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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: GLP and guideline study

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Report Date:
1986
Reference Type:
publication
Title:
Subchronic Inhalation and Oral Toxicity of N-Vinylpyrrolidone-2. Studies in Rodents
Author:
Klimisch, H.-J. et al.,
Year:
1997
Bibliographic source:
Fd. Chem. Toxicol., 35, 1061-1074, 1997

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
GLP compliance:
yes (incl. certificate)
Remarks:
testing lab.
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): 1-Vinyl-2-pyrrolidone; N-Vinylpyrrolidone (extra pure); NVP
- Physical state: clear, colourless liquid
- Analytical purity: >= 99.84%
- Stability under test conditions: For about 6 months at 15°C in a refrigerator

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Karl Thomae, Biberach an der Riss, D (strain : Chbb=THOM)
- Age at study initiation: 42 d
- Mean body weight at study initiation: males 186.7 (175-200) g; females 146.8 (137-158) g
- Housing: singly in type TK III stainless steel cages (Becker & Co., Castrop-Rauxel, D)
- Diet (ad libitum): ground Kliba 343 rat-mouse feed "A" (Klingenthalmuehle AG, Kaiseraugst, CH)
- Water (ad libitum): tap water
- Acclimation period: 6 d
- Routine inspection of feed and water indicated no contamination

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 30-70
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: drinking water
Vehicle:
water
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS: The test substance was weighed out for each test group and added to the appropriate amount of drinking water (likewise weighed). The water was then stirred with a magnetic stirrer for about 10 minutes to ensure complete dissolution of the test substance. The drinking water solutions were prepared twice a week (on Tuesdays and Fridays). NVP has been demonstrated to be stable in drinking water for a period of 4 days.
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
3 months
Frequency of treatment:
continuously in the drinking water
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
5, 12, 30, 75 ppm in the drinking water
Basis:
nominal in water
Remarks:
Doses / Concentrations:
ca. 0.4, 1, 2.6, 6 mg/kg/d
Basis:
actual ingested
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle
Details on study design:
Post-exposure period: none

Dose selection rationale: Several studies in which rats received the test substance in the drinking water had already been carried out.

First Pilot study: The doses of 6400 and 1600 ppm which were administered several times in the first of these caused serious clinical signs in the rats (great reduction in body weight, exsiccosis associated with great reductions in food and water consumption) so that these animals had to be sacrificed after 8 days of the study. When 700, 400 and 200 ppm were administered for 28 or 21 days, there were likewise dose-dependent and marked reductions in water and food consumption and decreased gains in body weight of both sexes. On gross-pathological examination of the animals (where done) gastritis was found in 3 male rats in the 6400 ppm group, and fatty degeneration of the liver parenchyma was found in 2 female animals which had received 700 ppm of test substance with the drinking water.

Second pilot study: On administration of 50 and 100 ppm for 21 days too, the female rats still showed reductions in water consumption. The figures ranged down to about 31% below those for the untreated control animals. Even at these doses no increase in tolerance of the administration of the test substance, or an associated increase in consumption of water, was found during the period of the study. In addition, the female rats in this pilot study showed a diminished food consumption (at 200 ppm, and signs thereof at 50 and 100 ppm) and a slightly reduced body weight gain. The haematological and clinicochemical examinations carried out after 21 days of administration of the test substance showed changes in the plasma protein composition at the two higher doses (100 and 200 ppm). Additionally, at the final evaluation, the animals in the 100 and 200 ppm groups additionally showed, reduced glucose levels (both sexes) and increased creatinine concentrations (only male animals). No changes in organs which might be connected with the administration of the test substance were found at necropsy.

In order substantially to avoid an effect on the state of health of the animals by a reduction in water consumption, the maximum dose administered in the drinking water in the present study was 75 ppm. At this dose, even with administration of the test substance for 3 months, no more than a marginal reduction in the water consumption was expected (< 20% compared with the control group) The other doses were set at 5, 12 and 30 ppm (factor 2 .5).

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
DETAILED CLINICAL OBSERVATIONS: Yes
BODY WEIGHT: Yes
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
OPHTHALMOSCOPIC EXAMINATION: Yes
HAEMATOLOGY: Yes
CLINICAL CHEMISTRY: Yes
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Statistics:
yes

Results and discussion

Results of examinations

Details on results:
Groups of ten male and ten female rats were used. Neither mortality nor clinical signs were observed throughout the study. Food intake and mean body weights were unchanged all over the study period. Water consumption was unchanged in the three lowest dose groups; in the highest dose group the water consumption was slightly, and only temporarily reduced in both sexes. The ophthalmological examinations which were carried out before and at the end of the study in the control and the highest dose groups showed no adverse effects. The clinicochemical and hematological investigations revealed reduced total protein and globulin concentrations in the plasma of both sexes in the highest dose group. In addition, the female animals in the highest dose group showed significantly lowered albumin concentrations at the end of the study. Other significant changes were regarded as not being related to the test substance. The mean kidney weights in males in the two highest dose groups were statistically significantly increased. However, no changes in the kidneys were observed on gross-pathological and histopathological examinations (no evidence for toxic fatty degeneration or degenerative parenchymal damage). All other observed gross and microscopic organ changes (mainly focal calcification in the kidneys) were assessed to be not substance-related. Based on the results of this study, the "no effect level" for male rats was in the range between 1 and 2.6 mg/kg/d (12 - 30 ppm) and for female rats in the range between 2.6 and 6 mg/kg/d (30 - 75 ppm).

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
1 mg/kg bw/day (actual dose received)
Sex:
male/female
Dose descriptor:
LOAEL
Effect level:
2.6 mg/kg bw/day (actual dose received)
Sex:
male/female

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
The administration of N-vinyl-2-pyrrolidone produced, under the experimental conditions selected, unambiguous findings related to the test substance only at a dose of 75 ppm (reduced consumption of water, dysproteinemia and - only in the male animals - increased kidney weights). At a dose of 30 ppm, only the male animals were found to have increased kidney weights, but this finding, in the same way as that in the 75 ppm group, had no morphological correlate in the examination under the light microscope. In contrast, no changes occurred at 5 and 12 ppm which could be attributed to the administration of N-vinyl-2-pyrrolidone. Thus, the no effect dose is in the concentration range between 12 and 30 ppm for male rats and between 30 and 75 ppm for female animals.