Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.005 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
75
Dose descriptor starting point:
NOAEL
Value:
0.8 mg/m³
Modified dose descriptor starting point:
NOAEC
Value:
0.4 mg/m³
Explanation for the modification of the dose descriptor starting point:

The 28 -day inhalation study is used for the derivation of DNEL.

Assuming that theinhalation absorption of rat is equal to the inhalation absorption human, for workers, the inhalatory N(L)OAEC rat needs to be corrected for the difference between respiratory rates under standard conditions and under conditions of light activity (sRVhuman versus wRV) considering that the rats were subjected to a 6h exposure/day and 5 days/week corrected N(L)OAEC = inhalatory N(L)OAEC * ( sRVhuman/wRV) = 0.8 mg/m3 * (5 m3/10 m3) = 0.4 mg/m3

AF for dose response relationship:
1
Justification:
The starting point for the DNEL calculation was a NOEL, therefore the default assessment factor, as a standard procedure, is 1.
AF for differences in duration of exposure:
6
Justification:
An assessment factor of 6 has been applied in order to consider the differences in the duration of the exposure between the sub-acute toxicity study and a chronic exposure.
AF for interspecies differences (allometric scaling):
1
Justification:
Allometric scaling does not apply in case of an inhalation study
AF for other interspecies differences:
2.5
Justification:
As no allometric factor has been used, an assessment factor for other interspecies differences has been chosen.
AF for intraspecies differences:
5
Justification:
Intraspecies AF for workers population
AF for the quality of the whole database:
1
Justification:
The available data are sufficient to correctly derive the inhalation DNEL.
AF for remaining uncertainties:
1
Justification:
There are no remaining uncertainties.
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
19.28 mg/m³
Most sensitive endpoint:
acute toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
12.5
Dose descriptor starting point:
NOAEC
Value:
143 mg/m³
Modified dose descriptor starting point:
NOAEC
Value:
241 mg/m³
Explanation for the modification of the dose descriptor starting point:

As high peak exposure is foreseen during the professional use of the substance, a DNEL for short-term exposure systemic effects has been derived. In an acute toxicity study after 4 hours of inhalation exposure, male rats showed effects at doses analytically determined starting from 0.143 mg/l. Therefore, this value can be used as a starting point in deriving the short-term inhalation DNEL for systemic effects. As the duration of the reference study is 4 hours (240 minutes), the relative concentration without observed systemic effects had to be corrected for a reference human exposure of 15 minutes, applying the Haber’s law: Cn x t = k. The regression coefficient (n) for extrapolating from longer to shorter exposure duration has a default value of 3, therefore: (0.143 mg/L)^3 x 240 min=k; 0.003 mg/L x 240 min=k; k=0.72mg/L x min. As C=(k/t) ; (0.72 mg/L x min)/(15 min)=C; C=(0.048 mg/L);C=0.36 mg/L. 

For workers, the NOAEC needs to be corrected for the differences in sRV of humans at rest and workers (at light activity). Therefore, the correct starting point in the DNEL derivation should be calculated as: 0.36 * (6.7 m3- 8h/10 m3– 8h) = 0.241 mg/L.

AF for dose response relationship:
1
Justification:
The starting point for the DNEL calculation was a NOEC, therefore the default assessment factor, as a standard procedure, is 1.
AF for interspecies differences (allometric scaling):
1
Justification:
Allometric scaling does not apply in case of inhalation-inhalation extrapolation from rats to humans.
AF for other interspecies differences:
2.5
Justification:
As no allometric factor has been used, an assessment factor for other interspecies differences has been chosen.
AF for intraspecies differences:
5
Justification:
Intraspecies AF for workers population
AF for the quality of the whole database:
1
Justification:
The available data are sufficient to correctly derive the inhalation DNEL.
AF for remaining uncertainties:
1
Justification:
There are no remaining uncertainties.

Local effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
repeated dose toxicity
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
48.2 mg/m³
Most sensitive endpoint:
acute toxicity
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
5
Dose descriptor starting point:
other: NOEC
Value:
241 mg/m³
AF for dose response relationship:
1
Justification:
The starting point for the DNEL calculation was a NOEC, therefore the default assessment factor, as a standard procedure, is 1.
AF for interspecies differences (allometric scaling):
1
Justification:
Allometric scaling does not apply in case of inhalation-inhalation extrapolation from rats to humans.
AF for other interspecies differences:
1
Justification:
No other assessment factor is needed for local effects.
AF for intraspecies differences:
5
Justification:
Intraspecies AF for workers population, according to ECETOC guidelines
Justification:
The available data are sufficient to correctly derive the inhalation DNEL
AF for remaining uncertainties:
1
Justification:
There are no remaining uncertainties.

