Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
29.62 mg/m³
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
25
Dose descriptor starting point:
NOAEL
Value:
300 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
740.52 mg/m³
Explanation for the modification of the dose descriptor starting point:

The corrected dose descriptor starting point (NOAEC) is obtained by conversion of the oral NOAEL of 300 mg/kg bw (F0 males systemic toxicity) from the Drinking water Extended One-Generation Reproductive Toxicity Study (EOGRTS) of 2-pyrrolidone in rats (according to OECD 443; Coder, 2020) taking into account the differences between experimental and human exposure conditions.

In detail, an oral absorption of 100 % and absorption by inhalation of 100 %, the sRV (standard respiratory volume of rats during 8 hours) of 0.38 m³/kg/day and a factor of 0.67 (derived of the standard respiratory volumes for workers under normal conditions and by light activity: 6.7 m³ and 10 m³) and a correction factor of 1.4 for differences in human and experimental exposure conditions: workers (5 working days) vs. rats (7 days continuous exposure) have been used.

The bioavailability between experimental animals and humans at the relevant level of exposure is assumed to be the same; therefore no further correction was necessary.

corrected NOAEC = 300 mg/kg bw/day * (100%/100%) *(1/0.38 m³/kg/day) * 0.67 m³ * 1.4 = 740.52 mg/m³

AF for dose response relationship:
1
Justification:
default (three doses were tested, using a spacing range of 2-4 fold)
AF for differences in duration of exposure:
2
Justification:
default (for extrapolation of subchronic to chronic exposure durations)
AF for interspecies differences (allometric scaling):
1
Justification:
default (no allometric scalling should be applied in case of oral-to-inhalation extrapolation)
AF for other interspecies differences:
2.5
Justification:
default (no substance and route specific information on toxicokinetic and toxicodynamic is available for animals and humans)
AF for intraspecies differences:
5
Justification:
default (for workers)
AF for the quality of the whole database:
1
Justification:
default (GLP guideline study of high quality)
AF for remaining uncertainties:
1
Justification:
default (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:
4.2 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
Dose descriptor starting point:
NOAEL
Value:
300 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
420 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

The corrected dose descriptor starting point (NOAEC) is obtained by conversion of the oral NOAEL of 300 mg/kg bw (F0 males systemic toxicity) from the Drinking water Extended One-Generation Reproductive Toxicity Study (EOGRTS) of 2-pyrrolidone in rats (according to OECD 443; Coder, 2020) taking into account the differences between experimental and human exposure conditions.

In detail, an oral absorption of 100 % and a dermal absorption of 100 % and a correction factor of 1.4 for differences in human and experimental exposure conditions: workers (5 working days) vs. rats (7 days continuous exposure) have been used.

The bioavailability between experimental animals and humans at the relevant level of exposure is assumed to be the same; therefore no further correction was necessary.

corrected NOAEC = oral NOAEL x (ABS oral-rat/ABS dermal-rat) x (ABS dermal-rat/ABS dermal-human) x (7/5 exposure) = 300 mg/kg bw/day * (100 %/100 %) * 1.4 = 420 mg/kg bw/day

AF for dose response relationship:
1
Justification:
default (three doses were tested, using a spacing range of 2-4 fold)
AF for differences in duration of exposure:
2
Justification:
default (for extrapolation of subchronic to chronic exposure durations)
AF for interspecies differences (allometric scaling):
4
Justification:
default (for rats)
AF for other interspecies differences:
2.5
Justification:
default (no substance and route specific information on toxicokinetic and toxicodynamic is available for animals and humans)
AF for intraspecies differences:
5
Justification:
default (for workers)
AF for the quality of the whole database:
1
Justification:
default (GLP guideline study of high quality)
AF for remaining uncertainties:
1
Justification:
default (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

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:

For 2 -pyrrolidone, DNELs are needed for long-term exposure by the inhalation and dermal exposure routes. Since 2 -pyrrolidone does not represent an acute hazard (not classified for acute toxicity), no DNELs need to be derived for acute / short.term exposures. Moreover, no DNELs are needed for local effects (acute /short-term and long-term exposure) because there is no adequate dose-response and route-specific information for these endpoints. Long-term systemic DNELs will cover sufficiently all local effects.

