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Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
29.39 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):
30
Modified dose descriptor starting point:
NOAEC
DNEL value:
882 mg/m³
Explanation for the modification of the dose descriptor starting point:
The inhalation route is typically covered by oral route information in the absence of data for this administration route
AF for dose response relationship:
1
AF for differences in duration of exposure:
6
Justification:
DNEL based on subacute oral study
AF for interspecies differences (allometric scaling):
1
Justification:
AF not used for inhalation route
AF for other interspecies differences:
1
AF for intraspecies differences:
5
AF for the quality of the whole database:
1
Justification:
GLP guideline study
AF for remaining uncertainties:
1
Justification:
No adverse effects observed at limit dose
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
8.33 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):
120
Modified dose descriptor starting point:
NOAEL
DNEL value:
1 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
The dermal route is typically covered by oral route information in the absence of data for this administration route.
AF for dose response relationship:
1
AF for differences in duration of exposure:
6
Justification:
DNEL based on subacute oral study
AF for interspecies differences (allometric scaling):
4
Justification:
rat/human
AF for other interspecies differences:
1
AF for intraspecies differences:
5
Justification:
worker
AF for the quality of the whole database:
1
Justification:
GLP guideline study
AF for remaining uncertainties:
1
Justification:
No adverse effects observed at limit dose
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

Kinetics (absorption figures for oral, dermal and inhalation route of exposure)

No data on absorption are available. According to Chapter R.8 of REACH Guidance on information requirements and chemical safety assessment, it is proposed in the absence of route-specific information on the starting route, to include a default factor of 2 in the case of oral-to-inhalation extrapolation. This approach will be taken forward to DNEL derivation. For dermal absorption, based on the physical-chemical properties of the substance (molecular weight < 500 g/mol [129.157 g/mol], log Kow -1.03 at 25°C, water solubility very soluble in water (miscible with water at 20°C at any ratio) low uptake is expected. Low dermal absorption is supported by the absence of adverse effects in the acute dermal toxicity study with N-(2-Hydroxyethyl)-2-pyrrolidon. Based on the above physical-chemical properties, oral absorption is also expected to be low. The absence of systemic effects at the high doses tested in the available oral toxicity studies with N-(2-Hydroxyethyl)-2-pyrrolidon supports low oral absorption. As both oral and dermal absorption are expected to be low a default factor of 1 for oral-to-dermal extrapolation was used for DNEL derivation .

Acute toxicity

N-(2-Hydroxyethyl)-2-pyrrolidon does not have to be classified for acute toxicity and therefore derivation of a DNELacute is not necessary.

 

Repeated dose toxicity

N-(2-Hydroxyethyl)-2-pyrrolidon was administered daily to rats by gavage at doses of 0, 100, 300 or 1000 mg/kg bw/day. Regarding clinical examinations, signs of general systemic toxicity were not observed in male or female parental animals up to the 1000 mg/kg bw/d dose of the compound. No treatment related adverse effects were observed on body weight, food consumption, heamatology, clinical chemistry or urinalysis.No treatment-related effects were seen in the Functional Observational Battery (FOB) parameters either. No treatment related effects were observed on organ weights of the parental animals nor when expressed as absolute - or relative weights. In the offspring, there were no treatment-related effects on body weight at any dose level. There were no external abnormalities noted at any dose group either. No treatment-related deaths or clinical signs of systemic toxicity in pups during lactation were noted at any treatment group.

 

Irritation / Sensitisation / Mutagenicity

N-(2-Hydroxyethyl)-2-pyrrolidon is considered to be not irritating to the skin and eye. Since the SIs were lower than 3 at all concentrations in the available LLNA, the results indicated that N-(2-hydroxyethyl)-2-pyrrolidon should not be considered a skin sensitiser.

Based on the available genetic toxicity data; non-mammalian and mammalian (mutagenicity and chromosome aberration) in vitro assays, the test substance is not classified for mutagenicity and thus not considered to be mutagenic. The results of the conducted Ames tests were mixed as dependent on the purity of the test-substance mutagenicity was observed. This however, is not supported by the mammalian tests as no mutagenicity was observed in the chromosome aberration and in the gene mutation assay which is the most significant assay.