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.83 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance and ECETOC Guidelines
Overall assessment factor (AF):
120
Dose descriptor starting point:
NOAEL
Value:
10 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:

Due to the absence of long-term toxicity data via the dermal route, data retried by the oral route are used.

Different repeated-dose oral toxicity studies are available.The following results are retrived:

1. Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test) -OECD 422:

- NOAEL for general toxicity in parents was considered to be 100 mg/kg/day (i.e. 133 mg/kg/day in terms of test item as registered) based on clinical findings in males,

- NOEL for reproductive performance was considered to be 300 mg/kg/day (i.e. 398 mg/kg/day as registered substance) in the absence of any treatment-related effect on mating and fertility at this dose-level

2. Developmental toxicity/teratogenicity-no guideline followed:

- NOAEL maternal toxicity: 10 mg/kg bw

- NOAEL developmental toxicity: 60 mg/kg bw

3. Repeated oral toxicity

- NOAEL (male) = 500 ppm = 93.75 mg/kg bw/day

 

All three studies are reliable; following a precautionary approach, for the DNEL the lowest NOAEL is considered.

No route-to-route extrapolation needed. It is assumed that dermal absorption will not be higher than oral absorption. However, a much lower dermal absorption is expected due to the absence of systemic effects during the acute dermal toxicity study, based on the physicochemical properties of the substance and based on the test results conudcted similar substance. In the test with the similar subsatnce only 1 % of dermal penetration was found. Following a precautionary approach and considering the fact that the test was based on results on similar substance, a 10 % is assumed for dermal absorption.

Therefore the NOAEL should be modified accordingly. NOAELmod = 10 mg/kg bw/day x 100 /10 = 100

AF for dose response relationship:
1
Justification:
The starting point for the DNEL calculation was a NOAEL, therefore the default assessment factor, as a standard procedure, is 1.
AF for differences in duration of exposure:
6
Justification:
An assessment factor of 6 has been applied in order to consider the differences in the duration of the exposure between the oral developmental toxicity study and a chronic exposure.
AF for interspecies differences (allometric scaling):
4
Justification:
Allometric scaling for rats involves a default assessment factor of 4.
AF for other interspecies differences:
1
Justification:
An additional AF for interspecies differences is considered not necessary, because allometric scaling will be conservative enough.
AF for intraspecies differences:
5
Justification:
Intraspecies AF for workers population
AF for the quality of the whole database:
1
Justification:
The available data are sufficient to correctly derive the inhalation DNEL
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties are foreseen.
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:
low hazard (no threshold derived)

Additional information - workers

Data considered in this hazard assessment derive from studies performed the substance itself and from studies performed on similar substances, according to a read-across principle. Full justification of read-across application is provided in a separate document.

DNELs for inhalation and dermal routes of exposure have been derived. The DNEL derived for inhalation route after long term-exposure (systemic effects) has been derived from the sub-acute toxicity study via inhalation route with rats. The DNELs derived for inhalation route after short term-exposure (systemic and local effects) have been derived from the results of a 4-hour exposure study. The NO(A)EC from these inhalation studies had to be corrected into the correct starting point, considering the differences in the duration of exposure between the laboratory animals at rest and workers at light activity. A qualitative assessment has been carried out for local effect after repeated inhalation exposure.

The DNEL derived for the dermal route after long-term exposure derives from the Developmental toxicity/teratogenicity study by oral route with rats.

Where the route of exposure in the relevant toxicity study was not the same of workers, a route-to-route extrapolation has been carried out.

The correct starting points were divided by an overall assessment factor, which was a result of various consideration on uncertainties in inter-and intra-species variations, and on differences in the duration of exposure between test animals and humans. Moreover, also the whole quality of the database was considered.

No DNELs were derived for local effects after long-term dermal exposure, and for systemic and local effects after short-term dermal exposure, because no hazard has been identified (i.e. the studies performed for the acute dermal toxicity endpoint, the skin irritation/corrosion endpoint and for the skin sensitization endpoint revealed no effects, and a low degree of percutaneous absorption is expected for the substance. No DNEL have been derived for the eye irritation effects, for which a qualitative approach has been followed, leading to a low hazard for this endpoint.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.005 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
150
Dose descriptor starting point:
NOAEC
Value:
0.8 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

The 28 -day inhalation study is used for the derivation of DNEL.