From all available data for the different human health endpoints it is clear that 2 -pyrrolidone exerts its effect by a threshold mode of action. Thus, DNELs can be calculated for the different threshold endpoints based on the most relevant dose descriptors per endpoint. DNELs are derived from the available toxicity data of 2 -pyrrolidone, reflecting the routes, duration and frequency of exposure. DNELs are derived for workers and the general population. The general population includes consumers and humans exposed via the environment. There are following annotations for each endpoint:

Acute/short-term exposure – systemic effects (dermal DNEL):

Chapter 8.7.3 of the REACH TGD (R.8) indicates that acute exposure DNEL values are not normally required. It is specified: "For some toxic substances, for which there may be peak exposures, a DNELacute need to be set and assessed in relation to the human peak exposure levels". This would be the case for substances with classification & labelling for acute hazards.

However, for 2 -pyrrolidone, "No hazard is identified” as it is not classified for acute hazards and has been shown to be not acutely toxic via the dermal route of exposure. The substance was non-toxic by ingestion in a vast majority of reliable studies (LD50 > 5,000 mg/kg bw). In addition no toxicity was found after percutaneous absorption (LD50 > 2,000 mg/kg bw) with the complete missing of substance related systemic effects at this dose.

So based on results of animal studies, 2-pyrrolidone does not pose an acute dermal hazard. Therefore, no acute / short-term DNEL for the dermal route of exposure is needed. Moreover, a DNEL would not be quantifiable (No adequate route-specific information) and local effects can be covered sufficiently by the long-term DNEL for systemic effects, provided high-peak acute exposure can be avoided.

Acute/short-term exposure – systemic effects (inhalation DNEL):

Chapter 8.7.3 of the REACH TGD (R.8) indicates that acute exposure DNEL values are not normally required. It is specified: "For some toxic substances, for which there may be peak exposures, a DNELacute need to be set and assessed in relation to the human peak exposure levels". This would be the case for substances with classification & labelling for acute hazards.

However, for 2 -pyrrolidone, "No hazard is identified” as it is not classified for acute hazards and has additionally a very low volatility with a vapor pressure of only 0.0175 hPa at 24.8 °C (BASF AG, 1994).

Moreover, the acute inhalation study on the test substance revealed an LC50 > 0.061 mg/L at saturated atmosphere (no death occurred, BASF AG, 1961).

So based on results of animal studies and the low vapour pressure 2-pyrrolidone does not pose an inhalation hazard and inhalation is not a likely route of exposure. Therefore, no DNEL is required and a DNEL is not quantifiable and not relevant (No adequate route-specific information) so that local effects can be covered sufficiently by the long-term DNEL for systemic effects.

Acute/short-term exposure – local effects (dermal DNEL):

Chapter 8.7.3 of the REACH TGD (R.8) indicates that acute and long-term local DNEL values are required for substances causing irritation, corrosion and/or sensitisation, assuming that the data allow setting a DNEL.

As such, "no hazard is identified" and no acute / short-term dermal DNEL for local effects is needed for 2 -pyrrolidone, since the substance has been found to be not irritating or sensitising to the skin. In detail, the substance 2-pyrrolidone was not irritating to the skin of rabbits after 4-hour application of test material. LD50 values above 2000 mg/kg bw with the complete missing of substance related systemic effects at this dose were reported for the test item in the dermal study. The substance is only irritating to the eyes (Eye Irrit. 2).

Therefore, an acute / short-term dermal DNEL is not quantifiable and not relevant (No adequate route-specific information) so that local effects can be covered sufficiently by the long-term DNEL for systemic effects.

Acute/short-term exposure – local effects (inhalation DNEL):

Chapter 8.7.3 of the REACH TGD (R.8) indicates that acute and long-term local DNEL values are required for substances causing irritation, corrosion and/or sensitisation, assuming that the data allow setting a DNEL.

