Registration Dossier

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

14.69 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

60

Dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

881.6 mg/m³

Explanation for the modification of the dose descriptor starting point:

For the systemic effects related to the main routes of exposure (dermal and inhalation) the NOAEL oral = 1000 mg/kg/day has been used.

CORRECTING FACTORS

a) Bioavailability

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

b) A route to route correcting factors and ABS factors

It is deemed necessary to correct the NOAEL oral in order to extrapolate the oral NOAEL to the NOAEC dermal and NOAEC inhalation ones.

Oral to Inhalation

Absorption: we know from toxico-kinetics evaluation that the substance is adsorbed after oral administration leading to some effects at higher dosage. Nevertheless the rate of this absorption is not known. In order to make a conservative evaluation of the extrapolation from oral rat to human inhalation route (end route), we assume that a limited absorption occurred during oral administration (starting route) as the worst case.Therefore a default ABS factor of 2 is included in the calculation of the corrected NOAEC inhalation.

AF for dose response relationship:

1

Justification:

No higher assessment factor for the dose relationship is considered necessary. The OECD 422 combined study has been performed with a good dose spacing (3-5 fold). Effect, even if mild, where distributed correctly within the doses, no exceptional cases of serious effects were observed. The study was performed in GLP with good number of animals and following strictly OECD study plan.

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 and the substance is not consider to bioaccumulate in the organism.

AF for interspecies differences (allometric scaling):

4

Justification:

4 is the allometric factor for animals used in testing (rats)

AF for other interspecies differences:

1

AF for intraspecies differences:

5

Justification:

This standard value is considered sufficient to cover the worker subpopulation 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.

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

29.39 mg/m³

Most sensitive endpoint:

acute toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

60

DNEL extrapolated from long term DNEL

Dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

881.6 mg/m³

Explanation for the modification of the dose descriptor starting point:

Acute studies did not reported clinical or morphological effects (gross pathology and histopathology); the single study was limited to limit test without effects at 2000 mg/kg. Therefore the use of LD50 values, based only on the mortality rate, with this poor set of effects can be very limited and is not deemed robust enough to set an appropriate DNELacute. It is known that using only mortality as a starting point for derivation of an appropriate DNEL ignores the possibility of sub-lethal toxicity at lower doses. For this reason it was decided to use the NOAEL oral available from OECD 422 study. No time scaling correction was introduced as correcting factors as described in the Appendix R.8.8 of Guidance for information requirements and chemical safety assessment; this assessment is considered conservative and time scaling correction not appropriate.

It’s known that DNEL acute can, by default, be set at 1-5 times the DNEL long-term in order to be more closer to reality of possible peak exposures (short exposure of 15 minutes) in particular for inhalation and dermal exposures (see Appendix R.8.8 of Guidance for information requirements and chemical safety assessment). For this reasons in order to stay on a more realistic side, it was decided to multiply the DNEL long term-systemic for a factor of 2. A factor of 2 is considered to guarantee a conservative evaluation of short exposures by these routes.

AF for dose response relationship:

1

Justification:

No higher assessment factor for the dose relationship is considered necessary. The OECD 422 combined study has been performed with a good dose spacing (3-5 fold). Effect, even if mild, where distributed correctly within the doses, no exceptional cases of serious effects were observed. The study was performed in GLP with good number of animals and following strictly OECD study plan.

AF for interspecies differences (allometric scaling):

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 and the substance is not consider to bioaccumulate in the organism.

AF for other interspecies differences:

4

Justification:

4 is the allometric factor for animals used in testing (rats)

AF for intraspecies differences:

1

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.

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

skin irritation/corrosion

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

skin irritation/corrosion

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

16.67 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

60

Dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

For the systemic effects related to the main routes of exposure (dermal and inhalation) the NOAEL oral = 1000 mg/kg/day has been used.

CORRECTING FACTORS

a) Bioavailability

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

b) A route to route correcting factors and ABS factors

It is deemed necessary to correct the NOAEL oral in order to extrapolate the oral NOAEL to the NOAEC dermal and NOAEC inhalation ones.

No default absorption value is apply when extrapolating oral to dermal route as, in general, dermal absorption is not higher than the oral one. The final NOAEL dermal is therefore equal to the NOAEL oral.

