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Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Data derived over an extensive series of robust guideline-equivalent experiments and presented in peer-reviewed journals and at professional conferences.

Data source

Referenceopen allclose all

Reference Type:
publication
Title:
Disposition and metabolism of N-Vinyl Pyrrolidone in the Rat
Author:
McClanahan, J. et al
Year:
1987
Bibliographic source:
Proceedings of the 2nd International Symposium of Povidone, University of Kentucky, School of Pharmacology, April12-15, 1987. pp. 318-329
Reference Type:
publication
Title:
Disposition of N-Vinyl 2-Pyrrolidone in the Rat
Author:
McClanahan, J. et al.
Year:
1983
Bibliographic source:
Drug Chem. Toxicol. 7(2), 129-148
Reference Type:
publication
Title:
Abstract no. 580, N-Vinyl 2-Pyrrolidone: Disposition and Metabolism Studies
Author:
Digenis, G.A, et. al.
Year:
1982
Bibliographic source:
The Toxicologist 2(1), 165

Materials and methods

Objective of study:
distribution
excretion
metabolism
Test guideline
Qualifier:
equivalent or similar to
Guideline:
other: no data
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): 1-ethenyl-2-pyrrolidinone (N-vinyl-2-pyrrolidinone; NVP)
- Analytical purity: no data
Radiolabelling:
yes
Remarks:
5 uCi 3H-NVP and 2.5 uCi 14C-NVP (3H:14C ratio = 2:1)

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals and environmental conditions:
3 seperate experiments reported:
- Urinary and Fecal Excretion
- Biliary Excretion
- Distribution

For excretion studies, animals were housed in metabolism cages for 6 days for collection of urine and feces

Administration / exposure

Route of administration:
intravenous
Vehicle:
water
Duration and frequency of treatment / exposure:
Single treatment
Doses / concentrations
Remarks:
Doses / Concentrations:
Urinary and Fecal Excretion: ca. 6 mg/kg
Biliary Excretion: ca 5.2 mg/kg
Distribution: ca. 4.4 mg/kg
No. of animals per sex per dose:
Urinary and Fecal Excretion: 4 rats
Biliary Excretion: 5 rats
Distribution: 3 rats
Control animals:
no
Details on dosing and sampling:
Urinary and Fecal Excretion: Rats were coadministered intravenously single doses of 5 uCi 3H-NVP and 2.5 uCi 14C-NVP (3H:14C ratio = 2:1) at the jugular vein. The animals were anesthetized for application. Urine and feces were collected for 6 days and examined for 3H- and 14C-activity. In additino, the 6 and 12 hour urine samples were analyzed for intact radiolabelled NVP. Urine samples were further analyzed by radiomonitored HPLC to indentify metabolites.

Biliary Excretion: Rats were anesthetized and remained in anesthesia throughout the study. Jugular vein and bile duct were cannulated and each rat was given an i.v. dose of 5 uCi 3H-NVP and 2.5 uCi 14C-NVP (3H:14C ratio = 2:1). Bile samples were collected every 15 min for 2 hours, then every 30 min for another 4 hours. These samples were examined for total radioactivity as well as for intact radiolabelled NVP.

Metabolism: Rats were coadministered intravenously single doses of 5uCi 3H-NVP and 2.5 uCi 14C-NVP (3H:14C ratio = 2:1) at the jugular vein. The animals were anesthetized for application. Urine was collected after 6 hours and examined by high performance liquid chromatography (HPLC).

Distribution: Rats were anesthetized and remained in anesthesia until sacrifice. The jugular vein was cannulated and each rat was given an i.v. dose of 5 uCi 3H-NVP and 2.5 uCi 14C-NVP (3H:14C ratio = 2:1). Six hours later, the rats were sacrificed and the major organs were excised and analyzed for radioactivity.

Results and discussion

Preliminary studies:
The disposition and metabolism of 1-ethenyl-2-pyrrolidinone (N-vinyl-2-pyrrolidinone; NVP) was studied in a series of preliminary experiments in male Sprague-Dawley rats. Initially, three rats were anesthetized and remained in anesthesia until sacrifice. The jugular vein was cannulated and each rat was given an i.v. dose of 5 uCi 14C-NVP. Six hours later, the rats were sacrificed and the major organs were excised and analyzed for radioactivity. Blood samples (0.4 ml) were withdrawn 10, 20, 30, 45, 60, 120, 240 and 360 minutes after application. In another experiment, nine rats were treated as described above and three rats each were sacrificed 15, 30 and 90 min after dosing for evaluation of 14C-activity in organs. The examination of the organs showed that the liver, kidneys and small intestine (including its contents) had the highest concentration of radioactivity. The lowest values were found in the spleen, adrenal glands, thymus, thyroid gland and brain. Blood levels of intact 14C-NVP decreased from 6.00 to 0.51% of the dose over the 6 hours period after application of 5uCi 14C-NVP. Blood levels followed a biphasic kinetic with a half-life or 1.9 hours.

