Registration Dossier

Administrative data

Description of key information

Oral: Taminco, 1999. 2-Pyrrolidone: Acute oral toxicity (Limit test) in the rat. According to the OECD guideline 401, rats, Sprague Dawley, gavage, 2000 mg/kg bw (male, female).
Dermal: MB Research, 1992. Acute oral toxicity (Limit test). Report No.MB-92-1432. According to the OECD guideline 402, rabbits New Zealand White, occlusive, 24 h, 2000 mg/kg bw.
Inhalation: BASF AG, 1961. Results of the toxicological pretesting, Pyrrolidone distilled. Report No. IX/407. Comparable to the OECD guideline 403, rats, whole body, 8h, saturated atmosphere.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1998-11-30 to 1998-12-17
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP study performed according to OECD guideline 401 and EU Method B1 with acceptable restriction which do not impair the overall conclusion from the data (purity of the test item is missing).
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study
Qualifier:
according to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
yes
Remarks:
1) No 95%-CI for LD50; 2) No dose-mortality curve and slope
Qualifier:
according to
Guideline:
EU Method B.1 (Acute Toxicity (Oral))
Principles of method if other than guideline:
Not applicable
GLP compliance:
yes (incl. certificate)
Remarks:
The Departament of health of the Goverment of the UK
Test type:
fixed dose procedure
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River (UK) Ltd., Margate, Kent, UK
- Age at study initiation: 8-12 weeks
- Weight at study initiation: males: 211-235 g/females: 200-225 g
- Fasting period before study: overnight
- Housing: groups of 5 by sex in solid-floor polypropylene cages furnished with woodflakes
- Diet: ad libitum Rat and Mouse expanded diet no. 1 (special diets services limited, Witham, Essex, UK)
- Water: ad libitum
- Acclimation period: at least 5 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-21 deg C
- Humidity (%): 44-67 %
- Air changes (per hr): 15 air changes per hr
- Photoperiod (hrs dark / hrs light): 12 hrs dark / 12 hrs light


IN-LIFE DATES: From: no data To: no data
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
MAXIMUM DOSE VOLUME APPLIED:
1.81 ml/kg (range finding study)

Doses:
2000 mg/kg bw (male, female)
No. of animals per sex per dose:
5 males dosed 2000 mg/kg bw
5 females dosed 2000 mg/kg bw
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: observations 0.5, 1, 2, 4 h after dosing and once daily for 14 days/ weighing prior to dosing on day 0 and on days 7 and 14
- Necropsy of survivors performed: yes (at the end of the study the animals were killed by cervical dislocation and subjected to gross pathatological examination)
- Other examinations performed: clinical signs (hunched posture), body weight, histopathology (external examination, opening of abdominal and thoracic cavities for examination of major organs)
Statistics:
no data
Preliminary study:
Range-finding test with 1 male and 1 female dosed once orally with 2 g/kg revealed reversible clinical effects (hunched posture) 2 days post-dosing
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Mortality:
no deaths
Clinical signs:
Incidents of hunched posture were noted in all treated animals during the day of dosing and persisted in one male on Day 1. All animals appeared normal two days after treatment (Table 1 in "Remarks on results")
Body weight:
Expected gain in bodyweight observed in all animals during the stuy.
Gross pathology:
no abnormalities
Other findings:
no data

Table 1: Individual Clinical Observations and Mortality Data

Dose level 

Animal 

Effects noted after dosing (hours)

         Effects noted during period after dosing (days)                                  

(mg/kg) 

 No.

 0,5

10 

11 

12 

13 

14 

2000

Male 3-0 

0

H

H

H

Male 3-1 

H

H

H

Male 3-2 

H

H

H

H

0

Male 3-3 

0

H

H

H

Male 3-4 

H

H

H

0

 0

0

Female 4-0 

H

H

H

H

Female 4-1

H

H

H

H

Female 4-2

H

H

H

0

Female 4-3 

0

H

H

H

Female 4-4

H

H

H

0

 0

0

0 = no signs of systemic toxicity

H = hunched posture

Interpretation of results:
other: no symbol and risk phrase required
Remarks:
Criteria used for interpretation of results: other: EC labelling regulations
Conclusions:
Acute oral median lethal dose (LD50) of 2-pyrrolidone in the Sprague-Dawley CD strain rat was found to be greater than 2000 mg/kg bodyweight.
Executive summary:

The study was performed to assess the acute oral toxicicty of the test material in the Sprague-Dawley CD strain rat. The method of the study is according to the OECD Guideline 401 and is compliant to the GLP requirements.

A single oral dose of undiluted test material at dose level of 2000 mg/kg/bw was given to a group of ten fasted animals. The animals were observed within 14 days for signs of toxicity.

