N-(n-octyl)-2-pyrrolidinone

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

17.45 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

Value:

174.5 mg/m³

Explanation for the modification of the dose descriptor starting point:

conversion from oral to inhalation (sRV * time = 0.8 L/min/kg bw rat *8*60 min = 0.38 m3/kg bw) and exposure adaption factor of the respiration volume for light activity (6.7 m3/10 m3 = 0.67)

AF for dose response relationship:

1

Justification:

NOAEL (oral, rat) = 100 mg/kg bw/d of an Ext. 1-Gen study with 3 doses.

AF for differences in duration of exposure:

2

Justification:

NOAEL of a sub-chronic study (Ext. 1-Gen study).

AF for interspecies differences (allometric scaling):

1

Justification:

Correction to NOAEC by route to route extrapolation.

AF for other interspecies differences:

1

Justification:

No evidence for species differences in the general mode of action (hepatic enzyme induction).

AF for intraspecies differences:

5

Justification:

default

AF for the quality of the whole database:

1

Justification:

Study according to GLP and OECD TG guideline.

AF for remaining uncertainties:

1

Justification:

default

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:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.5 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):

40

Modified dose descriptor starting point:

NOAEL

Value:

100 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

100 % resorption assumed (worst case). Calculated in vitro absorption by pig skin was 96 % (BASF AG, 2005).

AF for dose response relationship:

1

Justification:

NOAEL (oral, rat) = 100 mg/kg bw/d of an Ext. 1-Gen study with 3 doses.

AF for differences in duration of exposure:

2

Justification:

Given factor for a sub-chronic study (Ext. 1-Gen study).

AF for interspecies differences (allometric scaling):

4

Justification:

Given factor for scaling from rat to man.

AF for other interspecies differences:

1

Justification:

No evidence for species differences in the general mode of action (hepatic enzyme induction).

AF for intraspecies differences:

5

Justification:

default

AF for the quality of the whole database:

1

Justification:

Study according to GLP and OECD TG guideline.

AF for remaining uncertainties:

1

Justification:

default

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:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - workers

General considerations

As N-(n-Octyl)pyrrolidinone (NOP) is classified as Skin Corr. 1B, H314 (GHS EU), it should be attributed to a moderate hazard class according to the ECHA Guidance Part E - Risk Characterisation, E.3.4 (May 2008, updated Nov 2012). Appropriate RMMs (risk management measures) and OCs (operational conditions) should therefore be implemented, when developing exposure scenarios.

The primary route of anticipated occupational exposure to NOP is via skin contact. Given its low vapour pressure at room temperature (0.08 Pa at 20°C), inhalation of NOP is not likely to be high. However, exposition to aerosols or droplets of an inhalable size cannot be ruled out.

In animal studies NOP is virtually nontoxic after single ingestion (LD50 (oral, rat) > 2200 mg/kg bw; BASF AG, 1992), but of low toxicity after short-term skin contact (LD50 (dermal, rat) > 4000 mg/kg bw, with 3/10 dead animals after exposure to 4000 mg/kg bw; BASF AG, 1992). NOP was corrosive to the skin (OECD TG 404 study; BASF AG, 1992) and corrosive to the eyes (HET-CAM; BASF AG, 2006). NOP was not sensitizing in guinea pigs (GMPT; BASF AG, 1992). NOP was not mutagenic in bacteria and in mammalian cell culture (BASF AG, 2001 and 1992).

DNEL derivation: Point of departure

The starting point for the systemic long term inhalation and dermal DNEL is a NOAEL of 100 mg/kg bw/d, based on decreased body weight of female Wistar rats in an Extended One Generation Study (OECD TG 415 with exposure via diet; BASF AG, 2005). Pathology identified the liver and the thyroid glands as target organs. However, the increased liver weights in males and females at dose levels of 300 and 1000 mg/kg bw/d, as well as the occurrence of central hypertrophy/hyperplasia in the liver of high dose males and females were considered to be test substance related, but rather reflecting an adaptive effect (microsomal enzyme induction) than a toxicologically relevant and adverse finding. Additionally, the thyroid findings in males are considered to be secondary to the observed liver findings. Therefore, the males showed no adverse findings up to the highest dose of 1000 mg/kg bw/d. The NOAEL (fertility and reproduction) and NOAEL (developmental toxicity) were 1000 mg/kg bw/d and 300 mg/kg bw/d, respectively.

