ε-caprolactam

Basic toxicokinetics

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:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference

Reference 1

Reference Type:

study report

Title:

Unnamed

Year:

1981

Report date:

1981

Reference 2

Reference Type:

publication

Title:

The distribution of [14C]caprolactam in male, female and pregnant mice.

Author:

Waddell, W.J. et al.

Year:

1984

Bibliographic source:

Food Chem. Toxicol. 22, 293-303.

Materials and methods

Objective of study:

absorption

distribution

excretion

Principles of method if other than guideline:

The distribution of 14C-test substance was studied in female and 14.5-day-pregnant mice by whole-body autoradiography after administrating 6.5-6.7 mg test substance/kg bw (11-14 uCi/mouse) by oral intubation. Pregnant mice were frozen at 20 min, 1, 3, 9, and 24 hr after oral administration of the compound. The non-pregnant mouse was frozen at 3 hr after oral dosing.

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

Specific details on test material used for the study:

- Name of test material (as cited in study report): (Carbonyl-14C) Caprolactam
- Specific activity (if radiolabelling): 46.9 µCi/mg

Radiolabelling:

yes

Test animals

Species:

mouse

Strain:

Swiss Webster

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: pregnant mice 36-45 g, one female non pregnant mouse 33.5 g

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

not specified

Duration and frequency of treatment / exposure:

single

Doses / concentrations

Remarks:

6.5-6.7 mg/kg bw/day

No. of animals per sex per dose / concentration:

5

Details on dosing and sampling:

For breeding, a male mouse was allowed to remain overnight in a cage containing 4-6 female mice. The following morning the male mouse was removed and the female mice with vaginal plugs were considered to be 0.5 days pregnant at noon of this day. On day 14.5 of gestation five mice, weighing 36-45 g, were administered the 14C-test substance (6.5-6.7 mg test substance/kg bw, 11-14 µCi/mouse) by oral intubation. 20 min, 1, 3, 9 and 24 hr following the test substance treatment the mice were frozen by immersion in a dry ice/hexane bath at -75°C.
One female mouse, weighing 33.5 g was also administered 6.6 mg 14C-test substance/kg (10.3 µCi) by oral intubation and sacrificed 3 hr later.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on distribution in tissues:

At 20 min and 1 hr after the oral dosing, there was still considerable radioactivity within the contents of the stomach although significant amounts had already been absorbed and distributed throughout the animals. There was a noticeable increase in the radioactivity in the fetuses and brain of the mother during the first hr after dosing. Only kidney and nasal epithelium show specific tissue affinities at these early time intervals. By 1 h, there was heavy labeling within bile ducts in the liver indicating hepatic secretion of the test substance and/or metabolites. At 3 and 9 hr, the amount of radioactivity in most tissues of the mother was rapidly decreasing.
The concentration in the fetuses was greater than that in maternal tissues but it decreases with time. Maternal tissues in which radioactivity was retained are brain, nasal epithelium, lens of the eye, bone, inner ear, and Harder's gland. By 24 h almost all of the material was eliminated from the entire fetal-maternal unit. There were small residues of radioactivity in umbilical cords, amnion, yolk sac, maternal lens, and maternal Harder's gland and maternal liver. No radioactivity was retained in any other fetal tissue. There was a significant amount of radioactivity in nasal epithelium and the olfactory lobe of the brain.
In the single non-pregnant female, the sites of localization were identical in the adult tissues: brain, nasal epithelium, bone, and renal and hepatic elimination are seen.

Details on excretion:

Evidence of renal secretion and hepatic elimination into the intestinal contents was visible.

Applicant's summary and conclusion

Conclusions:

The test substance was efficiently eliminated by the kidney and liver. After 24 hr, the test substance was only measured in umbilical cords, amnion, yolk sac, maternal lens, maternal Harder's gland, and maternal liver. There was no retention in any fetal tissue.

Executive summary:

The test substance was rapidly absorbed from the stomach and was distributed throughout all animals including fetuses. There was efficient elimination by the kidney and liver, material secreted by the liver into bile and intestinal contents appeared not to be reabsorbed via an enterohepatic circulation. The kinetics of distribution and elimination appeared to be the same in female and pregnant animals. The only sites of retention of radioactivity after 24 hr (excluding renal and hepatic) were in umbilical cords, amnion, yolk sac, maternal lens, maternal Harder's gland, and maternal liver. The distribution into and removal from the fetuses was typical of molecules that freely diffuse across the placenta. There was no retention in any fetal tissue. No localization was seen that would suggest a site of toxic action except for that possibility in nasal epithelium.