AF for dose response relationship:

1

Justification:

No higher assessment factor for the dose relationship is considered necessary. The OECD 422 combined study has been performed with a good dose spacing (3-5 fold). Effect, even if mild, where distributed correctly within the doses, no exceptional cases of serious effects were observed. The study was performed in GLP with good number of animals and following strictly OECD study plan.

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 and the substance is not consider to bioaccumulate in the organism.

AF for interspecies differences (allometric scaling):

4

Justification:

4 is the allometric factor for animals used in testing (rats)

AF for other interspecies differences:

1

AF for intraspecies differences:

5

Justification:

This standard value is considered sufficient to cover the worker subpopulation 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.

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

33.33 mg/kg bw/day

Most sensitive endpoint:

acute toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

60

DNEL extrapolated from long term DNEL

Dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Acute studies did not reported clinical or morphological effects (gross pathology and histopathology); the single study was limited to limit test without effects at 2000 mg/kg. Therefore the use of LD50 values, based only on the mortality rate, with this poor set of effects can be very limited and is not deemed robust enough to set an appropriate DNELacute. It is known that using only mortality as a starting point for derivation of an appropriate DNEL ignores the possibility of sub-lethal toxicity at lower doses. For this reason it was decided to use the NOAEL oral available from OECD 422 study. No time scaling correction was introduced as correcting factors as described in the Appendix R.8.8 of Guidance for information requirements and chemical safety assessment; this assessment is considered conservative and time scaling correction not appropriate.

It’s known that DNEL acute can, by default, be set at 1-5 times the DNEL long-term in order to be more closer to reality of possible peak exposures (short exposure of 15 minutes) in particular for inhalation and dermal exposures (see Appendix R.8.8 of Guidance for information requirements and chemical safety assessment). For this reasons in order to stay on a more realistic side, it was decided to multiply the DNEL long term-systemic for a factor of 2. A factor of 2 is considered to guarantee a conservative evaluation of short exposures by these routes.

AF for dose response relationship:

1

Justification:

No higher assessment factor for the dose relationship is considered necessary. The OECD 422 combined study has been performed with a good dose spacing (3-5 fold). Effect, even if mild, where distributed correctly within the doses, no exceptional cases of serious effects were observed. The study was performed in GLP with good number of animals and following strictly OECD study plan.

AF for interspecies differences (allometric scaling):

4

Justification:

4 is the allometric factor for animals used in testing (rats)

AF for other interspecies differences:

1

AF for intraspecies differences:

5

Justification:

This standard value is considered sufficient to cover the worker subpopulation 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.

Hazard assessment conclusion:

high hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

Hazard assessment conclusion:

high hazard (no threshold derived)

Hazard assessment conclusion:

no hazard identified

All the DNELs values were derived starting from the OECD 422 combined repro study in rodent where a NOAEL (1000 mg(kg/day) was determined by oral administration of the substance at fixed doses of 300, 600 and 1000 mg/kg/day. This reference NOAEL was selected as the lowest one. Inhalation and dermal systemic DNELs were calculated adopting a route to route extrapolation assessment considering differences in the absorption rate by oral rat and inhalation humans.

DNELacute where also calculated in order to evaluate possible peak exposures (short exposure of 15 minutes) in particular for inhalation and dermal effects where. A factor of 2 was applied to the NOAELoral and deemed enough conservative.

Qualitative assessment was not deemed necessary for irritation/corrosivity, sensitisation (respiratory) and mutagenicity as for all this safety end-point the substance did not show any effects and hence was not classified. Carcinogenicity data were not available as no study or assessment were carried out. As discussed in paragraph 5.8.3, the substance is not expected to act as a carcinogen.

For skin sensitisation a qualitative approach were followed leading to evaluate the potency categorisation of the substance. All values are reported using appropriate units.

Among the DNEL values reported in table 17, we think that the most sensitive endpoints to be evaluated and applied for workers exposure during mixing processes is the inhalation exposure that can be consequence of a low but constant exposure to the chemical during operations even if the inhalation exposure is unlikely to occur on the basis of the physico-chemical characteristics of the substance and the handling during its manufacturing and use.

Hazard assessment conclusion: