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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
24.1 mg/m³
Most sensitive endpoint:
developmental toxicity / teratogenicity
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:
600 mg/m³
Modified dose descriptor starting point:
NOAEC
Value:
301.5 mg/m³
Explanation for the modification of the dose descriptor starting point:

Default (DNEL generation plugin)

AF for dose response relationship:
1
Justification:
Default (DNEL generation plugin)
AF for differences in duration of exposure:
1
Justification:
No AF is required since it is a developmental study.
AF for interspecies differences (allometric scaling):
1
Justification:
Default (DNEL generation plugin)
AF for other interspecies differences:
2.5
Justification:
Default (DNEL generation plugin)
AF for intraspecies differences:
5
Justification:
Default (DNEL generation plugin)
AF for the quality of the whole database:
1
Justification:
Default (DNEL generation plugin)
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties are identified
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:
10 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Dermal
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
50
Dose descriptor starting point:
NOAEL
Value:
500 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
500 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

No correction for differences between human and experimental exposure conditions is needed because exposure duration of 23 hours was in the dermal developmental toxicity study.

AF for dose response relationship:
1
Justification:
Default (DNEL generation plugin)
AF for differences in duration of exposure:
1
Justification:
No AF is required since it is a developmental study.
AF for interspecies differences (allometric scaling):
4
Justification:
Default (DNEL generation plugin)
AF for other interspecies differences:
2.5
Justification:
Default (DNEL generation plugin)
AF for intraspecies differences:
5
Justification:
Default (DNEL generation plugin)
AF for the quality of the whole database:
1
Justification:
Default (DNEL generation plugin)
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties are identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - workers

The calculation of the DNELs is performed in accordance with the principles given in ECHA (2012) “Guidance of Information Requirements and Chemical Safety Assessment, Chapter R.8: Characterisation of dose [concentration]-response for human health”.

Available dose descriptors:

N-Butylpyrrolidone is acutely toxic by oral route of exposure (LD50 = 300 - 2000 mg/kg bw, Harlan Laboratories, 2013; Report No. D41574) but not toxic by dermal route because LD50 value is > 2000 mg/kg bw (Harlan Laboratories, 2014a; Report No. 41401170). Inhalation is not relevant route of exposure due to the low vapour pressure of the substance (13 Pa at 25 °C) (Envigo, 2016). The substance is non-volatile and therefore no risk of irritation or sensitisation of respiratory tract exists. The substance is not acutely toxic via the dermal route of exposure, it is irritating but not sensitising to skin (Charles River Laboratories, 2014a; Report No. 20050801; Harlan Laboratories, 2015, Report No. 41500248). The available acute dermal toxicity study revealed only very slight erythema, small superficial scattered scabs and glossy skin. No other signes of dermal irritation were noted. The available dermal developmental toxicity study revealed no dermal findings at any dose level. Therefore, no DNELs for acute/short-term exposures (systemic and local effects) and for long-term exposures (local effects for both inhalation and dermal routes) need to be derived for workers. The systemic DNEL for long-term effects sufficiently covers local effects. However, an acute DNEL for oral route needs to be derived for consumers because N-butylpyrrolidone is classified into Cat. 4 (H302: Harmful if swallowed).

For the long-term exposure – systemic effects (inhalation and dermal DNEL), the NOAEC of 0.6 mg/L (corresponding to 152.6 mg/kg bw) and the NOAEL of 500 mg/kg bw established in the inhalation and dermal developmental toxicity studies, respectively, (Charles River Laboratories, 2016c,b; Report No. WIL - 387081 and WIL - 387079, respectively) were used as the starting points. Since developmental toxicity is the endpoint of concern for the structural analogues N-methylpyrrolidone and N-ethylpyrrolidone, the preference is given to developmental toxicity studies to derive the DNELs.

For the other non-threshold endpoints (mutagenicity, eye and skin irritation/corrosion) no DNELs can be derived because a No-Observed-Effect-Level could not be established from the relevant studies.

Modification of the starting point:

From all available data on the target and read-across substances it is clear that these substances exert their effects by a threshold mode of action. Thus, DNELs can be calculated for the threshold endpoints based on the most relevant dose descriptors per endpoint. DNELs are derived for workers and consumers.

Bioavailability (absorption):

There is substance-specific experimental information available on absorption by the oral route of exposure (an OECD 417 pharmacokinetic study in rats). Absorption rates for dermal and inhalation routes are assessed based on the physico-chemical properties of the substance and on the effects observed in treated animals in the available studies.