As such, "no hazard is identified" and no acute / short-term inhalation DNEL for local effects is needed for 2 -pyrrolidone since the substance has been found to have a low vapour pressure (0.0175 hPa at 24.8 °C; BASF, 1994) and since it is not irritating or sensitising to the respiratory system. The substance is only irritating to the eyes (Eye Irrit. 2).

Therefore, a DNEL is not quantifiable and not relevant (No adequate route-specific information) so that local effects can be covered sufficiently by the long-term DNEL for systemic effects.

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

A repeated dose data is available for the substance. The NOAEL was 207 mg/kg bw/day in the subchronic oral study (90 days). Nonetheless, a dermal systemic DNEL is calculated from the dose descriptor starting point from the oral (drinking water) EOGRTS in which a NOAEL of 300 mg/kg bw was established for F0 males systemic toxicity (Coder, 2020). This value is considered most reliable, due to the longer exposure duration of 133 days compared to the one of the repeated dose toxicity study in which the rats were exposed for 90 days .

The starting point for the DNEL derivation is the oral NOAEL (route-to-route extrapolation necessary).

Modification of the starting point: corrected NOAEC = 300 mg/kg bw x (100 %/100 %) x (7/5) = 300 * 1.4 = 420 mg/kg bw/day.

Derivation of DNEL: corr. NOAEC / (1 * 2 * 4 * 2.5 * 5 * 1 *1) = corr. NOAEC / 100 = 420 mg/m³ / 100 = 4.20 mg / m³

(Assessment factor of 2 for subchronic-to-chronic extrapolation; 4 for allometric scaling; 2.5 for remaining interspecies differences and 5 for workers; as such the overall assessment factor is 100)

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

There are no dose-response and route-specific information on repeated dose toxicity via inhalation. This exposure route is not relevant due to the low vapour pressure and the substance does not pose a hazard for humans by the inhalation route of exposure.

However, an inhalation systemic DNEL is calculated from the oral EOGRTS in which a NOAEL of 300 mg/kg bw was established for F0 males systemic toxicity (route-to-route-extrapolation necessary).

Modification of the starting point: corrected NOAEC = 300 mg/kg bw x (1/0.38 m³) x (100 %/100 %) x (6.7/10)m³ x 1.4 = 740.52 mg/m³.

Derivation of DNEL: corr. NOAEC / (1 * 2 * 1 * 2.5 * 5 * 1 *1) = corr. NOAEC / 25 = 740.52 mg/m³ / 25 = 29.62 mg / m³

(Assessment factor of 2 for subchronic-to-chronic extrapolation; 2.5 for remaining interspecies differences and 5 for workers; as such the overall assessment factor is 25)

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

Chapter 8.7.3 of the REACH TGD (R.8) indicates that acute and long-term local DNEL values are required for substances causing irritation, corrosion and/or sensitisation, assuming that the data allow setting a DNEL.

As such, "no hazard is identified" and no long-term dermal DNEL for local effects is needed for 2 -pyrrolidone since the substance has been found to be not irritating or sensitising to the skin. In detail, the substance 2-pyrrolidone was not irritating to the skin of rabbits after 4-hour application of test material. LD50 values above 2000 mg/kg bw with the complete missing of substance related systemic effects at this dose were reported for the test item in the dermal study. The substance is only irritating to the eyes (Eye Irrit. 2).

Therefore, a DNEL is not quantifiable and not relevant (No adequate route-specific information) so that local effects can be covered sufficiently by the long-term DNEL for systemic effects.

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

Chapter 8.7.3 of the REACH TGD (R.8) indicates that acute and long-term local DNEL values are required for substances causing irritation, corrosion and/or sensitisation, assuming that the data allow setting a DNEL.

As such, "no hazard is identified" and no long-term inhalation DNEL for local effects is needed for 2 -pyrrolidone since the substance has been found to have a low vapour pressure (0.0175 hPa at 24.8 °C; BASF, 1994) and since it is not irritating or sensitising to the respiratory system. The substance is only irritating to the eyes (Eye Irrit. 2).

