Hexahydro-2H-azepin-2-one, sodium salt

Basic toxicokinetics

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:

test procedure in accordance with national standard methods with acceptable 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

Test material information

Constituent 1

Reference substance name:

ε-caprolactam

EC Number:

203-313-2

EC Name:

ε-caprolactam

Cas Number:

105-60-2

Molecular formula:

C6H11NO

IUPAC Name:

azepan-2-one

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 or test system 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

Dose / conc.:

0.18 mg/kg bw (total dose)

Remarks:

± 0.018 mg/kg bw (mean ± SD)

No. of animals per sex per dose / concentration:

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 nodes^b	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
Fat^c	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.