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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:

17.63 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):

50

Modified dose descriptor starting point:

NOAEC

Value:

881.58 mg/m³

Explanation for the modification of the dose descriptor starting point:

NOAECcorr = NOAELoral*(1/0.38 m³/kg bw/day)*(ABSoral-rat/ABSinh-human)*(6.7 m³ (8h)/10 m³ (8h)) = 1000 mg/kg bw/day*(1/0.38 m³/kg bw/day)*(0.5/1)*0.67 = 881.58 mg/m³. In the absence of absorption data an oral absorption rate of 50% for the rat and 100% absorption by inhalation for humans was anticipated in a worst case approach according to ECHA "Guidance on information requirements and chemical safetys assessment Chapter R.8: Characterisation of dose [concentration]-response for human health", so the default value was used for calculation (default 0.5/1). ABSoral-rat=oral absorption rate in rats, ABSinh-human=inhalation absorption rate in humans.

AF for dose response relationship:

1

AF for differences in duration of exposure:

2

Justification:

DNEL is based on an oral subschronic (90-day) study.

AF for interspecies differences (allometric scaling):

1

Justification:

AF for allometric scaling already included in ECHA starting point derivation method; no further factor required.

AF for other interspecies differences:

2.5

AF for intraspecies differences:

5

Justification:

For workers.

AF for the quality of the whole database:

1

AF for remaining uncertainties:

2

Justification:

NOAEC derived from structurally related substance (read-across).

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

Most sensitive endpoint:

acute toxicity

Route of original study:

Oral

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

repeated dose toxicity

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

5 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):

200

Modified dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Dermal NOAEL=NOAELoral*( ABSoral-rat/ABSdermal-human) = 1000 mg/kg bw/day*(1/1) = 1000 mg/kg bw/day. ABSoral-rat=oral absorption rate in rats, ABSdermal-human=dermal absorption rate in humans.

AF for dose response relationship:

1

AF for differences in duration of exposure:

2

Justification:

DNEL is based on an oral subchronic (90-day) toxicity study.

AF for interspecies differences (allometric scaling):

4

Justification:

DNEL is based on a study in rat.

AF for other interspecies differences:

2.5

AF for intraspecies differences:

5

Justification:

For workers.

AF for the quality of the whole database:

1

AF for remaining uncertainties:

2

Justification:

NOAEL derived from structurally-related substance (read-across).

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

Route of original study:

Dermal

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

repeated dose toxicity

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - workers

Inhalation:

The long-term systemic inhalation DNEL has been derived from an oral NOAEL of 1000 mg/kg bw/day, derived from a subchronic (90-day) study with a structurally-related substance in rats. After route to route extrapolation by correction for the differences in the respiratory volumes of rats and humans over the relevant assessment period (8 h), correction for the differences in the respiratory volumes of humans in rest and during light activity a NOAECcorr of 881.58 mg/m³ has been used as dose descriptor starting point. Since respiratory rates depend directly on caloric demand no additional allometric scaling for metabolic differences between rats and humans is required anymore, and only an assessment factor of 2.5 has been included to account for remaining uncertainties between species. An additional assessment factor of 5 has been included to account for intraspecies differences among workers, and the read-across has been taken into account by inclusion of a further assessment factor of 2. In conclusion, a DNEL of 17.63 mg/m³ has been determined.

No acute systemic inhalatory DNEL has been derived as there were no relevant clinical effects observed at the limit dose of the test material in an acute oral toxicity study, and due to substance characteristics a higher absorption via the inhalation route than via the oral route is not to be expected.

No local DNELs for the inhalation route have been derived as no hazard has been identified in the repeated dose toxicity study via the oral route with a structurally-related substance, in the acute oral toxicity study with the test substance and in the acute dermal toxicity study with the test substance. Furthermore, the test substance does not show any irritating effects.

Dermal:

The long-term systemic dermal DNEL has also been derived from the oral NOAEL of 1000 mg/kg bw/day, derived from the subchronic (90-day) study with the structurally-related substance in rats. Route to route extrapolation has been done assuming equal rates for the oral absorption of the rat and the dermal absorption of humans. In a worst case approach the oral absorption rate of the rat is not assumed to be higher than the dermal absorption rate of humans, and although a lower absorption via the human skin is anticipated, an assessment factor of 1 has been used (assuming equal absorption) in the absence of appropriate data. Hence, as dose descriptor starting point for DNEL derivation a NOAELcorr of 1000 mg/kg bw/day has been used, followed by allometric scaling for interspecies differences between rats and humans, inclusion of an additional factor of 2.5 for other interspecies differences, an assessment factor of 5 to account for intraspecies differences among the workers and an additional assessment factor of 2 to account for the use of data from a structurally-related substance (read-across). In conclusion, a DNEL of 5 mg/kg bw/day has been derived.

No acute systemic dermal DNEL has been derived as there were no clinical effects observed in an acute dermal toxicity study.

No local DNELs for the dermal route have been derived as no hazard has been identified in the acute dermal toxicity study, and the substance is not irritating to the skin.

Eyes: The neat substance does not cause irritation to the eyes.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

4.35 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):

100

Modified dose descriptor starting point:

NOAEC

Value:

434.78 mg/m³

Explanation for the modification of the dose descriptor starting point:

NOAECcorr = NOAELoral*(1/1.15 m³/kg bw/day)*(ABSoral-rat/ABSinh-human) = 1000 mg/kg bw/day*(1/1.15 m³/kg bw/day)*(0.5/1) = 434.78 mg/m³. In the absence of absorption data an oral absorption rate of 50% for the rat and 100% absorption by inhalation for humans was anticipated in a worst case approach according to ECHA "Guidance on information requirements and chemical safetys assessment Chapter R.8: Characterisation of dose [concentration]-response for human health", so the default value was used for calculation (default 0.5/1). ABSoral-rat=oral absorption rate in rats, ABSinh-human=inhalation absorption rate in humans.

