Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
88.2 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):
10
Modified dose descriptor starting point:
NOAEC
DNEL value:
882 mg/m³
Explanation for the modification of the dose descriptor starting point:
The oral absorption was assumed to be half of the absorption via inhalation; Daily respiration volume for a worker of 10 mg/m3.
AF for dose response relationship:
1
Justification:
No effect was observed
AF for differences in duration of exposure:
1
Justification:
There is no need to consider the uncertainty related to exposure duration. According to the read-across approach, the NOAEL for chronic exposure is also considered to be greater than 1000 mg/kg bw/day, which indicates no difference due to the duration of exposure. In addition, based on the data on in-vitro metabolism study in gastric juice, no bioaccumulation potential can be reasonably derived.
AF for interspecies differences (allometric scaling):
1
Justification:
Prediction of inhalation exposure from data of oral experimental; the allometric scaling is already considered in the calculation of starting point.
AF for other interspecies differences:
1
Justification:
No effect was observed, therefore it is no need to consider the uncertainty related to toxicodynamic influence.
AF for intraspecies differences:
5
Justification:
Default value for systemic effects
AF for the quality of the whole database:
1
Justification:
All data are Klimish 1 or 2
AF for remaining uncertainties:
2
Justification:
The hazard assessment is based on the experimental data of the substance and read-across approach.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
25 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):
40
Modified dose descriptor starting point:
NOAEL
DNEL value:
1 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
According to ECHA REACH Guidance, it is assumed that dermal absorption is not higher than oral absorption, therefore a factor of 1 is introduced for oral-to-dermal extrapolation
AF for dose response relationship:
1
Justification:
No effect was observed
AF for differences in duration of exposure:
1
Justification:
There is no need to consider the uncertainty related to exposure duration. According to the read-across approach, the NOAEL for chronic exposure is also considered to be greater than 1000 mg/kg bw/day, which indicates no difference due to the duration of exposure. In addition, based on the data on in-vitro metabolism study in gastric juice, no bioaccumulation potential can be reasonably derived.
AF for interspecies differences (allometric scaling):
4
Justification:
Oral experiment was performed in rats
AF for other interspecies differences:
1
Justification:
No effect was observed, therefore it is no need to consider the uncertainty related to toxicodynamic influence.
AF for intraspecies differences:
5
Justification:
Default value for systemic effects
AF for the quality of the whole database:
1
Justification:
All data are Klimish 1 or 2
AF for remaining uncertainties:
2
Justification:
The hazard assessment is based on the experimental data of the substance and read-across approach.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

According to ECHA REACH Guidance, no DNELs for acute exposure and local effect were derived since no acute or local toxicity hazard has been identified. The long-term DNEL concerning systemic effects also covers possible acute toxic effects.

Long-term inhalatory systemic DNEL

The NOAEL of 1000 mg/kg bw/day regarding to systemic toxic effetcts from a 28-day oral toxicity study in rats was used for the derivation of the `DNEL long-term inhalation, systemic`. A factor of 2 was used for oral-to-inhalation extrapolation, which means for example that 50% (instead of 100%) absorption is assumed for oral absorption and 100% for inhalation. According to the ECHA REACH Guidance, the dose descriptor starting point NOAEC was calculated:

Starting point NOAEC(inhal.)     = NOEL(oral, rat) x 1/sRVrat xABS(oral-rat)/ABS(inh-human) x sRVhuman/wRV

                                            = 1000 mg/kg bw/d x 1/0.38 m3/kg/d x 50%/100% x 6.7 m3/10 m3
                                            = 882 mg/m3
with sRV: standard respiratory volume;ABS: Absorption; wRV: worker respiratory volume

Acording to the ECHA REACH Guidance, the DNEL was then obtained by applying assessment factors to the starting point:

- dose-response relationship:

There is no reason to consider special concern. Up to the limit dose for evaluation systemic toxicity (1000 mg/kg body weight per day) no effects related to the treatment have occurred. Statistical significant and/or dose-response relationship with regard to special target organ toxicity which has to be taken into account was not obsereved.

- differences in duration of exposure:

There is no need to consider the uncertainty related to exposure duration. According to the read-across approach, the NOAEL for chronic exposure is also considered to be greater than 1000 mg/kg bw/day, which indicates no difference due to the duration of exposure. In addition, based on the data on in-vitro metabolism study in gastric juice, no bioaccumulation potential can be reasonably derived.

- interspecies differences (allometric scalling):

No allometric scalling is considered here, because the allometric scaling is already considered in the calculation of starting point.

- other interspecies differences:

No effect was observed, therefore it is no need to consider the uncertainty related to toxicodynamic influence.

- intraspecies differences:

A defaut factor of 5 was applied for workers according to the guidance.

