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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Well documented publication which meets basic scientific principles

Data source

Reference
Reference Type:
publication
Title:
Percutaneous absorption of co-administered N-methyl-2-[' 4C]pyrrolidone and 2-['4C]pyrrolidone in the rat
Author:
Midgley I, et al.
Year:
1991
Bibliographic source:
Fd Chem. Toxic., Vol. 30(1), 57-64

Materials and methods

Objective of study:
absorption
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
The oral absorption of a mixture of N-methyl-2-pyrrolidinone and 2-pyrrolidinone has been investigated in rats in vivo.
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): 2-pyrrolidinone and N-methyl-2-pyrrolidinone, mixture (2:3)
- Physical state: liquid
- Specific activity (if radiolabelling): 4.9 (2-P) and 7.4 mCi/mmol (NMP)
- Locations of the label (if radiolabelling): N-methyl-2-[2-14C]pyrrolidinone; 2-[5-14C]pyrrolidinone
Radiolabelling:
yes
Remarks:
2-[14C]pyrrolidone

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River breeding Laboratories (Portage, MI, USA)
- Age at study initiation:
- Weight at study initiation: 192-239 g
- Fasting period before study:
- Housing: individual
- Individual metabolism cages: yes
- Diet: LAD1 Bioscure Ltd., Manea, UK ad libitum
- Water: ad libitum


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 30-70
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: water for oral adminstration and isopropanol for dermal administration
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
[14C]NMP / [14C]2-P mixure (22.5 mg / 15 mg) was prepared as an aqueous mixture (0.6 ml);

These doses were equivalent to about 112 mg NMP and 75 mg 2-P /kg bw

Duration and frequency of treatment / exposure:
single exposure, up to 120 hrs
Doses / concentrations
Remarks:
Doses / Concentrations:
ca. 112 mg NMP and 75 mg 2-P /kg bw
No. of animals per sex per dose:
33 males and 33 females in total; 3 per sex and time-point
Control animals:
yes, concurrent vehicle
Positive control:
not done
Details on study design:
- Dose selection rationale: no data
Details on dosing and sampling:
PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: urine, faeces, blood, plasma, serum, cage washes, bile, CO2
- Time and frequency of sampling: expired air: 24h intervals; other parameters at termination of animals

Sample collection:
Following blood withdrawal by cardiac puncture under halothane anaesthesia, the rats were killed by cervical dislocation in groups of six (three males, three females) per time point at selected times after dosing. Plasma was separated from the blood cells by centrifugation, and stored at about -20°C until analysed. Urine and faeces were collected at suitable intervals from the six rats in each group killed at the final killing time (i.e. 120 hr), and any [14C]CO2 present in the expired air was trapped in a mixture of ethanolamine-2-ethoxyethanol (1:3, v/v) at 24-hr intervals. After these rats were killed, the metabolism cages were washed thoroughly with water, and the washings, excreta and carcasses stored at about -20°C until analysed.

Statistics:
data not available

Results and discussion

Preliminary studies:
not applicable

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Absorption and distribution:
After oral administration, the concentrations of radioactivity were greatest in plasma of male and female rats at 2 hrs after dosing. (mean values 0.463% and 0.562% dose/ml). Radioactivity declined thereafter in a muliphasic manner with a terminal half-life of 29 and 27 hrs for male and female rats. the concentrations were still measureable 5 days after dosing when the mean values corresponded to 0.0006% of the total dose in both sexes.

