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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:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Well documented publication, acceptable with restrictions

Data source

Reference
Reference Type:
publication
Title:
Disposition of (14C) Caprolactam in the rat.
Author:
Unger PD, Salerno AJ and Friedman MA
Year:
1981
Bibliographic source:
Fd Comet. Toxicol. Vol. 19. pp. 457-462

Materials and methods

Objective of study:
absorption
distribution
excretion
metabolism
Principles of method if other than guideline:
The tissue distribution and excretion of [carbonyl-14C]caprolactam was studied in male Fischer 344 rats given a single oral dose of 0.18 mg/kg body weight. The rats were dosed by oral intubation and killed with ether after 0.5, 1, 2, 3, 4, 6, 15 or 24 hr (five animals at a time).
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): (Carbonyl-14C)caprolactam
- Radiochemical purity (if radiolabelling): >99%
- Specific activity (if radiolabelling): 5.32mCi/mmol
Radiolabelling:
yes

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratory, Wilmington, MA
- Mean weight at study initiation: 124±19 g

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: Labelled caprolactam was diluted with unlabelled compound to yield a mixture containing 0.143 mg/ml and 6-8 μCi/ml. The solvent vehicle was distilled water. The concentration of caprolactam in the dosing solution was verified by high-pressure liquid chromatography and the specific activity by liquid scintillation spectroscopy.


Duration and frequency of treatment / exposure:
single
Doses / concentrations
Remarks:
Doses / Concentrations:
0.18 ± 0.018 mg/kg bw (mean ± SD)
No. of animals per sex per dose:
40
Details on dosing and sampling:
PHARMACOKINETIC STUDY (distribution, excretion)
Animals were killed with ether after 0.5, 1, 2, 3, 4, 6, 15 or 24 hr (five animals at a time) of dosing.
The animals were housed individually in glass Roth-type metabolism cages (Bellacour Company, Laurelton, NY) which allowed separate collection of urine and feces, expired carbon dioxide was trapped in ethanolamine. Organ and tissue samples were taken at autopsy for quantification of radioactivity. Urine was collected on ice at the intervals indicated above. The contents of the urinary bladder were combined with the urine collected from each animal. The residual radioactivity in the urinary collection funnels of the metabolism cages was rinsed with water into separate containers and the radioactivity determined. The radioactivity in the fecal samples was also determined.


METABOLITE CHARACTERISATION STUDIES
The 6- and 24-hr urine samples collected from animals were subjected to analysis by high-pressure liquid chromatography. Metabolites were quantitated by determination of radioactivity in fractions collected from the HPLC eluate.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on distribution in tissues:
The concentrations of radioactivity in the tissues of the rats following administration are shown in Table 1. With the exception of the stomach, bladder, kidneys and fat, the concentrations of radioactivity in the tissues were similar to that in the blood.
The concentration of radioactivity in the fat was consistently lower than that in the blood or other tissues, indicating a low affinity of caprolactam and/or its metabolites for adipose tissue.
Disappearance of radioactivity from the stomach was monophasic and followed first-order kinetics (r > 0.96) with an elimination half-life of 1.87 hr. The high concentration of radioactivity found in the stomach was not surprising, since the animals were orally dosed. The concentration of radioactivity in the small intestine generally exceeded that of the blood by less than 40%. The increase was statistically significant only at the 0.5, 1.0, 3.0 and 24 hr observations (P < 0.05). Also, except at the latter times, the concentration of radioactivity in the small intestine never approached that in the stomach. The high concentrations of radioactivity observed in the kidneys and bladder reflect the importance of the urine as a route of excretion. The concentration of radioactivity in the liver did not significantly exceed that in the blood (P < 0.05), except after 24 hr. With the exception of the stomach, the concentration of radioactivity in all tissues was greatest 1 hr after dosing. Subsequently, the decrease in concentration of radioactivity in all tissues except the large intestine was monophasic and followed first order kinetics. The half-life of disappearance of radioactivity from the blood was 2.98 hr (r > 0.99).
Details on excretion:
Twenty-four hours after dosing, 77.6 ± 0.7% (mean ± SEM) of the administered radioactivity was excreted in the urine, 3.5 ± 1.1% in the feces and 1.5 ± 0.1% in the expired air of the animals. Elimination of radioactivity in the urine and expired air was most rapid during the initial 6 hr following dosing, after which excretion continued at a much reduced rate.