- the quality of the whole database:

The available data have been evaluated with regard to their reliability, relevance and completeness. All data are Klimish 1 or 2. Based hereupon no indications exist to assume limited reliability and/or relevance of the data base used.

- remaining uncertainties:

A factor of 2 was applied, because the hazard assessment is based on the experimental data of the substance and read-across approach.

Considering the available data, an overall assessment factor of 10 was applied. The DNEL of system effects for worker via inhalation route was calculated to be 88.2 mg/m3.

Long-term dermal systemic DNEL

The NOAEL of 1000 mg/kg bw/day regarding to systemic toxic effetcts from a 28-day oral toxicity study in rats was used for the derivation of the `DNEL long-term dermal, systemic`. It is assumed that dermal absorption is not higher than oral absorption, therefore a factor of 1 is introduced for oral-to-dermal extrapolation. According to the ECHA REACH Guidance, the dose descriptor starting point NOAEL was calculated:

Starting point NOAEC(derm.)     = NOEL(oral, rat) xABS(oral-rat)/ABS(derm-human)
                                                  = 1000 mg/kg bw/d

Acording to the ECHA REACH Guidance, the DNEL was then obtained by applying assessment factors to the starting point. Basically, the consideration of assessment factor for dermal exposure is the same as that for inhalation exposure, except for:

- interspecies differences (allometric scalling):

An allometric scalling of 4 is applied, because the prediction of dermal exposure was from data of oral experimental.

Considering the available data, an overall assessment factor of 40 was applied. The DNEL of system effects for worker via dermal route was calculated to be 25 mg/kg bw/day.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
21.8 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):
20
Modified dose descriptor starting point:
NOAEC
DNEL value:
435 mg/m³
Explanation for the modification of the dose descriptor starting point:
The oral absorption was assumed to be half of the absorption via inhalation; exporsure duration of 24 h/d for general population
AF for dose response relationship:
1
Justification:
No effect was observed
AF for differences in duration of exposure:
1
Justification:
There is no need to consider the uncertainty related to exposure duration. According to the read-across approach, the NOAEL for chronic exposure is also considered to be greater than 1000 mg/kg bw/day, which indicates no difference due to the duration of exposure. In addition, based on the data on in-vitro metabolism study in gastric juice, no bioaccumulation potential can be reasonably derived.
AF for interspecies differences (allometric scaling):
1
Justification:
Prediction of inhalation exposure from data of oral experimental; the allometric scaling is already considered in the calculation of starting point.
AF for other interspecies differences:
1
Justification:
No effect was observed, therefore it is no need to consider the uncertainty related to toxicodynamic influence.
AF for intraspecies differences:
10
Justification:
Default value for systemic effects
AF for the quality of the whole database:
1
Justification:
All data are Klimish 1 or 2
AF for remaining uncertainties:
2
Justification:
The hazard assessment is based on the experimental data of the substance and read-across approach.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
12.5 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):
80
Modified dose descriptor starting point:
NOAEL
DNEL value:
1 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
According to ECHA REACH Guidance, it is assumed that dermal absorption is not higher than oral absorption, therefore a factor of 1 is introduced for oral-to-dermal extrapolation
AF for dose response relationship:
1
Justification:
No effect was observed
AF for differences in duration of exposure:
1
Justification:
There is no need to consider the uncertainty related to exposure duration. According to the read-across approach, the NOAEL for chronic exposure is also considered to be greater than 1000 mg/kg bw/day, which indicates no difference due to the duration of exposure. In addition, based on the data on in-vitro metabolism study in gastric juice, no bioaccumulation potential can be reasonably derived.
AF for interspecies differences (allometric scaling):
4
Justification:
Prediction of inhalation exposure from data of oral experiment
AF for other interspecies differences:
1
Justification:
No effect was observed, therefore it is no need to consider the uncertainty related to toxicodynamic influence.
AF for intraspecies differences:
10
Justification:
Default value for systemic effects
AF for the quality of the whole database:
1
Justification:
All data are Klimish 1 or 2
AF for remaining uncertainties:
2
Justification:
The hazard assessment is based on the experimental data of the substance and read-across approach.
Acute/short term exposure
Hazard assessment conclusion:
no DNEL required: short term exposure controlled by conditions for long-term
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
12.5 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):
80
Modified dose descriptor starting point:
NOAEL
DNEL value:
1 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
oral-to-oral, the oral absorption is considered to be same between rat and human
AF for dose response relationship:
1
Justification:
No effect was observed
AF for differences in duration of exposure:
1
Justification:
There is no need to consider the uncertainty related to exposure duration. According to the read-across approach, the NOAEL for chronic exposure is also considered to be greater than 1000 mg/kg bw/day, which indicates no difference due to the duration of exposure. In addition, based on the data on in-vitro metabolism study in gastric juice, no bioaccumulation potential can be reasonably derived.
AF for interspecies differences (allometric scaling):
4
Justification:
Oral experiment was performed in rats
AF for other interspecies differences:
1
Justification:
No effect was observed, therefore it is no need to consider the uncertainty related to toxicodynamic influence.
AF for intraspecies differences:
10
Justification:
Default value for systemic effects
AF for the quality of the whole database:
1
Justification:
All data are Klimish 1 or 2
AF for remaining uncertainties:
2
Justification:
The hazard assessment is based on the experimental data of the substance and read-across approach.
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

According to ECHA REACH Guidance, no DNELs for acute exposure and local effect were derived since no acute toxicity hazard has been identified. The long-term DNEL concerning systemic effects also covers possible acute toxic effects.