AF for dose response relationship:

1

AF for differences in duration of exposure:

2

Justification:

DNEL is based on an oral subchronic (90-day) toxicity study.

AF for interspecies differences (allometric scaling):

1

Justification:

AF for allometric scaling already included in ECHA starting point derivation method; no further factor required.

AF for other interspecies differences:

2.5

AF for intraspecies differences:

10

Justification:

For the General Population.

AF for the quality of the whole database:

1

AF for remaining uncertainties:

2

Justification:

NOAEC derived from structurally-related substance (read-across).

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

Most sensitive endpoint:

acute toxicity

Route of original study:

Oral

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

repeated dose toxicity

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.5 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):

400

Modified dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Dermal NOAEL=NOAELoral*( ABSoral-rat/ABSdermal-human) = 1000 mg/kg bw/day*(1/1) = 1000 mg/kg bw/day. ABSoral-rat=oral absorption rate in rats, ABSdermal-human=dermal absorption rate in humans.

AF for dose response relationship:

1

AF for differences in duration of exposure:

2

Justification:

DNEL is based on an oral subchronic (90-day) toxicity study.

AF for interspecies differences (allometric scaling):

4

Justification:

DNEL is based on a study in rat.

AF for other interspecies differences:

2.5

AF for intraspecies differences:

10

Justification:

For the General Population.

AF for the quality of the whole database:

1

AF for remaining uncertainties:

2

Justification:

NOAEL derived from structurally-related substance (read-across).

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

Route of original study:

Dermal

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

repeated dose toxicity

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

skin irritation/corrosion

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

5 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):

400

Modified dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No route to route extrapolation required, subchronic study was done via the oral route.

AF for dose response relationship:

1

AF for differences in duration of exposure:

2

Justification:

DNEL is based on an oral subchronic (90-day) toxicity study.

AF for interspecies differences (allometric scaling):

4

Justification:

DNEL is based on a study in rat.

AF for other interspecies differences:

2.5

AF for intraspecies differences:

10

Justification:

For the General Population.

AF for the quality of the whole database:

1

AF for remaining uncertainties:

2

Justification:

NOAEL derived from structurally-related substance (read-across).

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

Route of original study:

Oral

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - General Population

Inhalation:

The long-term systemic inhalation DNEL has been derived from an oral NOAEL of 1000 mg/kg bw/day, derived from a subchronic (90-day) study with a structurally-related substance in rats. After route to route extrapolation by correction for the differences in the respiratory volumes of rats and humans over the relevant exposure period for the general public (24 h), a NOAECcorr of 434.78 mg/m³ has been used as dose descriptor starting point. Since respiratory rates depend directly on caloric demand, no additional allometric scaling for metabolic differences between rats and humans is required anymore, and only an assessment factor of 2.5 has been included to account for remaining uncertainties between species. An additional assessment factor of 10 has been included to account for intraspecies differences among the general public, and the read-across has been taken into account by inclusion of a further assessment factor of 2.

In conclusion, a DNEL of 4.35 mg/m³ has been determined.

No acute systemic inhalatory DNEL has been derived as there were no relevant clinical effects observed at the limit dose of the test material in an acute oral toxicity study, and due to substance characteristics a higher absorption via the inhalation route than via the oral route is not to be expected.

No local DNELs for the inhalation route have been derived as no hazard has been identified in the repeated dose toxicity study via the oral route with a structurally-related substance, in the acute oral toxicity study with the test substance and in the acute dermal toxicity study with the test substance. Furthermore, the test substance does not show any irritating effects.

Dermal:

The long-term systemic dermal DNEL has also been derived from the oral NOAEL of 1000 mg/kg bw/day, derived from the subchronic (90-day) study with a structurally-related substance in rats. Route to route extrapolation has been done assuming equal rates for the oral absorption of the rat and the dermal absorption of humans. In a worst case approach the oral absorption rate of the rat is not assumed to be higher than the dermal absorption rate of humans. Although a lower absorption via the human skin is assumed, an assessment factor of 1 has been used (assuming equal absorption) in the absence of appropriate data. Hence, as dose descriptor starting point for DNEL derivation a NOAELcorr of 1000 mg/kg bw/day has been used, followed by allometric scaling for interspecies differences between rats and humans, inclusion of an additional factor of 2.5 for other interspecies differences, an assessment factor of 10 to account for intraspecies differences among the general population and an additional assessment factor of 2 to account for the use of data from a structurally related substance (read-across). In conclusion, a DNEL of 2.5 mg/kg bw/day has been derived.

No acute systemic dermal DNEL has been derived as there were no clinical effects observed in an acute dermal toxicity study.

No local DNELs for the dermal route have been derived as no hazard has been identified in the acute dermal toxicity study, and the substance is not irritating to the skin.

Oral:

The starting point for the DNEL derivation was the oral NOAEL of 1000 mg/kg bw/day derived from the subchronic (90-day) study with a structurally-related substance in rats; no route to route extrapolation was necessary. In the absence of appropriate data an equal oral absorption for rats and humans has been assumed. Potential differences are anticipated to be sufficiently accounted for by the application of factors for allometric scaling and other interspecies differences as suggested by the ECHA REACH Guidance on DNEL derivation. Additionally, an assessment factor of 10 has been included to account for intraspecies differences among the general population, and an additional assessment factor of 2 to account for the use of data from a structurally-related substance (read-across). In conclusion, a DNEL of 2.5 mg/kg bw/day has been derived.

Eyes: The neat substance does not cause irritation to the eyes.