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
As shown in Table 2, 78% of the radioactivity excreted in the urine 6 hr after the oral administration was in the form of a major metabolite (MI). A lesser quantity of another metabolite (MII) was also found. The relative proportions of MI, MII, and the parent compound were not significantly different in the 24-hr urine.

Any other information on results incl. tables

Table 1. Distribution of radioactivity in male rats at intervals following the oral distribution of 0.18 mg (14C) caprolactam /kg bw.

Tissue

Time after dosing (h)

0.5

1

2

3

4

6

15

24

Liver

104±12

151±13

96±9

70±6

60±5

49±9

3.2±1

2±0.1

Spleen

91±8

140±12

100±7

71±7

60±4

44±7

1.6±0.1

1±0.1

Stomach*

1907±286

1538±397

735±196

931±235

719±258

690±135

1.7±0.1

0.7±0.1

Small intestine*

119±9

158±9

110±5

85±7

67±6

54±9

2.9±0.2

1.2±0.1

Large intestine*

64±6

93±3

77±2

72±6

66±7

64±5

37±9

8±0.9

Pancreas

101±9

116±4

78±9

58±5

50±6

35±6

1.5±0.1

2±1.3

Kidneys

130±13

247±19

189±5

171±9

146±18

105±18

4.1±0.2

1.4±0.02

Bladder

378±155

1240±223

1136±287

1201±230

573±235

797±192

56±13

-

Adrenals

74±16

162±35

70±6

59±7

61±9

41±7

-a

-

Testes

75±8

93±13

77±2

63±10

59±4

44±6

6.7±0.2

1.1±0.3

Epididymis

72±9

112±16

77±3

57±4

51±2

41±6

3±0.2

-

Thyroid

75±18

155±48

93±17

84±15

79±2

38±4

-

-

Pituitary

115±35

146±28

104±6

73±14

48±19

-

-

-

Thymus

85±10

128±13

86±5

58±5

49±3

37±6

2±0.1

-

Salivary gland

77±9

114±10

85±4

53±4

45±4

36±6

2±0.1

0.6±0.03

Lymph nodesb

66±17

90±6

62±6

54±3

57±6

32±6

-

-

Heart

91±10

116±4

90±5

58±6

48±4

38±7

1.3±0.1

0.4±0.1

Aorta

100±12

131±10

79±4

79±7

79±18

39±7

-

-

Lungs

78±16

135±11

93±5

63±6

52±4

46±8

2.1±0.1

0.9±0.1

Sternum

68±6

106±10

73±3

52±4

42±3

30±6

1.3±0.1

0.6±0.1

Muscle

75±8

112±11

78±3

54±4

46±3

35±5

1.1±0.1

0.3±0.04

Brain

69±8

81±8

77±4

54±5

47±3

37±6

1.4±0.1

0.4±0.05

Eyes

69±7

103±3

82±3

69±6

58±4

48±6

3.3±0.3

1.9±0.1

Skin

71±9

107±8

74±3

57±5

47±4

42±7

2.6±0.1

1.1±0.1

Fatc

18±2

41±7

15±4

21±2

25±3

13±1

1.5±0.1

2.4±0.2

Blood

88±9

128±9

95±6

62±6

53±4

40±7

2.6±0.9

0.7±0.1

Values are the means ± SEM of 5 determinations

* including contents

aThe level of radioactivity was too low for accurate measurement

bLymph nodes were excised from the serosal surface of the small intestine

cFat was taken from the supratesticular fat pad

 

Table 2. Caprolactam and its two major metabolites in the urine of rats dosed orally with 0.18 mg [14C]caprolactam/kg bw*

Component

Percentage of total urinary radioactivity after dosing (h)

6

24

Metabolite I (MI)

78.1 ± 3.6

79.3 ± 2.4

Metabolite II (MII)

16.9 ± 3.7

17.7 ± 2.1

Parent Compound

3.9 ± 1.2

2.3 ± 0.6

* Values are means ± SD for three determinations.

Applicant's summary and conclusion