Oral absorption:

N-butylpyrrolidone was fully absorbed to systemic circulation following oral dosing in male rats (OECD 417; Charles River Laboratories, 2016; Report No. 387082).

Molecular weight of 141.2490 g/mol, the Log Pow value of 1.256 and high water solubility (N-Butylpyrrolidone is miscible with water in all proportions) are supportive for an extended absorption by oral route of exposure. The effects observed in animal studies: the oral 90-day study (Harlan Laboratories, 2014b, Report No. 41303953) and the oral developmental study in rats (Charles River Laboratories, 2016a; Report No.: WIL - 387076) point to a significant absorption by oral route of exposure (for the detailed information on absorption please refer to section "Toxicokinetics, metabolism and distribution" of the CSR or section 7.1 of the IUCLID file). The oral absorption is set to 100 % (worst-case) for the purposes of hazard assessment (DNEL derivation). The oral absorption is considered to be the same in animals and in humans (worst-case).

Dermal absorption:

Moderate dermal absorption potential is expected for the target substance. The molecular weight of 141.2 g/mol and Log Pow value of 1.256 are favourable for dermal absorption while high water solubility (above 10,000 mg/L is expected for substances fully miscible in water) may hinder the substance’ transfer through the outer skin layer. Taking into account effects in animals studies, no signs of systemic toxicity were noted in animals treated dermally for 24 hours in the acute dermal study in rats (Harlan Laboratories, 2014a; Report No. 41401170) while deaths and clinical signs were noted in animals treated orally (Harlan Laboratories, 2013; Report No. D41574). Similarly, a lower NOAEL of 400 mg/kg bw was established in the oral developmental toxicity study (Charles River Laboratories, 2016a; Report No.: 387076) vs NOAEL of 500 mg/kg bw in the dermal developmental toxicity study (Charles River Laboratories, 2016b; Report No.: WIL - 387079). These findings point to a lower absorption potential of N-Butylpyrrolidone through the skin than via the gastrointestinal tract. Based on these data, 50 % dermal absorption is considered appropriate. Dermal absorption in rats and in humans is assumed to be the same since no information for dermal absorption of N-Butylpyrrolidone in humans is available.

Inhalation absorption

Absorption by inhalation is considered to be negligible since the substance may be not available for inhalation as a vapour due to its vapour pressure of 13 Pa at 25 °C (ECHA guidance R.7C, Table R.7.12-2). Absorption by inhalation is expected not to be higher than absorption by oral route. Therefore, 50 % absorption is assumed for inhalation route and considered to be equal in rats and in humans since no substance specific information is available.

Route-to-route extrapolation:

No correction for differences between routes of exposure is necessary since there is a dose descriptor for the same route in experimental animals as for a given human exposure route (three developmental studies in rats by oral, dermal and inhalation routes).

Exposure conditions:

Modification of the starting point for exposure conditions was necessary for inhalation route since the exposure by inhalation was 6 h in the developmental study while 8 h is the exposure in workers during a working shift. Further, a correction for differences in the respiratory volumes of workers under normal conditions (6.7 m³) and by light activity (10 m³) has been accounted.

No correction for daily exposure duration is necessary for dermal route because the exposure duration of 23 hours was in the dermal developmental toxicity study that covers largerly a potentially absorbed through the skin dose during 8 -h working shift in workers.

Applying of assessment factors and calculation of DNELs:

The assessment factors have been applied to the corrected starting point to obtain the endpoint specific DNELs. Assessment factors (AFs) correct uncertainties and variability within and between species in the effect data.

Interspecies differences:

The species-specific default assessment factor of 4 for allometric scaling for rats was applied in the case of employment of the dermal and oral NOAELs from developmental studies to derive the dermal and oral (only for general population) long-term DNELs.

No allometric scaling factor was applied in case of inhalation NOAEC using for the derivation of inhalation long-term DNEL.

An assessment factor of 2.5 was applied for remaining interspecies differences in toxicodynamics between rat and human in all cases.

Intraspecies differences:

An assessment factor of 5 was applied for workers for all exposure routes.

Extrapolation of duration:

No assessment factor is necessary when using NOAE(C)L from the developmental studies.

Quality of whole data base:

A default assessment factor of 1 was used.

Issues related to dose response:

A default assessment factor of 1 was applied when the NOAEL from the 90-day study was used (there was a clear dose response).