There were no deaths. Incidents of hunched posture were noted in all treated animals during the day of dosing. All animals appeared to be normal one to two days after treatment. No abnormalities were noted at necropsy.

The LD50 was found to be greater than 2000 mg/kg/bw.

Endpoint conclusion
Dose descriptor:
LD50
Value:
2 000 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline study with acceptable restrictions
Principles of method if other than guideline:
BASF-Test: Test was performed in principle as described in OECD Guideline 403.
The test demonstrates the toxicity of an atmosphere saturated with vapours of the volatile components of a test substance at the temperature chosen for vapour generation (room temperature). 3 rats per sex were exposed sequentially to the vapours, generated by bubbling 200 l/h air through a substance column of about 5 cm above a fritted glass disc in a glass cylinder for 8 h. The documentation of clinical signs was performed over a period of 7 days.
GLP compliance:
no
Test type:
other: BASF Inhalation Test
Species:
rat
Strain:
other: Hannover
Sex:
male/female
Details on test animals and environmental conditions:
Mean body weight at test initiation: ca. 152 g
Route of administration:
inhalation: vapour
Type of inhalation exposure:
not specified
Vehicle:
other: unchanged (no vehicle)
Analytical verification of test atmosphere concentrations:
no
Duration of exposure:
8 h
Concentrations:
saturated vapour
No. of animals per sex per dose:
6
Control animals:
no
Details on study design:
- Duration of observation period following administration: 7 days
- Frequency of observations: daily
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs
Sex:
male/female
Dose descriptor:
other: IRT (Inhalation Risk Test)
Exp. duration:
8 h
Remarks on result:
other: mortality 0/6 animals
Sex:
male/female
Dose descriptor:
LC0
Effect level:
0.061 mg/L air (nominal)
Based on:
test mat.
Exp. duration:
8 h
Mortality:
All animals survived.
Clinical signs:
other: An intermittent agitation of the animals was noticed shortly after treatment initiation.
Body weight:
The mean body weight was ca. 152 g at test initiation, and ca. 166 g at the end of the observation period.
Gross pathology:
No treatment related changes observed.

The inhalation of a enriched/saturated vapor-air-mixture caused no mortality within 8 h.

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: expert judgment
Conclusions:
nontoxic if inhaled
Executive summary:

The sudy was performed according a standard inhalation hazard BASF Test. The principles of the performing of this test is similar with the requirements of the OECD guideline 403.

A saturated test atmosphere of test material was generated. At this conditions 0/6 rats died after 8 h exposure (BASF AG 1961). Intermittent agitation directly after treatment ignition was the only clinical sign observed; there were no necropsy findings in the survivors after 7 d observation period.

No LC50 value could be established because no mortalities were occured during the test. LC0 is 0.061 mg/L (saturated atmosphere)

Endpoint conclusion
Dose descriptor:
discriminating conc.
Value:
61 mg/m³

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Peer reviewed database
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals and environmental conditions:
Following a quarantine period of at least one week, five healthy male and five healthy female New Zealand Albino rabbits were randomly assigned to the treatment group. The pretest weight range was 2.3 -2.6 kg for males and 2.1 -2.5 kg for females. The test article was used as received and the dose was based on the sample weight as calculated from the specific gravity. The test article was applied to the prepared dermal site, one time, by syringe type applicator at a dose level of 2.0 g/kg. The test site was covered with a gauze patch, secured with non-irritating tape and gentle pressure was applied to the gauze to aid the distribution of the test article over the area. The torso was wrapped with plastic that was secured with non-irritating tape. At 24-hours after initiation, the patches were removed and residual test article was removed with distilled water.
Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
REMOVAL OF TEST SUBSTANCE
- Washing (if done): water
Duration of exposure:
24 h
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
5
Control animals:
not specified
Details on study design:
The animals were observed 1, 2 and 4 hours post dose and once daily for 14 days for toxicity and pharmacological effects. Animals were observed twice daily for 14 days for mortality. The test sites were scored for dermal irritation at 24 hours post dose and on days 7 and 14 using the numerical Draize scale. Body weights were recorded pretest, weekly and at death or termination. All animals were examined for gross pathology. Abnormal tissues were preserved in 10% buffered formalin and saved for possible future microscopic examination.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Mortality:
All animals survived the 2000 mg/kg dermal application.
Clinical signs:
There were no abnormal systemic signs noted in 9/10 animals. One male exhibited red staining of the nose/mouth area and an apparent cataract in the right eye on day 5, with the ocular abnormality persisting through day 14 but this was considered to result from a self-inflicted injury unrelated to test material administration.
Body weight:
Body weight gains were normal at all weighing periods.
Gross pathology:
Necropsy did not reveal any treatment related changes.
Other findings:
IRRITATION EFFECTS
Dermal reactions were slight to well-defined on day 1 but were absent on days 7 and 14.
Interpretation of results:
practically nontoxic
Remarks:
Migrated information Criteria used for interpretation of results: expert judgment
Conclusions:
2-pyrrolidone is nontoxic to the rabbit skin.
Executive summary:

The study was performed according to the OECD Guideline 402 and is comliant to the GLP requirements.

