Dodecane-12-lactam

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

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 Type:

publication

Title:

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

Author:

Waddell WJ, Marlowe C and Friedman MA

Year:

1984

Bibliographic source:

Fd Chem. Toxic.

Materials and methods

Objective of study:

distribution

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 417 (Toxicokinetics)

Deviations:

not specified

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:

[Carbonyl-14C]caprolactam prepared by New England Nuclear (Boston, MA); specific activity 46.9 µCi/mg

Radiolabelling:

yes

Remarks:

[Carbonyl-14C]caprolactam

Test animals

Species:

mouse

Strain:

Swiss Webster

Sex:

male/female

Details on test animals or test system and environmental conditions:

animals: Swiss-webster mice (male/female) from Laboratory Supply Co.
food: standard food (Purina Lab Chow No. 5001; Ralston Purina Co. Inc., St. Louis, MO)
water: ad libitum
mating procedure: male mouse remained overnight in a cage containing 4-6 females; following morning the male was removed; female mice with vaginal plugs were considered to be 0.5 days pregnant at noon on this day

Administration / exposure

Route of administration:

other: oral administration and i.v. administration

Vehicle:

other: water (oral administration); saline (i.v. administration)

Details on exposure:

female pregnant mice:
- on Day 14.5 of gestation adminstration by oral intubation of 6.5-6.7 mg [14C]caprolactam/kg (= 11-14 µCi/mouse) to 5 female pregnant mice (36. 0-45.0g bw)
- mice were frozen by immersion in into dry ice/hexane bath (-75°C) 20 min, 1, 3, 9 and 24 hours after administration

female none-pregnant mouse:
- one mouse (33.5 g bw) was given 6.6 mg [14C]caprolactam/kg (= 10.3 µCi) by oral intubation and was frozen in the above described way 3 hours later.

male mice:
- 6.4-6.9 mg/kg (=7.1-8.2 µCi/mouse) of [14C]caprolactam was injected i.v. in two male mice (23-25 g bw)
- mice were frozen 20 min and 9 hours later

Duration and frequency of treatment / exposure:

female pregnant mice:
- once for 20 min, 1, 3, 9 and 24 hours respectively

female none-pregnant mouse:
- once for 3 hours

male mice:
- once for 20 min and 9 hours respectively

Doses / concentrations

Remarks:

Doses / Concentrations:
female pregnant mice:
- 6.5-6.7 mg [14C]caprolactam/kg (= 11-14 µCi/mouse)

female none-pregnant mouse:
- 6.6 mg [14C]caprolactam/kg (= 10.3 µCi)

male mice:
- 6.4-6.9 mg/kg (=7.1-8.2 µCi/mouse)

No. of animals per sex per dose / concentration:

female pregnant mice:
- 5 female pregnant mice


female none-pregnant mouse:
- one mouse

male mice:
- two male mice

Control animals:

not specified

Positive control reference chemical:

no data

Details on study design:

-animals were exposed to [14C]caprolactam as described under "Details on exposure"
- whole body autoradiography was conducted to demonstrate the sites of localization of caprolactam and metabolites of caprolactam.
- sections were made from the animals and exposed against Kodak type AA X-ray film (exposure times: 6 weeks for mouse exposed for 20min to [14C]caprolactam ; 34 weeks for mice exposed for 3,9 or 24 hours to [14C]caprolactam)

Details on dosing and sampling:

no further relevant details

Statistics:

No statistics; density of autoradiogramms visually scored (ranking 1-7) and divided by exposure time (explained but not shown in the publication). This was done for internal laboratory estimations.

Results and discussion

Preliminary studies:

no data available

Toxicokinetic / pharmacokinetic studies

Details on absorption:

20 min after oral uptake:
- still considerable amounts in stomach
- significant amount absorbed and distributed throughout the animals

Details on distribution in tissues:

20 min after oral uptake:
- significant amount distributed throughout the animals
- no differences in pattern of distribution among male, non-pregnant and pregnant mice could be detected

Transfer into organs

Transfer into organs 1

Test no.:

#1

Transfer type:

blood/placenta barrier

Observation:

other: noticable increase of radioactivity in foetuses 60 min after oral uptake

Transfer into organs 2

Test no.:

#2

Transfer type:

blood/brain barrier

Observation:

other: noticable increase of radioactivity in brain of parental animal 60 min after oral uptake

Transfer into organs 3

Test no.:

#3

Transfer type:

other: tissue affinity

Observation:

other: kidney and nasal epithelium showed specific tissue affinity at early time intervals (within 1 hour after dosage)

Transfer into organs 4

Test no.:

#4

Transfer type:

other: bile ducts and liver

Observation:

other: 1 hour after dosing bile ducts and liver were heavily labelled

Details on excretion:

e-Caprolactam is rapidly eliminated by renal and hepatic routes. Metabolism in liver prior to secretion into bile seems likely. There are indications that enterohepatic circulation is absent.

Toxicokinetic parameters

Toxicokinetic parameters 1

Test no.:

#5

Toxicokinetic parameters:

other: 3 hours and 9 hours after dosing amount of radioactivity in most tissues of femal parental animals decreased rapidly. In general the time dependent decrease appears to be biphasic (very steep between 1 and 3 hours)

Toxicokinetic parameters 2

Test no.:

#6

Toxicokinetic parameters:

other: In general concentration of radioactivity in foetuses was greater than in maternal issues but decreased with time. There was no retention of radioactivity observed in foetuses.

Toxicokinetic parameters 3

Test no.:

#7

Toxicokinetic parameters:

other: radioactivity retained in following maternal tissues: brain, nasal epithelium, optic lens, bone, inner ear, Hraderian gland. After 24 hours almost all radioactivity had been eliminated from the whole pregnant female.

Toxicokinetic parameters 4

Test no.:

#8

Toxicokinetic parameters:

other: As expected distribution of radioactivity in tissues after i.v. injection (male mice) was faster than after oral application

Metabolite characterisation studies

Metabolites identified:

not specified

Details on metabolites:

no information available

Any other information on results incl. tables

no further relevant remarks

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): no bioaccumulation potential based on study results
After oral administration caprolactam was rapidly absorbed and distributed troughout the animals including the foetuses. No differences in pattern of distribution among male, non-pregnant and pregnant mice could be detected in this study. There was no retention of radioactivity observed in foetuses. Caprolactam is rapidly eliminated by renal and hepatic routes. Metabolism in liver prior to secretion into bile seems likely. There are indications that enterohepatic circulation is absent.

Executive summary:

In this study mice (male, female and pregnant female) were exposed to radioactive labeled [14C]caprolactam, which was orally administered or injected i.v.. After the mice were killed autoradiographies were made from sections of the animals and the time dependend distribution of radioactivity was examined. After oral administration radioactivity was rapidly absorbed and distributed troughout the animals including the foetuses. There was no retention of radioactivity observed in foetuses.
No differences in pattern of distribution among male, non-pregnant and pregnant mice could be detected. After i.v. injection of radioactivity distribution was faster than after oral administration. Caprolactam is rapidly eliminated by renal and hepatic routes. Metabolism in liver prior to secretion into bile seems likely. There are indications that enterohepatic circulation is absent.