Calculation of DNELs:

Long-term exposure – systemic effects (inhalation DNEL):

The inhalation rat NOAEC of 0.6 mg/L (600 mg/m³) was corrected for differences in exposure conditions:

Corrected inhalation NOAEC = inhalation NOAEC x (6h/8h) x (6.7 m³/10 m³) = 600 mg/m³ x (6/8) x (6.7/10) = 301.5 mg/m³

DNEL = 301.5 mg/m³/(2.5 x 5 x 1 x 1 x 1) = 24.12 mg/m³.

Assessment factors are: 2.5 – remaining interspecies differences, 5 – intraspecies, 1 – study duration (developmental study), 1 – dose response, 1 – quality of data base. The total AF amounts to 12.5.

Long-term exposure – systemic effects (dermal DNEL):

For the dermal rat NOAEL of 500 mg/kg bw no modification was necessary, because dermal absorption is considered to be the same in animals and in humans. Additionally, an exposure duration of 23 hours in the dermal developmental study was sufficient to ensure that amount of the substance that could be dermally absorbed during 8 -h working shift by workers is not underestimated:

DNEL = 500 mg/kg bw/(4 x 2.5 x 5 x 1 x 1 x 1) = 10 mg/kg bw.

Assessment factors are: 4 – interspecies, 2.5 – remaining interspecies differences, 5 – intraspecies, 1 – study duration (sub-chronic study), 1 – dose response, 1 – quality of data base. The total AF amounts to 50.

Selected DNELs

DNEL systemic inhalation = 24.1 mg/m³

DNEL systemic dermal (long-term) = 10 mg/kg bw

 

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4.29 mg/m³
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
25
Dose descriptor starting point:
NOAEC
Value:
600 mg/m³
Modified dose descriptor starting point:
NOAEC
Value:
107.1 mg/m³
Explanation for the modification of the dose descriptor starting point:

Default (DNEL generation plugin)

AF for dose response relationship:
1
Justification:
Default (DNEL generation plugin)
AF for differences in duration of exposure:
1
Justification:
No AF is required since it is a developmental study.
AF for interspecies differences (allometric scaling):
1
Justification:
Default (DNEL generation plugin)
AF for other interspecies differences:
2.5
Justification:
Default (DNEL generation plugin)
AF for intraspecies differences:
10
Justification:
Default (DNEL generation plugin)
AF for the quality of the whole database:
1
Justification:
Default (DNEL generation plugin)
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties are identified.
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:
5 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Dermal
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
100
Dose descriptor starting point:
NOAEL
Value:
500 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
500 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

No correction for differences between human and experimental exposure conditions is needed because exposure duration of 23 hours was in the dermal developmental toxicity study.

AF for dose response relationship:
1
Justification:
Default (DNEL generation plugin)
AF for differences in duration of exposure:
1
Justification:
No AF is required since it is a developmental study.
AF for interspecies differences (allometric scaling):
4
Justification:
Default (DNEL generation plugin)
AF for other interspecies differences:
2.5
Justification:
Default (DNEL generation plugin)
AF for intraspecies differences:
10
Justification:
Default (DNEL generation plugin)
AF for the quality of the whole database:
1
Justification:
Default (DNEL generation plugin)
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties are identified.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other:
Overall assessment factor (AF):
100
Dose descriptor starting point:
NOAEL
Value:
400 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
400 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Default (DNEL generation plugin)

AF for dose response relationship:
1
Justification:
Default (DNEL generation plugin)
AF for differences in duration of exposure:
1
Justification:
No AF is required since it is a developmental study.
AF for interspecies differences (allometric scaling):
4
Justification:
Default (DNEL generation plugin)
AF for other interspecies differences:
2.5
Justification:
Default (DNEL generation plugin)
AF for intraspecies differences:
10
Justification:
Default (DNEL generation plugin)
AF for the quality of the whole database:
1
Justification:
Default (DNEL generation plugin)
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties are identified.
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4 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):
100
DNEL extrapolated from long term DNEL
Dose descriptor starting point:
NOAEL
Value:
400 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
400 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

not applicable

AF for dose response relationship:
1
Justification:
default
AF for interspecies differences (allometric scaling):
4
Justification:
default
AF for other interspecies differences:
2.5
Justification:
default
AF for intraspecies differences:
10
Justification:
default
AF for the quality of the whole database:
1
Justification:
default
AF for remaining uncertainties:
1
Justification:
Factor of 1 is used to extrapolate the acute DNEL from the long-term DNEL.