Assuming that the inhalation absorption of rat is equal to the inhalation absorption human, for general population, no correction needs to be done 

AF for dose response relationship:
1
Justification:
The starting point for the DNEL calculation was a NOEC, therefore the default assessment factor, as a standard procedure, is 1.
AF for differences in duration of exposure:
6
Justification:
An assessment factor of 6 has been applied in order to consider the differences in the duration of the exposure between the sub-acute toxicity study and a chronic exposure.
AF for interspecies differences (allometric scaling):
1
Justification:
Allometric scaling does not apply in case of inhalation-inhalation extrapolation from rats to humans.
AF for other interspecies differences:
2.5
Justification:
As no allometric factor has been used, an assessment factor for other interspecies differences has been chosen.
AF for intraspecies differences:
10
Justification:
Intraspecies AF for general population
AF for the quality of the whole database:
1
Justification:
The available data are sufficient to correctly derive the inhalation DNEL
AF for remaining uncertainties:
1
Justification:
There are no remaining uncertainties.
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
5.72 mg/m³
Most sensitive endpoint:
acute toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
25
Modified dose descriptor starting point:
NOAEC
Value:
143 mg/m³
Explanation for the modification of the dose descriptor starting point:

In an acute toxicity study after 4 hours of inhalation exposure, male rats showed effects at doses analytically determined starting from 0.143 mg/L. Therefore, this value can be used as a starting point in deriving the short-term inhalation DNEL for systemic effects

AF for dose response relationship:
1
Justification:
The starting point for the DNEL calculation was a NOEC, therefore the default assessment factor, as a standard procedure, is 1.
AF for interspecies differences (allometric scaling):
1
Justification:
Allometric scaling does not apply in case of inhalation-inhalation extrapolation from rats to humans.
AF for other interspecies differences:
2.5
Justification:
As no allometric factor has been used, an assessment factor for other interspecies differences has been chosen.
AF for intraspecies differences:
10
Justification:
Intraspecies AF for general population
AF for the quality of the whole database:
1
Justification:
The available data are sufficient to correctly derive the inhalation DNEL.
AF for remaining uncertainties:
1
Justification:
There are no remaining uncertainties.

Local effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
repeated dose toxicity
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
14.3 mg/m³
Most sensitive endpoint:
acute toxicity
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
10
Dose descriptor starting point:
other: NOEC
Value:
143 mg/m³
AF for dose response relationship:
1
Justification:
The starting point for the DNEL calculation was a NOEC, therefore the default assessment factor, as a standard procedure, is 1.
AF for interspecies differences (allometric scaling):
1
Justification:
Allometric scaling does not apply in case of inhalation-inhalation extrapolation from rats to humans.
AF for other interspecies differences:
1
Justification:
No other assessment factor is needed for local effects.
AF for intraspecies differences:
10
Justification:
Intraspecies AF for general population
AF for the quality of the whole database:
1
Justification:
The available data are sufficient to correctly derive the inhalation DNEL
AF for remaining uncertainties:
1
Justification:
There are no remaining uncertainties.

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.41 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
240
Dose descriptor starting point:
NOAEL
Value:
10 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:

Due to the absence of long-term toxicity data via the dermal route, data retried by the oral route are used.

Different repeated-dose oral toxicity studies are available.The following results are retrived:

1. Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test) -OECD 422:

- NOAEL for general toxicity in parents was considered to be 100 mg/kg/day (i.e. 133 mg/kg/day in terms of test item as registered) based on clinical findings in males,

- NOEL for reproductive performance was considered to be 300 mg/kg/day (i.e. 398 mg/kg/day as registered substance) in the absence of any treatment-related effect on mating and fertility at this dose-level

2. Developmental toxicity/teratogenicity-no guideline followed:

- NOAEL maternal toxicity: 10 mg/kg bw

- NOAEL developmental toxicity: 60 mg/kg bw

3. Repeated oral toxicity

- NOAEL (male) = 500 ppm = 93.75 mg/kg bw/day

 

All three studies are reliable; following a precautionary approach, for the DNEL the lowest NOAEL is considered.

No route-to-route extrapolation needed. It is assumed that dermal absorption will not be higher than oral absorption. However, a much lower dermal absorption is expected due to the absence of systemic effects during the acute dermal toxicity study, based on the physicochemical properties of the substance and based on the test results conudcted similar substance. In the test with the similar subsatnce only 1 % of dermal penetration was found. Following a precautionary approach and considering the fact that the test was based on results on similar substance, a 10 % is assumed for dermal absorption.

Therefore the NOAEL should be modified accordingly. NOAELmod = 10 mg/kg bw/day x 100 /10 = 100

AF for dose response relationship:
1
Justification:
The starting point for the DNEL calculation was a NOEL, therefore the default assessment factor, as a standard procedure, is 1.
AF for differences in duration of exposure:
6
Justification:
An assessment factor of 6 has been applied in order to consider the differences in the duration of the exposure between the sub-acute study and a chronic exposure.
AF for interspecies differences (allometric scaling):
4
Justification:
Allometric scaling for rats involves a default assessment factor of 4.
AF for other interspecies differences:
1
Justification:
An additional AF for interspecies differences is considered not necessary, because allometric scaling will be conservative enough.
AF for intraspecies differences:
10
Justification:
Intraspecies AF for general population
AF for the quality of the whole database:
1
Justification:
The available data are sufficient to correctly derive the inhalation DNEL
AF for remaining uncertainties:
1
Justification:
There are no remaining uncertainties.
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:
acute toxicity

