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Toxicological information

Basic toxicokinetics

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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:
other: basic information given

Data source

Reference
Reference Type:
publication
Title:
Uptake, metabolism and elimination of cyclohexanone in humans.
Author:
Mraz, J., Galova, E., Nohova, H.
Year:
1994
Bibliographic source:
Int. Arch. Environ. Health 66, 203-208

Materials and methods

Objective of study:
other: metabolism and toxicokinetic
Principles of method if other than guideline:
The goal of this study was to obtain, under well-defined experimental conditions, sufficient data on the metabolism and elimination of CH-one in humans for the development of a new biological exposure test.
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Radiolabelling:
no

Test animals

Species:
human
Sex:
male/female

Administration / exposure

Route of administration:
other: percutaneous and inhalative
Details on exposure:
Percutaneous absorption:
A vessel containing pure CH-one liquid (22°C) was placed in a fume hood and the volunteer immersed his or her dry left hand in CH-one up to the wrist. After 30 min, the volunteer took the hand out of the CH-one, washed it thoroughly with warm water and saop and applied a protective cream. Urine was then collected for the subsequent 72 h and analysed for 1,2-CH-diol. The permeation rate of CH-one through skin was calculated.

Inhalation exposures:
The exposure experiments were conducted in groups of 3 or 4 subjects in a closed exposure chamber (volume 64m3), with the required concentration of vapour maintained by the method of Sedivic et al. In principle, a calculated amount of liquid CH-one was evaporated before the exposure, and further vapour supply was controlled by feedback from a Carlo erba gas chromatograph equipped with an automatic gas smapling valve, and analysing at atmosphere at 5-min intervals. Analyses ere performed on a stainless steel column filldd with 20% Carbowax 20M on silanized Gas Chrom P and operated at 100°C. The difference between the prepared and rquired vapour concenetration was always below 5%. The coefficient of variation of concentration measurements during the exposures was from 4% to 8%. Mean temperature and relative humidity during the exposures were 26°C and 70%, respectively.
All exposures were conducted over a period of 8 hours. In addition to single-day exposures with 8 subjects, 4 persons were exposed to CH-one, ca. 200 mg x m-3, for 5 consecutive days, 8 h/day. Volunteers were at rest during the exposure experiments. They left the exposure chamber at 2-h intervals for 2-3 min to void urine.
Duration and frequency of treatment / exposure:
see details on exposure
Doses / concentrations
Remarks:
Doses / Concentrations:
see details on exposure
No. of animals per sex per dose:
4 male and 4 female humans

Results and discussion

Any other information on results incl. tables

Percutaneous absorption: Percutaneous absorption of CH-one was assessed in an experiment in which subjects immersed one hand in pure solvent for 30 min. The total amounts of 1.2-CH-diol excreted during the following 72 h were 25 - 63 umol (mean 45 umol). The permeation rate of CH-one through the skin of the hand, as calculated from these date, was 0.037 - 0.969 mg x cm-2 x h-1 (mean 0.056 mg x cm-2 x h-1).

Inhalation: The metabolites CH-ol, 1,2 -CH-diol and 1,4 -CH-diol were monitored in urine voided during a 72-h period following the 8 -h exposure of volunteers to CH-one vapour at a concentration of 101 -406 mg x m-3. The analytical procedure conjugates and therefore each compound determined represents the sum of its conjugated and unconjugated forms. Whereas CH-ol in urine accounted for barely 1% of the absorbed doses, .2 -and 1.4-CH-diol were the major metabolites of CH-one. Parent CH-one was not detected in urine. Within the range of exposures to CH-one, 101 - 406 mg x m-3, the metabolic yields of CH-ol and CH-diols were effectively constant. Similarly invariable was the character of the mean urinary excretion curves, as typified by the results for the medium exposure (207 mg x m-3). Peak excretion of CLH-ol was always achieved at the end of the exposure period, after which it decayed rapidely. The excretion curves for 1.2- and 1.4 -CH-diol reached their peaks a few hours postexposure, with subsequent elimination half-lives of 15.7 +/- 2.2 and 18.3 +/- 3.5 h, respectively. With repeated exposure to CH-one vapour for 5 consecutive days there was no cumulation of urinay CH-ol whereas cumulation of CH-diols was observed, which reflects the half-lives of the individual metabolites. The maximum excretion rates of CH-diols on days 2 and 3 of the repeated exposure were higher by approx. 30% and 50%, respectively, than the values found on day 1.

Applicant's summary and conclusion