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - General Population

The principles of the DNEL calculation for the general population are the same as already described for workers. However, there are additional considerations or deviations for:

Modification of the starting point:

Bioavailability (absorption):

The oral absorption in rats and in humans is assumed to be the same since no information for oral absorption for the target substance in rats and in humans is available.

Exposure conditions:

No differences in the respiratory volumes under normal conditions and by light activity in humans were taken into account. A correction factor of 0.178571 (from the DNEL-calculator plug-in) is used to account differences between daily exposure conditions (6h vs 24 h) of animals and humans, respectively, and for uncertainties related to daily recovery periods of 18 hours in animals vs no recoveries during continuous 24 hours exposure in general population.

Applying of assessment factors:

A higher assessment factor of 10 (in place of 5 for workers) for intraspecies variation/differences of human population was used.

Calculation of endpoint-specific DNEL for general population

Long-term exposure - systemic effects (inhalation):

The inhalation NOAEC of 600 mg/m³ was converted into the corrected inhalation NOAEC:

Corrected inhalation NOAEC = inhalation rat NOAEC x 0.178571.

Inhalation NOAEC = 600 mg/m³ x 0.178571 = 107.1 mg/m³

DNEL = 107.1 mg/m³/(2.5 x 10 x 2 x 1 x 1) = 4.3 mg/m³.

Assessment factors are: 2.5 – remaining interspecies differences, 10 – intraspecies, 1 – study duration (developmental study), 1 – dose response (clear dose response), 1 – quality of data base (default). The total AF amounts to 25.

Long-term exposure - systemic effects (dermal):

No correction was necessary for dermal rat NOAEL of 500 mg/kg bw (please see above: workers).

DNEL = 500 mg/kg bw/(4 x 2.5 x 10 x 1 x 1 x 1) = 5 mg/kg bw.

Assessment factors are: 4 – interspecies, 2.5 – remaining interspecies differences, 10 – intraspecies, 1 – study duration (developmental study), 1 – dose response, 1 – quality of data base. The total AF amounts to 100.

Long-term exposure - systemic effects (oral):

The oral NOAEL of 400 mg/kg bw does not need to be modified.

The oral NOAEL of 400 mg/kg bw was not modified for differences in absorption by oral route in rats and in humans since no information on oral absorption is available for humans: oral absorptionrat= oral absorptionhuman.

DNEL = 400 mg/kg bw/(4 x 2.5 x 10 x 1 x 1 x 1) = 4 mg/kg bw. Assessment factors are: 4 – interspecies, 2.5 – remaining interspecies differences, 10 – intraspecies, 1 – study duration (developmental study), 1 – dose response (clear dose response), 1 – quality of data base (default). The total AF amounts to 100.

Acute/short-term exposure - systemic effects (oral):

Acute oral toxicity of N-Butylpyrrolidone determined by acute toxic class method according to OECD 423 guideline resulted in LD50 of 300 -2000 mg/kg bw leading to classification and labelling into Cat. 4 (H302: harmful if swallowed) (Harlan Laboratories, 2013; Report No. D41574). Therefore, a DNEL for acute toxic effects by oral route needs to be derived. At 300 mg/kg bw, the lowest dose tested, no mortalities were observed in treated animals. The animals had only slightly decreased activity and ruffled fur. Therefore, the dose of 300 mg/kg bw can be considered as NOAEL.

The acute oral NOAEL of 300 mg/kg bw needs not to be modified for differences in absorption by oral route in rats and in humans since no substance- and route specific information is available: oral absorptionrat= oral absorptionhuman.

DNEL = 300 mg/kg bw/(4 x 2.5 x 10 x 1 x 1 x 1) = 3 mg/kg bw. Assessment factors are: 4 – interspecies, 2.5 – remaining interspecies differences, 10 – intraspecies, 1 – study duration (acute exposure in humans and acute study), 1 – dose response (NOAEL is used), 1 – quality of data base (default). The total AF amounts to 100.

Since the derived DNEL of 3 mg/kg bw is close to the long-term DNEL of 4 mg/kg bw, it appears that the long-term DNEL is more appropriate due to uncertainties related to the DNEL derivation method using "acute NOAEL". Therefore, the long-term DNEL of 4 mg/kg bw is considered valid also for the acute DNEL.

Selected DNELs

DNEL systemic inhalation = 4.3 mg/m³

DNEL systemic dermal (long term) = 5 mg/kg bw

DNEL systemic oral (long-term) = 4 mg/kg bw

DNEL systemic oral (acute/short-term) = 4 mg/kg bw