Long-term inhalatory systemic DNEL

The NOAEL of 1000 mg/kg bw/day regarding to systemic toxic effetcts from a 28-day oral toxicity study in rats was used for the derivation of the `DNEL long-term inhalation, systemic`. A factor of 2 was used for oral-to-inhalation extrapolation, which means for example that 50% (instead of 100%) absorption is assumed for oral absorption and 100% for inhalation. According to the ECHA REACH Guidance, the dose descriptor starting point NOAEL was calculated:

Starting point NOAEC(derm.)     = NOEL(oral, rat) x 1/sRVrat xABS(oral-rat)/ABS(inh-human)
                                            = 1000 mg/kg bw/d x 1/1.15 m3/kg/d x 50%/100%
                                            = 435 mg/m3
with sRV: standard respiratory volume;ABS: Absorption

Acording to the ECHA REACH Guidance, the DNEL was then obtained by applying assessment factors to the starting point:

- dose-response relationship:

There is no reason to consider special concern. Up to the limit dose for evaluation systemic toxicity (1000 mg/kg body weight per day) no effects related to the treatment have occurred. Statistical significant and/or dose-response relationship with regard to special target organ toxicity which has to be taken into account was not obsereved.

- differences in duration of exposure:

There is no need to consider the uncertainty related to exposure duration. According to the read-across approach, the NOAEL for chronic exposure is also considered to be greater than 1000 mg/kg bw/day, which indicates no difference due to the duration of exposure. In addition, based on the data on in-vitro metabolism study in gastric juice, no bioaccumulation potential can be reasonably derived.

- interspecies differences (allometric scalling):

No allometric scalling is considered here, because the allometric scaling is already considered in the calculation of starting point.

- other interspecies differences:

No effect was observed, therefore it is no need to consider the uncertainty related to toxicodynamic influence.

- intraspecies differences:

A defaut factor of 10 was applied for general population according to the guidance.

- the quality of the whole database:

The available data have been evaluated with regard to their reliability, relevance and completeness. All data are Klimish 1 or 2. Based hereupon no indications exist to assume limited reliability and/or relevance of the data base used.

- remaining uncertainties:

A factor of 2 was applied, because the hazard assessment is based on the experimental data of the substance and read-across approach.

Considering the available data, an overall assessment factor of 20 was applied. The DNEL of system effects for general population via inhalation route was calculated to be 21.8 mg/m3.

Long-term dermal systemic DNEL

The NOAEL of 1000 mg/kg bw/day regarding to systemic toxic effetcts from a 28-day oral toxicity study in rats was used for the derivation of the `DNEL long-term dermal, systemic`. It is assumed that dermal absorption is not higher than oral absorption, therefore a factor of 1 is introduced for oral-to-dermal extrapolation. According to the ECHA REACH Guidance, the dose descriptor starting point NOAEL was calculated:

Starting point NOAEC(derm.)     = NOEL(oral, rat) xABS(oral-rat)/ABS(derm-human)
                                                  = 1000 mg/kg bw/d

Acording to the ECHA REACH Guidance, the DNEL was then obtained by applying assessment factors to the starting point. Basically, the consideration of assessment factor for dermal exposure is the same as that for inhalation exposure, except for:

- interspecies differences (allometric scalling):

An allometric scalling of 4 is applied, because the prediction of dermal exposure was from data of oral experimental.

Considering the available data, an overall assessment factor of 80 was applied. The DNEL of system effects for general population via dermal route was calculated to be 12.5 mg/kg bw/day.

Long-term oral systemic DNEL

The NOAEL of 1000 mg/kg bw/day regarding to systemic toxic effetcts from a 28-day oral toxicity study in rats was used for the derivation of the `DNEL long-term oral, systemic`. The derivation of DNEL for oral route is similar as that for dermal route:

The starting point NOAEC(oral)     = NOEL(oral, rat) xABS(oral-rat)/ABS(oral-human)
                                                  = 1000 mg/kg bw/d

An overall assessment factor of 80 was applied. The DNEL of system effects for genaral poputation via oral route was calculated to be 12.5 mg/kg bw/day.