 

Reproduction toxicity

No reproductive toxicity and no developmental toxicity was observed in a combined repeated dose toxicity study with the reproduction/developmental toxicity screening test (OECD 422) in rats with N-(2 -Hydroxyethyl)-2 -pyrrolidon (tested at 0, 100, 300 or 1000 mg/kg bw/day). Thus, the NOAEL for reproductive and developmental toxicity was considered 1000 mg/kg bw/day. No DNEL has to be derived for developmental and reproductive toxicity.

 

DNEL derivation

For short-term toxicity, no DNEL needs to be derived for all routes of exposure, because N-(2-Hydroxyethyl)-2-pyrrolidon is not classified for acute toxicity.

 

Oral

For long-term toxicity, regarding systemic effects, a NOAEL of 1000 mg/kg bw/day was observed in a combined 28-day repeated dose toxicity study with reproduction/developmental toxicity screening test. This NOAEL is used in the derivation of the DNELs. An absorption of 50% is assumed for the oral route.

 

Inhalation

In the absence of route-specific information, route-to-route extrapolation was performed for DNEL calculation. A default factor of 2 for oral-to-inhalation extrapolation was used as proposed in Chapter R.8.4.2 of the REACH Guidance on information requirements and chemical safety assessment. It was assumed that there is no first pass effect (data to demonstrate this are lacking). The NOAEL from the combined 28-day repeated dose toxicity study with reproduction/developmental toxicity screening test was used for derivation of the systemic DNELlong-term for the inhalation route. An absorption of 100% is assumed for the inhalation route.

 

Dermal

Long-term dermal toxicity data are not available and therefore route-to-route extrapolation is performed. A default factor of 1 for oral-to-dermal extrapolation was used as proposed in Chapter R.8.4.2 of the REACH Guidance on information requirements and chemical safety assessment. It was assumed that there is no first pass effect (data to demonstrate this are lacking).

 

 

Worker DNELs

Long-term –inhalation, systemic effects (based on combined oral toxicity, reproduction/ developmental toxicity screening study with rats)

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 1000 mg/kgbw/day

No effects observed at the highest dose tested.

Step 2) Modification of starting point

2

 

 

0.38 m3/kg bw

 

 

 

6.7 m3/10 m3

Ratio of inhalation to oral absorption (default value, as proposed in the REACH guidance (R.8.4.2)

 

Standard respiratory volume of a rat, corrected for 8 h exposure, as proposed in the REACH Guidance (R.8.4.2)

 

Correction for activity driven differences of respiratory volumes in workers compared to workers in rest (6.7 m3/10 m3).

Modified dose-descriptor

1000 / 2 / 0.38 x (6.7/10) = 882 mg/m3

Step 3) Assessment factors

 

 

Interspecies

1

No allometric scaling has to be applied in case of oral to inhalation route to route extrapolation.

Intraspecies

5

Default assessment factor

Exposure duration

6

subacute to chronic extrapolation

Dose response

1

 

Quality of database

1

 

DNEL

Value

 

882 / (1 x 5 x 6 x 1x 1) = 882 /30 = 29.39 mg/m3

Long-term – dermal, systemic effects (based on combined oral toxicity, reproduction/ developmental toxicity screening study with rats)

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 1000 mg/kg bw/day

No effects observed at the highest dose tested.

Step 2) Modification of starting point

1

On the assumption that, in general, dermal absorption will not be higher than oral absorption, no default factor should be introduced when performing oral to dermal extrapolation.

Modified dose-descriptor

 

Step 3) Assessment factors

 

 

Interspecies

4

Assessment factor for allometric scaling

Intraspecies

5

Default assessment factor

Exposure duration

6

Subacute to chronic extrapolation

Dose response

1

 

Quality of database

1

 

DNEL

Value

 