Therefore, a DNEL is not quantifiable and not relevant (No adequate route-specific information) so that local effects can be covered sufficiently by the long-term DNEL for systemic effects.

Mutagenicity / Eye and skin irritation/corrosion:

For the other non-threshold endpoints (mutagenicity, eye and skin irritation/corrosion) no DNELs can be derived because no No-Observed-Effect-Level could be established from the relevant studies. A qualitative risk assessment will be performed for mutagenicity and eye irritation as the substance is classified as Repr. 1B (H360) and Eye Irrit. 2 (H319).

 

Modification of the starting point:

From all available data on the 2-pyrrolidone for the different human health endpoints, it is clear that the substance exert its effects by a threshold mode of action. Thus, DNELs can be calculated for the different threshold endpoints based on the most relevant dose descriptors per endpoint. DNELs are derived based on the available toxicity data for the target reflecting the routes, the duration and the frequency of exposure. DNELs are derived for workers and the general population. The general population includes consumers and humans exposed via the environment.

Bioavailability (absorption):

There is substance-specific experimental information on absorption by the oral and dermal (percutan) route available. No experimental data on the inhalation route has been found. 2-pyrrolidone is readily absorbed via the intestinal tract and in addition percutaneously (Midgley et al., 1992). About 77.5 % of the percutaneous applied dose was absorbed through the skin. After oral administration, maximum plasma concentrations of the parent compound reached levels of 25 to 30 mg/L after 2 hours. The absorption rates are assessed based on the physico-chemical properties and on the effects observed in treated animals in the available studies.

For DNEL derivation purposes the worst case absorption values of 100 % were used (please also see remarks below).

Oral absorption:

Due to the molecular weight of 85.1 g/mol, a logPow of -0.71, high water solubility (completely miscible in water) together with the results found in the toxicokinetic studies, absorption via the oral route is considered to be high for the substance (for the detailed information on absorption please refer to section “Toxicokinetics, metabolism and distribution” of this CSR or section 7.1 of IUCLID file). The oral absorption is set to 100 % since physico-chemical properties and toxicokinetic data show significant absorption from the gastro-intestinal tract. The oral absorption is considered to be the same in animals and in humans (worst-case).

Dermal absorption:

Significant dermal absorption is expected for the 2-pyrrolidone. The log Pow of -0.71, the high water solubility and the low molecular weight of 85.1 g/mol point to a high absorption through the skin.In general, log P values between -1 and 4 are favourable for absorption (ECHA guidance R.7.C, 2017). Following, a default value of 100% skin absorption is generally used unless molecular mass is above 500 and log P is outside the range [-1, 4], in which case a value of 10% skin absorption is chosen (de Heer et al., 1999). Hence, for 2 -pyrrolidone a dermal absorption of 100 % is assumed. Dermal absorption in rats, rabbits and human is assumed to be the same since no information for dermal absorption of 2 -pyrrolidone in humans is available.

Reference:

1.      De Heer C, Wilschut A, Stevenson H and Hakkert BC (1999) Guidance document on the estimation of dermal absorption according to a tiered approach: an update.V98.1237. 1999. Zeist, NL, TNO.

 

Inhalation absorption

Absorption by inhalation is considered to be negligible due to the low vapour pressure (0.0175 hPa at 24.8 °C) and the high water solubility that might cause the substance to be retained in the mucus of the lung. Absorption by inhalation is expected not to be higher than absorption by oral route. However, 100 % absorption (worst case) is assumed for inhalation route and considered to be equal in rats and in humans since no substance specific information is available and worst-case assumption should be made for route-to-route extrapolation according to ECHA guidance R.8, 2012.