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
41.67 µg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
240
Dose descriptor starting point:
NOAEL
Value:
10 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Different repeated-dose oral toxicity studies are available. The following results are retrived:

1. Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test) -OECD 422:

- NOAEL for general toxicity in parents was considered to be 100 mg/kg/day (i.e. 133 mg/kg/day in terms of test item as registered) based on clinical findings in males,

- NOEL for reproductive performance was considered to be 300 mg/kg/day (i.e. 398 mg/kg/day as registered substance) in the absence of any treatment-related effect on mating and fertility at this dose-level

2. Developmental toxicity/teratogenicity-no guideline followed:

- NOAEL maternal toxicity: 10 mg/kg bw

- NOAEL developmental toxicity: 60 mg/kg bw

3. Repeated oral toxicity

- NOAEL (male) = 500 ppm = 93.75 mg/kg bw/day

 

All three studies are reliable; following a precautionary approach, for the DNEL the lowest NOAEL is considered.

AF for dose response relationship:
1
Justification:
The starting point for the DNEL calculation was a NOAEL, therefore the default assessment factor, as a standard procedure, is 1.
AF for differences in duration of exposure:
6
Justification:
An assessment factor of 6 has been applied in order to consider the differences in the duration of the exposure between the sub-acute toxicity study and a chronic exposure.
AF for interspecies differences (allometric scaling):
4
Justification:
Allometric scaling for rats involves a default assessment factor of 4.
AF for other interspecies differences:
1
Justification:
An additional AF for interspecies differences is considered not necessary, because allometric scaling will be conservative enough.
AF for intraspecies differences:
10
Justification:
Intraspecies AF for general population
AF for the quality of the whole database:
1
Justification:
The available data are sufficient to correctly derive the inhalation DNEL
AF for remaining uncertainties:
1
Justification:
There are no remaining uncertainties.
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
12.5 mg/kg bw/day
Most sensitive endpoint:
acute toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
40
Dose descriptor starting point:
NOAEL
Value:
500 mg/kg bw/day
AF for dose response relationship:
1
Justification:
The starting point for the DNEL calculation was a NOAEL, therefore the default assessment factor, as a standard procedure, is 1.
AF for interspecies differences (allometric scaling):
4
Justification:
Allometric scaling for rats involves a default assessment factor of 4.
AF for other interspecies differences:
1
Justification:
An additional AF for interspecies differences is considered not necessary, because allometric scaling will be conservative enough.
AF for intraspecies differences:
10
Justification:
Intraspecies AF for general population
AF for the quality of the whole database:
1
Justification:
The available data are sufficient to correctly derive the inhalation DNEL
AF for remaining uncertainties:
1
Justification:
There are no remaining uncertainties.

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - General Population

Data considered in this hazard assessment were derived from studies performed the substance itself and from studies performed on similar substances, according to a read-across principle. Full justification of read-across application is provided in a separate document.

DNELs for inhalation and dermal routes of exposure have been derived. The DNEL derived for inhalation route after long term-exposure (systemic effects) has been derived from the sub-acute toxicity study via inhalation route with rats.

Developmental toxicity/teratogenicity study by oral route with rats. The DNELs derived for inhalation route after short term-exposure (systemic and local effects) have been derived from the results of a 4-hour exposure study. The NO(A)EC from these inhalation studies had to be corrected into the correct starting point, considering the differences in the duration of exposure between the laboratory animals and general population. A qualitative assessment has been carried out for local effect after repeated inhalation exposure.

The DNEL derived for the dermal route after long-term exposure derives from the Developmental toxicity/teratogenicity study by oral route with rats.

Where the route of exposure in the relevant toxicity study was not the same of workers, a route-to-route extrapolation has been carried out. 

Also DNELs for oral exposure have been derived: the DNEL for long-term exposure derived from the NOAEL determined in the Developmental toxicity/teratogenicity study by oral route with rats, while the DNEL for short-term exposure derives from the NOEL for systemic effects observed in one of the oral acute toxicity study available.

The correct starting points were divided by an overall assessment factor, which was a result of various consideration on uncertainties in inter-and intra-species variations, and on differences in the duration of exposure between test animals and humans. Moreover also the whole quality of the database was considered.

No DNELs were derived for local effects after long-term dermal exposure, and for systemic and local effects after short-term dermal exposure, because no hazard has been identified (i.e. the studies performed for the acute dermal toxicity endpoint, the skin irritation/corrosion endpoint and for the skin sensitization endpoint revealed no effects, and a low degree of percutaneous absorption is expected for the substance. No DNEL have been derived for the eye irritation effects, for which a qualitative approach has been followed, leading to a low hazard for this endpoint.