1000 / (4 x 5 x 6 x 1 x 1) = 1000/120 = 8.33 mg/kg bw/day

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
7.25 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):
60
Modified dose descriptor starting point:
NOAEC
DNEL value:
435 mg/m³
Explanation for the modification of the dose descriptor starting point:
The inhalation route is typically covered by oral route information in the absence of data for this administration route.
AF for dose response relationship:
1
AF for differences in duration of exposure:
6
Justification:
DNEL based on subacute oral study
AF for interspecies differences (allometric scaling):
1
AF for other interspecies differences:
1
AF for intraspecies differences:
10
Justification:
general population
AF for the quality of the whole database:
1
Justification:
GLP guideline study
AF for remaining uncertainties:
1
Justification:
No adverse effects observed at limit dose
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4.17 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
240
Modified dose descriptor starting point:
NOAEL
DNEL value:
1 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
The dermal route is typically covered by oral route information in the absence of data for this administration route.
AF for dose response relationship:
1
AF for differences in duration of exposure:
6
Justification:
DNEL based on subacute oral study
AF for interspecies differences (allometric scaling):
4
Justification:
rat/human
AF for other interspecies differences:
1
AF for intraspecies differences:
10
Justification:
general population
AF for the quality of the whole database:
1
Justification:
GLP guideline study
AF for remaining uncertainties:
1
Justification:
No adverse effects observed at limit dose
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4.17 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):
240
Modified dose descriptor starting point:
NOAEL
DNEL value:
1 000 mg/kg bw/day
AF for dose response relationship:
1
AF for differences in duration of exposure:
6
Justification:
DNEL based on subacute oral study
AF for interspecies differences (allometric scaling):
4
Justification:
rat/human
AF for other interspecies differences:
1
AF for intraspecies differences:
10
Justification:
general population
AF for the quality of the whole database:
1
Justification:
GLP guideline study
AF for remaining uncertainties:
1
Justification:
No adverse effects observed at limit dose
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

Kinetics (absorption figures for oral, dermal and inhalation route of exposure)

No data on absorption are available. According to Chapter R.8 of REACH Guidance on information requirements and chemical safety assessment, it is proposed in the absence of route-specific information on the starting route, to include a default factor of 2 in the case of oral-to-inhalation extrapolation. This approach will be taken forward to DNEL derivation. For dermal absorption, based on the physical-chemical properties of the substance (molecular weight < 500 g/mol [129.157 g/mol], log Kow -1.03 at 25°C, water solubility very soluble in water (miscible with water at 20°C at any ratio) low uptake is expected. Low dermal absorption is supported by the absence of adverse effects in the acute dermal toxicity study with N-(2-Hydroxyethyl)-2-pyrrolidon. Based on the above physical-chemical properties, oral absorption is also expected to be low. The absence of systemic effects at the high doses tested in the available oral toxicity studies with N-(2-Hydroxyethyl)-2-pyrrolidon supports low oral absorption. As both oral and dermal absorption are expected to be low a default factor of 1 for oral-to-dermal extrapolation was used for DNEL derivation .

Acute toxicity

N-(2-Hydroxyethyl)-2-pyrrolidon does not have to be classified for acute toxicity and therefore derivation of aDNELacute is not necessary.

 

Repeated dose toxicity

N-(2-Hydroxyethyl)-2-pyrrolidon was administered daily to rats by gavage at doses of 0, 100, 300 or 1000 mg/kg bw/day. Regarding clinical examinations, signs of general systemic toxicity were not observed in male or female parental animals up to the 1000 mg/kg bw/d dose of the compound. No treatment related adverse effects were observed on body weight, food consumption, heamatology, clinical chemistry or urinalysis.No treatment-related effects were seen in the Functional Observational Battery (FOB) parameters either. No treatment related effects were observed on organ weights of the parental animals nor when expressed as absolute - or relative weights. In the offspring, there were no treatment-related effects on body weight at any dose level. There were no external abnormalities noted at any dose group either. No treatment-related deaths or clinical signs of systemic toxicity in pups during lactation were noted at any treatment group.

 

Irritation / Sensitisation / Mutagenicity

N-(2-Hydroxyethyl)-2-pyrrolidon is considered to be not irritating to the skin and eye. Since the SIs were lower than 3 at all concentrations in the available LLNA, the results indicated that N-(2-hydroxyethyl)-2-pyrrolidon should not be considered a skin sensitiser.

Based on the available genetic toxicity data; non-mammalian and mammalian (mutagenicity and chromosome aberration) in vitro assays, the test substance is not classified for mutagenicity and thus not considered to be mutagenic. The results of the conducted Ames tests were mixed as dependent on the purity of the test-substance mutagenicity was observed. This however, is not supported by the mammalian tests as no mutagenicity was observed in the chromosome aberration and in the gene mutation assay which is the most significant assay.