Supportingly, in a 28-day and a 90-day feeding study with NOP in rats (OECD TG 407 study, BASF AG 1992 and OECD TG 408, GAF Chemicals Corp. 1991) the NOEL was 50 mg/kg bw/d.

In the 90 -day study in dogs (ISP, 1991), the NOAEL was considered to be 30 mg/kg bw/d after oral administration via capsules. The significant effects seen at 90 mg/kg bw/d were limited to incidental cases for some blood parameters, a significant increase of liver weights and at worse mild hepatocellular hypertrophy. Using this NOAEL for DNEL derivation would result in comparable values compared to the current DNEL derivation. For example, the systemic long-term DNELs for workers are shown:

- inhalation DNEL = NOAEL (90d, oral, dog) /1.4 (allometric scaling) *70 kg bw /10 m3 (light work) / 2 (exposure duration) /5 (intraspecies differences) = 30 mg/kg bw/d /1.4 *70 kg bw /10 /2 /5 = 15 mg/m3.

- dermal DNEL = NOAEL (90d, oral, dog) /1.4 (allometric scaling) /2 (exposure duration) /5 (intraspecies differences) = 2.1 mg/kg bw/d.

No local (long term or acute/short term) DNELs and no systemic short term DNELs were derived, because NOP is classified as Skin Corr. 1B, H314 (GHS EU) and dose-response information is not available (ECHA Guidance Part R.8 - Characterisation of dose [concentration]-response for human health; Dec 2010, updated Nov 2012).

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

5.75 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

Dose descriptor starting point:

NOAEL

Value:

100 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

115 mg/m³

Explanation for the modification of the dose descriptor starting point:

NOAEC = NOAEL /1.15 m3/kg bw (ECHA GD R.8, p. 58 (v2.1, Nov 2012)

AF for dose response relationship:

1

Justification:

NOAEL (oral, rat) = 100 mg/kg bw/d of an Ext. 1-Gen study with 3 doses

AF for differences in duration of exposure:

2

Justification:

NOAEL of a sub-chronic study (Ext. 1-Gen study)

AF for interspecies differences (allometric scaling):

1

Justification:

Correction to NOAEC by route to route extrapolation

AF for other interspecies differences:

1

Justification:

Hepatic enzyme induction as an adaptive response is a general mode of action.

AF for intraspecies differences:

10

Justification:

default

AF for the quality of the whole database:

1

Justification:

Study according to GLP and OECD TG guideline.

AF for remaining uncertainties:

1

Justification:

default

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:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.25 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):

80

Dose descriptor starting point:

NOAEL

Value:

100 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

100 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

resorption (oral/dermal): *1

AF for dose response relationship:

1

Justification:

e1gen study with 3 doses

AF for differences in duration of exposure:

2

Justification:

e1gen study (subchronic --> chronic)

AF for interspecies differences (allometric scaling):

4

Justification:

Default factor for scaling from rat to man.

AF for other interspecies differences:

1

Justification:

Hepatic enzyme induction as an adaptive response is a general mode of action.

AF for intraspecies differences:

10

Justification:

default

AF for the quality of the whole database:

1

Justification:

GLP, OECD guideline studies

AF for remaining uncertainties:

1

Justification:

default

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:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.25 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):

80

Dose descriptor starting point:

NOAEL

Value:

100 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

no modification

AF for dose response relationship:

1

Justification:

e1Gen study with 3 doses

AF for differences in duration of exposure:

2

Justification:

e1Gen (subchronic --> chronic)

AF for interspecies differences (allometric scaling):

4

Justification:

default (rat --> human)

AF for other interspecies differences:

1

Justification:

Hepatic enzyme induction as an adaptive response is a general mode of action.

AF for intraspecies differences:

10

Justification:

default

AF for the quality of the whole database:

1

Justification:

GLP OECD guideline studies

AF for remaining uncertainties:

1

Justification:

default

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - General Population

For discussing general considerations and the point of departure, see discussion for workers above.