Route-to-route extrapolation:

Oral-to-inhalation extrapolation is performed to obtain a long-term inhalation NOAEC for systemic effects. The following formula was used:

corrected inhalatory NOAEC = oral NOAEL x (1/sRVrat) x (ABSoral-rat/ABSinh-human) x (6.7 m³/10 m³) x (7/5);

where sRV is standard respiratory volume of rats during 8 hours (= 0.38 m³/kg/day); ABS-absorption and 6.7 m³ and 10 m³ are standard respiratory volumes for workers under normal conditions and by light activity, and 7d/5d is the different exposure duration in rats and human workers - workers (5 working days) vs. rats (7 days continuous exposure)

 

Oral-to-dermal extrapolation is performed to obtain long-term dermal NOAEL for systemic effects. The following formula was used:

corrected dermal NOAEL = oral NOAEL * (ABS oral-rat/ABS dermal-rat) * (ABS dermal-rat/ ABSs dermal-human), * 7d/5d;

where ABS is absorption, and 7d/5d is the different exposure duration in rats and human workers - workers (5 working days) vs. rats (7 days continuous exposure)

Exposure conditions:

No modification of the starting points for exposure conditions was necessary since the systemic dose after oral administration of the test material was already assessed in respiratory volume taken for rats during 8 h (0.38 m³).

Differences in the respiratory volumes between experimental animals and humans were used when an oral rat NOAEL from the subchronic oral EOGRTS in rats was used to assess inhalation exposure in humans. 0.38 m³/kg/day is the standard respiratory volumes in rats during 8h exposure. 6.7 and 10 m³ are standard respiratory volumes for workers under normal conditions and by light activity, respectively.

Furthermore, the different exposure condition in human workers and rats was taken into account (workers - 5 working days - versus - rats - 7 days continuous exposure).

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 oral NOAEL from the subchronic oral EOGRTS in rats, which was used to derive the dermal long-term DNEL.

No allometric scaling factor was applied when the oral NOAEL from the EOGRTS was used for the derivation of inhalation long-term DNEL.

An assessment factor of 2.5 was always 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 endpoints and for all exposure routes.

Extrapolation of duration:

An assessment factor of 2 was applied for duration of exposure (subchronic study).

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 subchronic oral EOGRTS was used.

 

Calculation of of endpoint-specific DNELs for workers:

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

For the oral rat NOAEL of 300 mg/kg bw for F0 males systemic toxicity the following conversion was necessary:

corrected dermal NOAEC = oral NOAEL x (ABS oral-rat/ABS dermal-rat) x (ABS dermal-rat/ABS dermal-human) x (exposure of animals per week)

correc. dermal NOAEC = 300 x (100 %/100 %) x (100 %/ 100 %) x (7/5) = 420 mg/kg bw

DNEL = 420 mg/kg bw/(1 x 2 x 4 x 2.5 x 5 x 2 x 1 x 1) = 420 mg/kg bw/25 = 4.20 mg/kg bw.

Assessment factors are: 2 - study duration (subchronic-to-chronic extrapolation), 4 – interspecies, 2.5 – remaining interspecies differences, 5 – intraspecies, 1 – dose response, 1 – quality of data base.

The total AF amounts to 100.

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

The oral rat NOAEL of 300 mg/kg bw for F0 males systemic toxicity was converted into the inhalation NOAEC:

corrected inhalation NOAEC = oral NOAEL x (1/sRVrat) x (ABS oral-rat/ABS inhalation-human) x (6.7 m³/10 m³) x (Exposure of animals per week)

correc. inhal. NOAEC = 300 mg/kg bw x (1/0.38 m³) x (100 %/100 %) x (6.7/10)m³ x 1.4 = 740.52 mg/m³.

Derivation of DNEL: corr. NOAEC / (1 x 2 x 1 x 2.5 x 5 x 1 x 1) = corr. NOAEC / 25 = 740.52 mg/m³ / 25 = 29.62 mg / m³

Assessment factor are: 2 for subchronic-to-chronic extrapolation; 2.5 for remaining interspecies differences and 5 - intraspecies (for workers);

The total AF amounts to 25.