 

Reproduction toxicity

No reproductive toxicity and no developmental toxicity was observed in a combined repeated dose toxicity study with the reproduction/developmental toxicity screening test (OECD 422) in rats with N-(2 -Hydroxyethyl)-2 -pyrrolidon (tested at 0, 100, 300 or 1000 mg/kg bw/day). Thus, the NOAEL for reproductive and developmental toxicity was considered 1000 mg/kg bw/day. No DNEL has to be derived for developmental and reproductive toxicity.

 

DNEL derivation

For short-term toxicity, no DNEL needs to be derived for all routes of exposure, because N-(2-Hydroxyethyl)-2-pyrrolidon is not classified for acute toxicity.

 

Oral

For long-term toxicity, regarding systemic effects, a NOAEL of 1000 mg/kg bw/day was observed in a combined 28-day repeated dose toxicity study with reproduction/developmental toxicity screening test. This NOAEL is used in the derivation of the DNELs. An absorption of 50% is assumed for the oral route.

 

Inhalation

In the absence of route-specific information, route-to-route extrapolation was performed for DNEL calculation. A default factor of 2 for oral-to-inhalation extrapolation was used as proposed in Chapter R.8.4.2 of the REACH Guidance on information requirements and chemical safety assessment. It was assumed that there is no first pass effect (data to demonstrate this are lacking). The NOAEL from the combined 28-day repeated dose toxicity study with reproduction/developmental toxicity screening test was used for derivation of the systemic DNELlong-term for the inhalation route. An absorption of 100% is assumed for the inhalation route.

 

Dermal

Long-term dermal toxicity data are not available and therefore route-to-route extrapolation is performed. A default factor of 1 for oral-to-dermal extrapolation was used as proposed in Chapter R.8.4.2 of the REACH Guidance on information requirements and chemical safety assessment. It was assumed that there is no first pass effect (data to demonstrate this are lacking).

 

General population DNELs

Long-term – oral, systemic effects (based on combined oral toxicity, reproduction/ developmental toxicity screening study with rats)

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 1000 mg/kg bw/day

No effects observed at the highest dose tested

Step 2) Modification of starting point

-

-

Step 3) Assessment factors

 

 

Interspecies

4

Assessment factor for allometric scaling.

Intraspecies

10

Default assessment factor

Exposure duration

6

Subacute to chronic extrapolation

Dose response

1

 

Quality of database

1

 

DNEL

Value

 

1000 / (4 x 10 x 6 x 1 x 1) = 1000/240 = 4.17 mg/kg bw/day

Long-term – inhalation, systemic effects (based on combined oral toxicity, reproduction/developmental toxicity screening study with rats)

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 1000 mg/kg bw/day

No effects observed at the highest dose tested.

Step 2) Modification of starting point

2

 

 

1.15 m3/kg bw

 

  

Proportion inhalation absorption (default value, as proposed in the REACH guidance (R.8.4.2)

 

Standard respiratory volume of a rat, corrected for 24 h exposure, as proposed in the REACH Guidance (R.8.4.2) 

Modified dose-descriptor

1000 / 2 /1/1.15 = 435 mg/m3

Step 3) Assessment factors

 

 

Interspecies

1

No allometric scaling has to be applied in case of oral to inhalation route to route extrapolation.

Intraspecies

10

Default assessment factor

Exposure duration

6

Subchronic to chronic extrapolation

Dose response

1

 

Quality of database

1

 

DNEL

Value

 

435 / (1 x 10 x 6 x 1 x 1) = 435/60 = 7.25 mg/m3

Long-term – dermal, systemic effects (based on combined oral toxicity, reproduction/developmental toxicity screening study with rats)

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 1000 mg/kg bw/day

No effects observed at the highest dose tested.

Step 2) Modification of starting point

1

On the assumption that, in general, dermal absorption will not be higher than oral absorption, no default factor should be introduced when performing oral to dermal extrapolation.

Modified dose-descriptor

 

Step 3) Assessment factors

 

 

Interspecies

4

Assessment factor for allometric scaling.

Intraspecies

10

Default assessment factor

Exposure duration

6

Subacute to chronic extrapolation

Dose response

1

 

Quality of database

1

 

DNEL

Value

 

1000 / (4 x 10 x 6 x 1 x 1) = 1000/240 = 4.17 mg/kg bw/day