The 5 albino New Zealand White rabbits were administered dermal to a single dose of 2 -pyrrolidone at dose level of 2000 mg/kg/bw under occlusive conditions for 24 h.

There were no deaths, systemic signs of toxicity and no treatment related changes at necropsy. The body weight gain was normal. The dermal reactions were slight to well-defined. Such reactions are considered to be adaptive in nature.

2 -pyrrolidone is not toxic to the skin.

Endpoint conclusion
Dose descriptor:
LD50
Value:
2 000 mg/kg bw

Additional information

Acute toxicity: oral

In the GLP- and OECD-compliant acute oral toxicity study (Taminco, 1999), 2000 mg/kg bw was administered by gavage to Sprague Dawley rats. The animals were observed for signs of toxicity during 14 days. Thereafter, all animals were sacrificed and subjected to gross pathological examination. Major organs were investigated histopathologically. Hunchered posture was a clinical sign and nothing was found at necropsy. All animals appeared normal two days after treatment.

In a limit test five male and five female Sprague-Dawley rats were treated with 5000 mg/kg bw under standardized conditions; the test method is comparable to OECD guideline 401 (BASF AG, 1981). The animals were observed for 14 days, necropsy was performed even with the survivors. The LD50 is >5000 mg/kg bw for male and female rats. There were no mortalities, clinical signs of toxicity and no abnormalities at necropsy were observed. LD50 of ca. 5000 mg/kg bw was also established in an old BSF study (BASF, 1953).

In another supporting study using again a test method comparable to OECD guideline 401, five Wistar rats per sex were administered 5000, 6400, 8000 and 10000 mg/kg bw, respectively (BASF AG 1961). The animals were observed for 14 days, necropsy was performed even with the survivors. Here, the LD50 was ca. 8000 mg/kg bw. Mortality was observed in the two highest doses. Clinical signs were reported for all groups mainly including staggering, convulsive twitches, prone or  lateral position and intermittent breathing. The surviving animals of the 8000 mg/kg bw group recovered within 5 days, lower dosed animals within two days. Necropsy of the animals that died during the observation period revealed fatty liver and mouldered gastro-intestinal tracts, while survivors showed no necropsy findings. A higher concentration range of 2 -pyrrolidone (3200, 6400, 8000, 10,000 and 12,5000 µL/kg bw (ca. 3700 -14500 mg/kg bw)) was tested in Sprague Dawley rats (BASF, 1971). Mortalities occurred in a dose-dependent manner within the first 24 hours following treatment. Clinical signs were tonic-clonic convulsion, lateral position, salivation by females and apathy by males. Survivors recovered within 2 days. Gross pathology included heart dilatation and spherical form, hyperaemia in liver and lung and ulceration of the stomach in two high dose groups. Grey colouration of the liver was observed in the highest (14,500 mg/kg bw) dose group. LD50 was 9486 mg/kg bw.

Acute toxicity: dermal

In a guideline and GLP conform limit test, 2000 mg/kg bw 2-Pyrrolidone were administered to five male and five female New Zealand White rabbits under occlusive conditions (MB Research, 1992). The animals were observed for 14 days, then necropsy was performed. The LD50 is >2000 mg/kg bw for both sexes since no mortality was observed. There were no treatment related clinical signs or necropsy findings observed and body weight gain was normal. Local irritation effects were slight to well-defined on day one but were reversible within at least 14 days.

Acute toxicity: Inhalation

An inhalation hazard test similar to the annex of OECD guideline 403 was conducted. A saturated test atmosphere of test material was generated. At this conditions 0/6 rats died after 8 h exposure (BASF AG 1961). Intermittent agitation directly after treatment ignition was the only clinical sign observed; there were no necropsy findings in the survivors after 7 -day observation period.

No LC50 value could be established because no mortalities were occurred during the test. LC0 is 0.061 mg/L (saturated atmosphere).

Justification for classification or non-classification

The available data for 2-Pyrrolidone indicate a relative low potential for acute toxicity.

In a vast majority of reliable studies, the oral LD50 is > 5000 mg/kg bw for rats.

In an inhalation hazard test with rats exposed to a saturated test atmosphere of 2-Pyrrolidone for 8 h there were no mortalities and only transient clinical signs (intermittent respiration) were observed. The dermal LD50 was > 2000 mg/kg bw for rabbits with the complete missing of substance related systemic effects at this dose. Therefore, classification is not warranted according to the criteria of EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulations No 1272/2008.