Quantitative analysis of of plasma by HPLC showed, that at 30 min after dosing the proportions of unchanged NMP and 2-P reflected the 3: 2 ratio, demonstrating little metabolism at this time point. Both parent compounds together accounted for at least 80% of plasma radioactivity until 8 hrs post-administration indicating little first-pass metabolism.
Details on distribution in tissues:
not measured
Details on excretion:
Metabolism and excretion:
Biotransformation became more evident 8 hours post-administration and by 12 hrs virtually all of the plasma radioactivity was found in form of unknown polar metabolites. Plasma levels of the unchanged pyrrolidinones were not measurable during the terminal phase of plasma radioactivity disposition after oral dosing.
Following oral co-administration to male and female rats, 94.8% and 94.5% of the radioactive dose were excreted within 5 days. Radioactivity was mainly excreted through the urine (85-88% of the total dose) mostly within 24 hours. Faecal excretion was of minor importance representing only 1-2% of the total dose. 6-7% of the oral dose was eliminated as CO2 in the expired air, which indicates the extent of metabolic degradation of the pyrrolidinone ring. Only about 1% of the total dose remained in the carcass, demonstrating that the excretion was virtually complete by the end of 5 days post-exposure. Recovery of radioactivity in excreta is presented in Table 2 in "Remarks on results".
Toxicokinetic parametersopen allclose all
Test no.:
#1
Toxicokinetic parameters:
Tmax: 2h after oral route of administration
Test no.:
#2
Toxicokinetic parameters:
Tmax: 6 and 2 h for males and females, respectively after dermal administration
Test no.:
#1
Toxicokinetic parameters:
Cmax: 0.171 and 0.215 % dose/ml for m/f respectively after oral administration
Test no.:
#2
Toxicokinetic parameters:
Cmax: 0.052 and 0.093% for m/frespectively after dermal administration
Test no.:
#1
Toxicokinetic parameters:
AUC: 1.07 and 1.33 % dose/ml.h after oral administration
Test no.:
#2
Toxicokinetic parameters:
AUC: 0.31 and 0.59 % dose/ml.h after dermal administration

Metabolite characterisation studies

Metabolites identified:
not measured
Details on metabolites:
12 hours following oral administration little or none of the intact pyrrolidinones were found in plasma and virtually all of the radioactivity was associated with unknown polar metabolites.

Any other information on results incl. tables

The only results of measured radioactivity of 2 -pyrrolidone in plasma are presented in "Toxicokinetic parameters". All pharmakokinetic parameters are presented in Table 1 atttached in "Attached background material".

Table 2: Excretion balance of radioactivity following co-administration of 14C -NMP and 2 -P to rats

Oral

 

Dermal

Sample

Time (hr)

M

F

M

F

Urine

0-6

16.0

21.4

5.5

11.0

6-24

65.2

60.9

45.3

46.7

24-72

2.9

4.2

8.1

8.8

72-120*

1.1

1.3

2.4

3.3

 

Total

85.2

87.8

61.3

69.8

Faeces

0-24

1.2

0.6

0.7

0.5

24-72

0.8

0.5

0.8

0.6

72-120

0.1

0.1

0.1

0.2

 

Total

2.1

1.2

1.6

1.3

Expired air

0-24

6.8

4.8

3.5

4.2

24-72

0.6

0.6

2.0

2.0

72-120

0.1

0.1

0.5

0.5

 

Total

7.5

5.5

6.0

6.7

Total excretion

0-120

94.8

94.5

68.9

77.8

Carcass

120

1.1

1.2

1.0

1.1

Dose dressing

120

10.7

11.3

Dose-site wash

120

1.2

0.3

Treated skin

120

11.2

2.0

Untreated skin

120

ND

<0.1

Total recovery

0-120

95.9

95.7

93.0

92.5

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): no bioaccumulation potential based on study results
2-pyrrolidone is considered to be fully excreted within 5 days.
Executive summary:

The percutaneous absorption has been investigated in rats of a mixture (3:2, w/w) of N-methyl-2-pyrrolidinone (NMP) and 2-pyrrolidinone (2-P). Co-administration of the two 14 C-radiolabelled compounds was performed by the dermal and oral routes.

Radioactivity was excreted predominantly through the urine after either route of administration, and comparison of the respective excretion profiles indicated that about three-quarters of the applied dose was absorbed through the skin. NMP appeared to be absorbed through the skin more extensively and at a slightly faster rate than 2-P; total percutaneous absorption tended to be more extensive in female than in male rats.

Only about 1% of the dose was retained in the carcasses, demonstrating that the excretion of radioactivity was virtually complete by the end of the 5-day collection period.