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Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.78 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):

112.5

Dose descriptor starting point:

LOAEL

Value:

100 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

88 mg/m³

Explanation for the modification of the dose descriptor starting point:

LOAEL (oral) = 100 mg/kg/day has been considered conservative enough to cover also the reproductive (fertility and developmental) end-point; as NOAEL for reproduction was estimated at 300 mg/kg/day.

In the study, considered for this evaluation (OECD 422 combined study), some effects were seen at 100 mg/kg/day only for general toxicity, while reproductive effects were seen well above this level (3 fold); the NOAEL for effects on reproduction was set at 300 mg/kg/day.

No information on bioavailability to oral administration of the substance to animals and humans are available; therefore it is assumed that the same bioavailability occurs in the two species (1 is applied).

The substance is adsorbed after oral administration leading to some effects at higher dosage. Nevertheless the rate of this absorption is not known. For a conservative evaluation, a limited absorption is assumed to occur during oral administration (starting route). Therefore a default ABS factor of 2 is included in the calculation of the corrected NOAEC inhalation.

AF for dose response relationship:

3

Justification:

When the starting point for the DNEL calculation is a LOAEL, it is suggested to use an assessment factor between 3 to obtain the most suitable and realistic NAEL(No Adverse Effect Level).
This assessment factor should take into account the dose spacing, the shape and the slope of the dose response curve, the extent and severity of the effects seen at the LOAEL.
In the study considered for this evaluation (OECD 422 combined study), some effects were seen at 100 mg/kg/day only for general toxicity, while reproductive effects were seen well above this level (3 fold); the NOAEL for effects on reproduction was set at 300 mg/kg/day.
Regarding the dose response relationship, all effects seen at 100 mg/kg/day (LOAEL) are less important in severity (overall “minimal” and not all treatment related effects seen at the higher doses (MD and HD) are present at the Low Dose).
The Low Dose (LD) = 100 mg/kg/day was spaced three fold from the Median Dose (MD) = 300 mg/kg/day; this means that the slope of the dose response curve is well pronounced.
An assessment factor equal to 3 has been considered.

AF for differences in duration of exposure:

3

Justification:

The value selected is referred to the OECD 422 combined study, which can be considered as sub-acute study in terms of treatment period. A higher factor is not deemed necessary as no indication of increase of severe toxicity is available.

AF for interspecies differences (allometric scaling):

1

Justification:

Allometric scaling is not appropriate for inhalation route; this is already implicitly done in the calculation of corrected inhalatory NOAEC

AF for other interspecies differences:

2.5

Justification:

Default assessment factor for other interspecies differences.

AF for intraspecies differences:

5

Justification:

This standard value is considered sufficient to cover the worker sub-population as it is not composed by very young, very old or very ill persons.

AF for the quality of the whole database:

1

Justification:

The testing programme was considered good in relation to the registration level, reliability of data is very good (GLP and quality certification of the testing laboratories). All studies and data/results were consistent for hazard assessment and classification/labelling purposes.

AF for remaining uncertainties:

1

Justification:

There are no remaining uncertainties.

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Most sensitive endpoint:

acute toxicity

Route of original study:

Oral

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.22 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):

450

Dose descriptor starting point:

LOAEL

Value:

100 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

100 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

LOAEL (oral) = 100 mg/kg/day has been considered conservative enough to cover also the reproductive (fertility and developmental) end-point; as NOAEL for reproduction was estimated at 300 mg/kg/day.

In the study, considered for this evaluation (OECD 422 combined study), some effects were seen at 100 mg/kg/day only for general toxicity, while reproductive effects were seen well above this level (3 fold); the NOAEL for effects on reproduction was set at 300 mg/kg/day.

No information on bioavailability to oral administration of the substance to animals and humans are available; therefore it is assumed that the same bioavailability occurs in the two species (1 is applied).

No default absorption value is applied when extrapolating oral to dermal route as, in general, dermal absorption is not higher than the oral one.

AF for dose response relationship:

3

Justification:

When the starting point for the DNEL calculation is a LOAEL, it is suggested to use an assessment factor between 3 to obtain the most suitable and realistic NAEL(No Adverse Effect Level).
This assessment factor should take into account the dose spacing, the shape and the slope of the dose response curve, the extent and severity of the effects seen at the LOAEL.
In the study considered for this evaluation (OECD 422 combined study), some effects were seen at 100 mg/kg/day only for general toxicity, while reproductive effects were seen well above this level (3 fold); the NOAEL for effects on reproduction was set at 300 mg/kg/day.
Regarding the dose response relationship, all effects seen at 100 mg/kg/day (LOAEL) are less important in severity (overall “minimal” and not all treatment related effects seen at the higher doses (MD and HD) are present at the Low Dose).
The Low Dose (LD) = 100 mg/kg/day was spaced three fold from the Median Dose (MD) = 300 mg/kg/day; this means that the slope of the dose response curve is well pronounced.
An assessment factor equal to 3 has been considered.

AF for differences in duration of exposure:

3

Justification:

The value selected is referred to the OECD 422 combined study, which can be considered as sub-acute study in terms of treatment period. A higher factor is not deemed necessary as no indication of increase of severe toxicity is available.

AF for interspecies differences (allometric scaling):

4

Justification:

Allometric scaling factor for rats as compared to humans.

AF for other interspecies differences:

2.5

Justification:

Default assessment factor for other interspecies differences.

AF for intraspecies differences:

5

Justification:

This standard value is considered sufficient to cover the worker sub-population as it is not composed by very young, very old or very ill persons.

AF for the quality of the whole database:

1

Justification:

The testing programme was considered good in relation to the registration level, reliability of data is very good (GLP and quality certification of the testing laboratories). All studies and data/results were consistent for hazard assessment and classification/labelling purposes.

AF for remaining uncertainties:

1

Justification:

There are no remaining uncertainties.

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Most sensitive endpoint:

acute toxicity

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:

high hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

low hazard (no threshold derived)

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

Explanation for the modification of the dose descriptor starting point:

The substance is intended only to industrial use. No general population exposure is foreseen (see CSR Section 9).

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected