Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
43.73 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):
25
Modified dose descriptor starting point:
NOAEC
DNEL value:
1 093.16 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)*(0.62/1)*0.67 = 1093.16 mg/m³. The available absorption data demonstrated an oral absorption rate of 62.2% for the rat, so a factor of 0.62 was used in the calculations instead of the default value (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) 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:
1
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
Route of original study:
By inhalation
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:
10 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):
100
Modified dose descriptor starting point:
NOAEL
DNEL 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:
1
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 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 and under consideration of the oral absorption rate of 62% for the test substance demonstrated in rats (Prier, 1960) a NOAECcorr of 1093.16 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. In conclusion, a DNEL of 43.73 mg/m³ has been determined.

No acute systemic inhalatory DNEL has been derived as there were no relevant clinical effects observed at the highest feasible aerosol concentration with a respirable MMAD in an acute inhalation toxicity study.

No local DNELs for the inhalation route have been derived as no hazard has been identified in the acute inhalation toxicity study.

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 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 study demonstrating only 62% oral absorption in the rat is available (Prier, 1960) and 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 and an assessment factor of 5 to account for intraspecies differences among the workers. In conclusion, a DNEL of 10 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:
10.78 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):
50
Modified dose descriptor starting point:
NOAEC
DNEL value:
539.13 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)*(0.62/1) = 539.13 mg/m³.The available absorption data demonstrated an oral absorption rate of 62.2% for the rat, so a factor of 0.62 was used in the calculations instead of the default value (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:
1
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
Route of original study:
By inhalation
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:
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
DNEL 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:
1
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):
200
Modified dose descriptor starting point:
NOAEL
DNEL 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:
1
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 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), and under consideration of the oral absorption rate of 62% for the test substance demonstrated in rats (Prier, 1960), a NOAECcorr of 539.13 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. In conclusion, a DNEL of 10.78 mg/m³ has been determined.

No acute systemic inhalatory DNEL has been derived as there were no relevant clinical effects observed at the highest feasible aerosol concentration with a respirable MMAD in an acute inhalation toxicity study.

No local DNELs for the inhalation route have been derived as no hazard has been identified in the acute inhalation toxicity study.

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 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 study demonstrating only 62% oral absorption in the rat is available (Prier, 1960) and 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 and an assessment factor of 10 to account for intraspecies differences among the general population. 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.

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 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. In conclusion, a DNEL of 5 mg/kg bw/day has been derived.

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