 

Selected DNELs

DNEL systemic dermal = 4.20 mg/kg bw

DNEL systemic inhalation = 29.62 mg/m³

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.985 mg/m³
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
50
Dose descriptor starting point:
NOAEL
Value:
134 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
99.26 mg/m³
Explanation for the modification of the dose descriptor starting point:

The corrected dose descriptor starting point (NOAEC) is obtained by conversion of the oral NOAEL of 134 mg/kg bw for F1 neonatal systemic toxicity from the Drinking water Extended One-Generation Reproductive Toxicity Study (EOGRTS) of 2-pyrrolidone in rats (according to OECD 443; Coder, 2020) taking into account the differences between experimental and human exposure conditions.

In detail, an oral absorption of 100 % and absorption by inhalation of 100 %, the sRV (standard respiratory volume of rats during 24 hours) of 1.35 m³/kg/day have been used (sRVhuman 8h for the general population = 6.7 / 60 kg = 0.1117 m³/kg bw/8 h, as such sRV human 24 h for the general population = 3.3351 m³/kg bw/24 h. Consequently the sRVrat 24 h = sRVhuman 24 h * 4 = 1.35 m³/kg bw/24 h).

The bioavailability between experimental animals and humans at the relevant level of exposure is assumed to be the same; therefore no further correction was necessary.

corrected NOAEC = 134 mg/kg bw/day * (100 %/100 %) *(1/1.35 m³/kg/day) = 99.26 mg/m³

AF for dose response relationship:
1
Justification:
default (three doses were tested, using a spacing range of 2-4 fold
AF for differences in duration of exposure:
2
Justification:
default (for extrapolation of subchronic to chronic exposure durations)
AF for interspecies differences (allometric scaling):
1
Justification:
default (no allometric scalling should be applied in case of oral-to-inhalation extrapolation)
AF for other interspecies differences:
2.5
Justification:
default (no substance and route specific information on toxicokinetic and toxicodynamic is available for animals and humans)
AF for intraspecies differences:
10
Justification:
default (for general population)
AF for the quality of the whole database:
1
Justification:
default (GLP guideline study of high quality)
AF for remaining uncertainties:
1
Justification:
default (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:
0.67 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):
200
Dose descriptor starting point:
NOAEL
Value:
134 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
134 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

The corrected dose descriptor starting point (NOAEC) is obtained by conversion of the oral NOAEL of 134 mg/kg bw for F1 males neonatal systemic toxicity from the Drinking water Extended One-Generation Reproductive Toxicity Study (EOGRTS) of 2-pyrrolidone in rats (according to OECD 443; Coder, 2020) taking into account the differences between experimental and human exposure conditions.

In detail, an oral absorption of 100 % and a dermal absorption of 100 % have been used.

The bioavailability between experimental animals and humans at the relevant level of exposure is assumed to be the same; therefore no further correction was necessary.

corrected NOAEC = oral NOAEL x (ABS oral-rat/ABS dermal-rat) x (ABS dermal-rat/ABS dermal-human) = 134 mg/kg bw/day * (100 %/100 %) = 134 mg/kg bw/day

AF for dose response relationship:
1
Justification:
default (three doses were tested, using a spacing range of 2-4 fold)
AF for differences in duration of exposure:
2
Justification:
default (for extrapolation of subchronic to chronic exposure durations)
AF for interspecies differences (allometric scaling):
4
Justification:
default (for rats)
AF for other interspecies differences:
2.5
Justification:
default (no substance and route specific information on toxicokinetic and toxicodynamic is available for animals and humans)
AF for intraspecies differences:
10
Justification:
default (for general population)
AF for the quality of the whole database:
1
Justification:
default (GLP guideline study of high quality)
AF for remaining uncertainties:
1
Justification:
default (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

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.67 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):
200
Dose descriptor starting point:
NOAEL
Value:
134 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Not applicable: oral study and oral exposure

The bioavailability between experimental animals and humans at the relevant level of exposure is assumed to be the same; therefore no further correction was necessary.

