Cyclohexanone oxime

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1991

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable, well-documented publication

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

1991

Report date:

1991

Materials and methods

Objective of study:

toxicokinetics

Principles of method if other than guideline:

No guideline available

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Cyclohexanone oxime

EC Number:

202-874-0

EC Name:

Cyclohexanone oxime

Cas Number:

100-64-1

Molecular formula:

C6H11NO

IUPAC Name:

cyclohexanone oxime

Test material form:

not specified

Details on test material:

- Name of test material (as cited in study report): cyclohexanone oxime
- Analytical purity: unlabelled material from supplier recrystallised

Radiolabelling:

yes

Remarks:

[1-C14]-cyclohexanone oxime, specific activity 6.85 mCi per mmol

Test animals

Species:

rat

Strain:

Fischer 344

Sex:

male

Administration / exposure

Route of administration:

other: exposure routes: oral, dermal and i.v

Vehicle:

other: oral exposure: water, dermal exposure: acetone

Details on exposure:

Dermal exposure: The interscapular region was clipped 24 h before exposure. The animals were anesthesised with ketamine and 30 mg/kg bw were applied at 0.2 mL/kg bw in a circular area of 1 cm2. The application site was covered with a perforated metal tissue capsule, glued directly to the skin. The aminals were kept individually in metabolism cages and sacrificed 24 h after exposure.

Duration and frequency of treatment / exposure:

single exposures: oral (gavage), dermal and i.v.

Doses / concentrations

Remarks:

Doses / Concentrations:
#1) oral (gavage): 1, 10 or 30 mg/kg bw
#2) dermal (semiocclusive): 30 mg/kg bw
#3) i.v.: 1 mg/kg bw

No. of animals per sex per dose / concentration:

3

Control animals:

no

Results and discussion

Main ADME results

Main ADME results 1

Type:

absorption

Results:

Oral exposure: nearly complete; Dermal exposure: about 5%

Main ADME results 2

Type:

distribution

Results:

Throughout the whole body

Main ADME results 3

Type:

metabolism

Results:

Cyclohexanone, cyclohexanol, cyclohexane-1,2-diol; alcohols glucuronidated

Main ADME results 4

Type:

excretion

Results:

After orale exposure: nearly complete excretion after 24 h

Toxicokinetic / pharmacokinetic studies

Details on absorption:

#1: Based on the distribution and excretion data (see below), a nearly complete absorption can be assumed after oral exposure.

#2: Based on the distribution and excretion data (see below), a low absorption can be assumed after dermal exposure (4-5%).

Details on distribution in tissues:

#1: Oral exposure (6 h after exposure): large mass compartiments such as muscle (12.6% of administered dose), skin (4.0%) and fat (2.9%) accounted for about 50% of the retained total radioactivity. The gastrointestinal tract (incl. contents), liver, kidney and blood also contained high concentrations. Brain, spleen, testes and lungs contained few radioactivity.
Oral exposure, 24 h after exposure: very low levels of radioactivity (2-3%) were retained in the tissues 24 hours after exposure.

#2: 24 h after dermal exposure, skin and muscle revealed the highest amounts of retained radioactivity (0.1% of admininstered dose each)

Details on excretion:

Oral exposure, within 6 h after dosing (only 30 mg/kg bw tested): 40% of the radioactivity was excreted in urine, 1% in feces.

Oral exposure, within 24 h after dosing (1-30 mg/kg bw): The majority of the radioactivity (68-87% of the dose) was excreted in the urine. Elimination in the feces accounted for 5-9% of the dose, 2% were expired as CO2 and very low levels of radioactivity (2-3%) were retained in the tissues 24 hours after exposure.

Dermal exposure (within 24 h after exposure start): 3.9% was excreted in urine, < 0.1% in feces, 4.5% remained at the application site and 0.4% in tissues.
23% volatilised within 3-5 min after application

Toxicokinetic parameters

Toxicokinetic parameters 1

Test no.:

#3

Toxicokinetic parameters:

other: volume of distribution: 0.65 L/kg

Toxicokinetic parameters 2

Test no.:

#3

Toxicokinetic parameters:

half-life 1st: in plasma: 1.6 min

Toxicokinetic parameters 3

Test no.:

#3

Toxicokinetic parameters:

half-life 2nd: in plasma: 18.2 min

Toxicokinetic parameters 4

Test no.:

#3

Toxicokinetic parameters:

AUC: 32,100,000 min x µg/L

Toxicokinetic parameters 5

Test no.:

#3

Toxicokinetic parameters:

other: clearance: 0.036 L/Kg/min

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

Three main metabolites were identified in urine of treated animals: the monoglucuronides of cis- and trans-cyclohexane-1,2-diol, and the glucuronide of cyclohexanol.
In vitro incubations of the test substance with rat liver S9 fraction contained cyclohexanone and cylohexanol, cis- and trans-cyclohexane-1,2-diol

Any other information on results incl. tables

Distribution and elimination after dermal application were not different from those observed after oral administration.

Based on the identidied metabolites, the authors proposed the following metabolism scheme:

Cyclohexanone oxime is cleaved in the initial step to cyclohexanone and hydroxylamine. Cyclohexanone is further metabolised to cyclohexanol and cyclohexane-1,2-diols, which were glucuronidated and excreted in urine.

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): no bioaccumulation potential based on study results
Under the conditions of this study no bioaccumulation has to be expected

Executive summary:

Rats were exposed orally to cyclohexanone oxime in doses of 1 to 30 mg/kg bw. The substance was distributed throughout the whole body. Within 24 h 68 -87% of the administered dose was excreted in the urine, elimination in the feces accounted for 5-9% of the dose, 2% were expired as CO2 and very low levels of radioactivity (2-3%) were retained in the tissues 24 hours after exposure. The main metabolites in urine were monoglucuronides of cis- and trans-cyclohexane-1,2-diol, and the glucuronide of cyclohexanol. It can be assumed that absorption after oral exposure is nearly complete.

Dermal exposure: within 24 h after exposure start, 3.9% was excreted in urine and 0.1% in feces, 4.5% remained at the application site and 23% had volatilised within 3-5 min after application. Therefore the systemic uptake after dermal exposure is in the range of 5% of the administered dose.

The plasma half-life after i.v. exposure was 1.6 min (first phase) and 18.2 min (second phase).