N-(n-octyl)-2-pyrrolidinone

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

From 27 Sep 1990 to 2 July 1991

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Study run to a method comparable with current guidelines and to GLP.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1991

Report date:

1991

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

EPA OPP 82-1 (90-Day Oral Toxicity)

Deviations:

no

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

N-(n-octyl)-2-pyrrolidinone

EC Number:

403-700-8

EC Name:

N-(n-octyl)-2-pyrrolidinone

Cas Number:

2687-94-7

Molecular formula:

C12 H23 N O

IUPAC Name:

1-octylpyrrolidin-2-one

Details on test material:

Batch No.: KC90731
Purity: 99.6%

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Inc., Portage, MI
- Age at study initiation:approximately 4 weeks
- Weight at study initiation: The weight range was 182-211 grams for the males and 127-160 grams for the females.
- Fasting period before study:
- Housing: in suspended stainless steel cages
- Diet (e.g. ad libitum): Purina Certified Rodent Chow #5002 (ground meal)
- Water (e.g. ad libitum): ad libitum fresh water (municipal source)
- Acclimation period: 14days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 64-79°F
- Humidity (%): 40-70%
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light): 12-hour light/12-hour dark cycle

IN-LIFE DATES: From: To:

Administration / exposure

Route of administration:

oral: feed

Vehicle:

corn oil

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS:

DIET PREPARATION
- Rate of preparation of diet (frequency): diets were prepared for seven- or fourteen-day feeding period
- Mixing appropriate amounts with (Type of food): 1% corn oil
- Storage temperature of food: at room temperature

VEHICLE
- Justification for use and choice of vehicle (if other than water):
- Concentration in vehicle:
- Amount of vehicle (if gavage):
- Lot/batch no. (if required):Lot no.s were in report. NOV2590A, MAY2891A, JUL1691A
- Purity:

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The test diets were analyzed for verification of test article concentration after each preparation during the first month and monthly thereafter.

Duration of treatment / exposure:

90 days

Frequency of treatment:

daily

Doses / concentrations

Remarks:

Doses / Concentrations:
60, 600, 6000ppm (increased to 8000 ppm and again to 10000 ppm)
Basis:
nominal in diet

No. of animals per sex per dose:

10

Control animals:

yes, plain diet

Details on study design:

Dosage conversion ppm in diet to mg/kg bw/day:
60 ppm = 4-7 mg/kg (females) and 3-7 mg/kg (males)
600 ppm = 43-69 mg/kg (females) and 33-65 mg/kg (males)
10000ppm = 608-924 mg/kg (females) and 492-718 mg/kg (males)

The study consisted of a control and 3 treated groups with 10 animals per sex in each group. The test article was blended with rodent meal to prepare dietary concentrations of 60, 600 and 6000 ppm. Due to the lack of frank toxicity at the high-dose level, the concentration of the test was increased from 6000 to 8000 ppm on study day 29 and from 8000 to 10000 ppmon study day 43. Control animals were fed basal diet.
All animals were observed daily for clinical signs of toxicity. Body weights and food consumption were measured and recorded weekly. Clinical pathology and ophthalmology examinations were performed at or near the end of the treatment period. All tissues collected from control and high-dose animals, all tissues from animals sacrificed during the study and the lungs, liver, kidneys and gross lesions from all low- and mid-dose animals were processed for histopathological examination.

Examinations

Observations and examinations performed and frequency:

All animals were observed daily for clinical signs of toxicity. Body weights and food consumption were measured and recorded weekly. Clinical pathology and ophthalmology examinations were performed at or near the end of the treatment period.

Sacrifice and pathology:

At the end of the treatment period (study days 92 and 91), all surviving rats were sacrificed. Half of the rats from each dose-sex group were sacrificed each day.
GROSS PATHOLOGY:The animals were subjected to a complete necropsy examination which included examination of the external surfaces, the cranial, thoracic, abdominal and pelvic cavities and their viscera.
HISTOPATHOLOGY: All tissues collected from control and high-dose animals, all tissues from animals sacrificed during the study and high-dose animals, all tissues from animals sacrificed during the study and the lungs, liver, kidneys and gross lesions from all low- and mid-dose animals were processed for histopathological examination.

Other examinations:

Organ weights

Statistics:

Statistical analyses were performed by a Digital VAX 11/730 computer. All tests were two-tailed with a minimum significance level of 5%. Continuous data including body weights, body weight gains, food consumption, organ weights, and clinical pathology data were analyzed by one-way analysis of variance(ANOVA). When significance was observed with ANOVA, group by group comparison was performed with Dunnett's Test.

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

no effects observed

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

not specified

Details on results:

Dietary administration of the substance produced signs of systemic toxicity in both males and females at the 10000 ppm level. Reduced body weight gain and/or food consumption, increased absolute and relative liver weights and minimal to mild hepatocyte hypertrophy were observed in the 10000 ppm group. No treatment-related mortalities or clinical signs of toxicity were observed during the study and no treatment-related differences were noted in the clinical pathology, ophthalmology or gross necropsy observations for males or females in any of the study groups. No treatment-related changes were observed in body weight gain, food consumption, organ weights and histopathology for males or females in the 60 and 600 ppm groups.

Effect levels

Dose descriptor:

NOEL

Effect level:

600 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: 600 ppm = 43-69 mg/kg (females) and 33-65 mg/kg (males)

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

Dietary administration of the substance for at least 90 days produced signs of systemic toxicity in both males and females at the 10000 ppm level. Reduced body weight gain and/or food consumption, increased absolute and relative liver weights and minimal to mild hepatocyte hypertrophy were observed for both males and females in the 10000 ppm group. Therefore, based on the results of this study, a level of 600 ppm was considered a no-observed-effect level (NOEL) for systemic toxicity following dietary administration of the substance for at least 90 days.