In a follow-up experiment, four rats each were given a 5.0 uCi or 2.0 uCi i.v. dose of 14C-NVP; two rats each were given 2.86 uCi or 1.16 uCi. Urine, feces and expired carbon dioxide (only of the rats given 2.86 or 1.16 uCi) were collected for up to 6 days and analysed for total radioactivity. For biliary excretion studies, another four rats were anesthetized and remained in anesthesia throughout the study. Jugular vein and bile duct were cannulated and each rat was given an i.v. dose of 5 uCi 3H-NVP and 2.5 uCi 14C-NVP. Bile samples were collected every 15 min for 2 hours, then every 30 min for another 4 hours. These samples were examined for total radioactivity as well as for intact radiolabelled NVP. By 12 hours after application, 74.9% of the administered dose was determined in urine and 0.43% was found in feces. Rats given 2 uCi had excreted 85.8% in the urine and 1.06% in the feces. Intact 14C-NVP excreted to the urine within the first 12 hours after these two doses ranged from 0 to 0.585% in the 5 uCi-group and from 0 to 0.398% in the 2 uCi-group. Urinary and fecal excretion of 14C-activity was similar in the rats given 2.86 and 1.16 uCi. The cumulative radioactivity found in the expired carbon dioxide 48 hours after the 2.86 uCi dose and 54 hours after the 1.16 uCi dose was less than 3.5% of the administered dose. Six hours after i.v. administration of a 5.0 uCi dose, 18.7% of the 14C-activity was determined in the bile. Intact NVP excreted to the bile was found as 0.46% of the 14C-dose 6 hours after administration.
Main ADME resultsopen allclose all
Type:
excretion
Results:
Urine: Within 12 hours after dosing, 67.7% of the administered amount of 3H-radioactivity and 68.8% of the administered dose of 14C-radioactivity was determined in urine.
Type:
excretion
Results:
Uriine: Inact NVP excreted in the urine was less than 0.31% of the total dose.
Type:
excretion
Results:
Urine: About 89% of either dose was excreted in urine by day 2 with very little excreted after day 6.
Type:
excretion
Results:
Feces: 0.22% of 3H-activity and 0.19% of 14C-activity was found after 12 hours. By day 6, around 5 to 8% was excreted in feces.
Type:
excretion
Results:
Biliary excretion of radioactivity: Six hours after i.v. administration, 24.9% of the 3H dose and 23.3% of the 14C dose was determined in the bile.
Type:
excretion
Results:
Biliary excretion of intact NVP: Intact NVP excreted to the bile was found as 0.88% of the 3H dose and 0.85% of the 14C dose 6 hours after adminstration.
Type:
metabolism
Results:
The two major matabolites could not be identified and accounted for ca. 50% of 14C radioactivity and ca. 33% of 3H radioactivity. Further details below.
Type:
distribution
Results:
The liver, kidneys and small intestine (including its contents) had the highest concentration of radioactivity for both radiolabels (about 5, 1 and 2.5% of the dose administered, respectively).
Type:
distribution
Results:
The lowest values were found in the spleen, adrenal glands, thymus, thyroid gland and brain (0.01 - 0.15% of the dose administered). The values for 3H- and 14C-radioactivity were similar.

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
Urine analysis by radiomonitored reversed phase HPLC showed two major peaks acounting 50 and 33% of both the 3H- and 14C-excreted activity, eluting at 14.0 and 52.5 min, respectively. Minor peaks were determined at an elution time of 30.5 min, containing 5% of each radiolabel and at an elution time of 27.5 min containing 11.7% of the 3H-activity and 5.6% of the 14C-activity. According to the authors, the peak eluting at 27.5 min might be attributed to an overlap between N-acetyl-gamma-amino butyric acid and 2-pyrrolidinone. The minor metabolite eluting at 30.5 min was believed to be N-vinyl succinimide. The major metabolite remained unidentified. No further data.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): low bioaccumulation potential based on study results