AF for dose response relationship:
1
Justification:
default (three doses were tested, using a spacing range of 2-4 fold)
AF for differences in duration of exposure:
2
Justification:
default (for extrapolation of subchronic to chronic exposure durations)
AF for interspecies differences (allometric scaling):
4
Justification:
default (for rats)
AF for other interspecies differences:
2.5
Justification:
default (no substance and route specific information on toxicokinetic and toxicodynamic is available for animals and humans)
AF for intraspecies differences:
10
Justification:
default (for the general population)
AF for the quality of the whole database:
1
Justification:
default (GLP guideline study of high quality)
AF for remaining uncertainties:
1
Justification:
default (no remaining uncertainties are identified)
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

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 target chemical in rats and in humans is available.

Respiratory volumes:

Adaptions in the respiratory volumes under normal conditions and by light activity in humans were taken into account. A default respiratory volume of 1.35 m³/kg bw for rats (general population) was used to convert dermal NOAEL into inhalation NOAEC, referring to 24h exposure instead of 8h (worker).

Additional explanation: the sRV (standard respiratory volume of rats during 24 hours) of 1.35 m³/kg/day has been used (sRVhuman 8h for the general population = 6.7 / 60 kg = 0.1117 m³/kg bw/8 h, as such sRV human 24 h for the general population = 3.3351 m³/kg bw/24 h. Consequently, the sRVrat 24 h = sRVhuman 24 h * 4 = 1.35 m³/kg bw/24 h).

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 DNELs for general population

Long-term exposure - systemic effects (oral):

The oral NOAEL of 134 mg/kg bw for F1 males neonatal systemic toxicity was not modified for differences in absorption by oral route since no substance- and route specific information is available: Oral NOAEL rat = oral NOAEL human = 134 mg/kg bw.

DNEL = 134 mg/kg bw/ (1 x 2 x 4 x 2.5 x 10 x 1 x 1) = 0.67 mg/kg bw.

Assessment factors are: 2 - study duration, 4 – interspecies, 2.5 – remaining interspecies differences, 10 – intraspecies, 1 – dose response (clear dose response), 1 – quality of data base (default).

The total AF amounts to 200.

Long-term exposure - systemic effects (dermal):

For the oral rat NOAEL of 134 mg/kg bw for F1 males neonatal systemic toxicity the following conversion was necessary:

dermal NOAEL = oral NOAEL x (ABS oral-rat/ABS dermal-rat) x (ABS dermal-rat/ABS dermal-human) = 134 mg/kg bw

DNEL = 134 mg/kg bw/(1 x 2 x 4 x 2.5 x 10 x 1 x 1) = 0.67 mg/kg bw.

Assessment factors are: 2 - study duration (subchronic-to-chronic extrapolation), 4 – interspecies, 2.5 – remaining interspecies differences, 10 – intraspecies, 1 – dose response, 1 – quality of data base.

The total AF amounts to 200.

 

Long-term exposure - systemic effects (inhalation):

The oral NOAEL of 134 mg/kg bw for F1 males neonatal systemic toxicity was converted into the inhalation NOAEC:

Corrected inhalation NOAEC = oral rat NOAEL x (1/1.35 m³/kg bw/day) x (ABS oral-rat/ABS inhal-human), where 1.35 is the standard respiratory volume (m³/kg bw) of rats during 24 h exposure (according to Functionalities of IUCLID 6 DNEL calculator), ABS is absorption (values are the same as described for workers).

Corrected Inhalation NOAEC = 134 mg/kg bw x (1/1.35 m³/kg/day) x (100%/100%) = 99.26 mg/m³

DNEL = 99.26 mg/m³/ (1 x 2 x 1 x 2.5 x 10 x 1 x 1) = 1.985 mg/m³.

Assessment factors are: 2 - study duration (subchronic-to-chronic extrapolation), 2.5 – remaining interspecies differences, 10 – intraspecies, 1 – dose response (clear dose response), 1 – quality of data base (default).

The total AF amounts to 50

 

Selected DNELs

DNEL systemic oral = 0.67 mg/kg bw

DNEL systemic dermal = 0.67 mg/kg bw

DNEL systemic inhalation = 1.985 mg/m³