues related to dose-response

1

Quality of whole database

1

Overall AF

100

 

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:
low hazard (no threshold derived)

Additional information - General Population