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Administrative data

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Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
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
Objective of study:
toxicokinetics
Principles of method if other than guideline:
The study was conducted following guidelines as published by the Environmental Protection Agency under the Toxic Substances Control Act (TSCA).
GLP compliance:
yes (incl. QA statement)
Remarks:
testing lab.
Radiolabelling:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
The animals arrived in good condition and were housed in an animal room during a two-week quarantine and pre-exposure period and the 72-hour post-exposure sample collection period. The animals were housed singly in suspended stainless steel wire cages during the pre-exposure period and in stainless steel metabolism cages during the 72-hour sample collection period. Bedding was changed two times per week. Rodent meal was fed to the animals ad libitum. Municipal water was available to the animals ad libitum and water bottles were changed weekly. The certified feed is analyzed by the supplier to assure that no contaminants are present in the feed that could interfere with the study; results of these assays are on file in the project files. The municipal water system is analyzed on a regular basis by the municipal water treatment plant laboratory and results of these analyses are retained on file at TL; additional samples are submitted by TL every six months for analysis and these results are also on file at TL. The animals were housed in environmentally controlled animal rooms maintained at 72 + 3° F and a 12-hour light/dark cycle. Rats were used in this study since this species, is routinely used in metabolism studies reported to regulatory agencies. Extra rats not used in the inhalation exposures were euthanized and discarded after completion of the study.
Route of administration:
inhalation: vapour
Vehicle:
not specified
Details on exposure:
Each animal was weighed immediately prior to exposure and again immediately following the six-hour exposure period and after 72 hours. Animals during and after exposure were observed for any clinical signs of toxicity and mortality. Blood samples were obtained from each animal immediately following exposure and after 24 and 72 hours during the post-exposure period. After exposure, the animals were placed in metabolism cages for the collection of urine samples at intervals of 0-24, 24-48 and 48-72 hours.
Duration and frequency of treatment / exposure:
6 h, 72 h post-exposure period
Dose / conc.:
400 ppm
Remarks:
males
Dose / conc.:
1 600 ppm
Remarks:
females
No. of animals per sex per dose / concentration:
5
Control animals:
yes, concurrent no treatment
Positive control reference chemical:
no data
Details on dosing and sampling:
Blood samples were obtained immediately following the dosing period and after 24 and 72 hours for analysis of free cyclohexanone and cyclohexanol in blood sera. After exposure, the animals were placed in metabolism cages and urine samples were collected from each animal at intervals of 0-24 hours, 24-48 hours and 48-72 hours; urine samples were analyzed for free cyclohexanone and cyclohexanol as well as conjugated metabolites of cyclohexanone. Body weights of each animal were determined immediately prior to and after exposure and at the end of the 72-hour sample collection period. Chamber air samples were analyzed periodically during the 6-hour exposure period.
Statistics:
no data
Details on excretion:
In urine samples, total excretions of free cyclohexanone and cyclohexanol were 16.16 and 14.55 ug, respectively, at 400 ppm and 142.93 and 264.08 ug, respectively, at 1600 ppm; results indicate a ten-fold or more increase in excretion of these products at a four-fold increase in exposure level. Urinary excretion occurred primarily during the first 24 hours although detectable but not quantifiable traces of both products were seen in the 48 and 72-hour urine samples at the 1600 ppm level. Total excretion of conjugated cyclohexanol was 13,306.15 and 72,446.56 ug, respectively, at the 400 and 1600 ppm exposure levels. Excretion occurred primarily found in the 48 to 72-hour urine samples at 1600 ppm whereas detectable but not quantitated levels were found at 400 ppm. Total excretion of conjugated cyclohexanol at 1600 ppm was increased slightly less than six-fold with the four-fold increase in dose. An unexpected conjugated product in urine chromatographing with a GC retention-time similar to cyclohexanone was found at both exposure levels; total excretions of this product (cyclohexanone) at 400 and 1600 ppm were 546.69 and 890.94 ug, respectively. The four-fold increase in dose level produced only about a 5O% increase in excretion of this material.

The time weighted average air concentrations attained in these single six-hour exposures were 350 and 1479 ppm at the desired 400 and 1600 ppm concentrations, respectively.

Rats at both concentrations of the test material lost weight during the six-hour exposure period and also during the subsequent three-day post-exposure period while housed in metabolism cages; weight losses were slightly greater at 1600 ppm. Rats during exposure exhibited clinical signs characterized as decreased activity and sedation due to anesthetic properties of the test material; the sedation was more pronounced at 1600 ppm as these animals after the six-hour exposure were still anesthetized during the collection of the immediate post-exposure blood samples. All animals appeared alert and normal during the three-day post-exposure period and all animals survived to necropsy at the end of the 72-hour post-exposure period. Blood serum levels of free cyclohexanone and free cyclohexanol immediately following exposure at 400 ppm were 26.01 +/- 6.30 and 20.48 +/- 3.54 ug/ml, respectively. At 1600 ppm, blood levels of free cyclohexanone and cyclohexanol were 121.76 +/- 15.16 and 140.43 +/- 22.19 ug/ml, respectively, indicating that blood levels of each product were increased five to seven times with a four-fold increase in exposure. The products were rapidly cleared from blood sera as only trace quantities of cyclohexanol were seen in 24-hour samples at the 1600 ppm exposure level. In urine samples, total excretions of free cyclohexanone and cyclohexanol were 16.16 and 14.55 ug, respectively, at 400 ppm and 142.93 and 264.08 ug, respectively, at 1600 ppm; results indicate a ten-fold or more increase in excretion of these products at a four-fold increase in exposure level. Urinary excretion occurred primarily during the first 24 hours although detectable but not quantifiable traces of both products were seen in the 48 and 72-hour urine samples at the 1600 ppm level. Total excretion of conjugated cyclohexanol was 13,306.15 and 72,446.56 ug, respectively, at the 400 and 1600 ppm exposure levels. Excretion occurred primarily found in the 48 to 72-hour urine samples at 1600 ppm whereas detectable but not quantitated levels were found at 400 ppm. Total excretion of conjugated cyclohexanol at 1600 ppm was increased slightly less than six-fold with the four-fold increase in dose. An unexpected conjugated product in urine chromatographing with a GC retention-time similar to cyclohexanone was found at both exposure levels; total excretions of this product (cyclohexanone) at 400 and 1600 ppm were 546.69 and 890.94 ug, respectively. The four-fold increase in dose level produced only about a 5O% increase in excretion of this material.

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
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
Objective of study:
metabolism
toxicokinetics
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
Radiolabelling:
no
Species:
human
Sex:
male/female
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 64 m³), 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 sampling valve, and analysing at atmosphere at 5-min intervals. Analyses were performed on a stainless steel column filled 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:
Percutaneous absorption: 30 min exposure, urine collection for subsequent 72 hours
Inhalation exposures: 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 hour intervals for 2 - 3 min to void urine.
Dose / conc.:
101 mg/m³ air
Dose / conc.:
207 mg/m³ air
Dose / conc.:
406 mg/m³ air
No. of animals per sex per dose / concentration:
4 male and 4 female humans
Details on absorption:
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).
Details on excretion:
Inhalation exposure
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.
Metabolites identified:
yes
Details on metabolites:
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.

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.

Description of key information

In the Tegeris study (1987) rats were exposed to Cyclohexanone by inhalation at air concentrations of 400 (males) and 1600 (females) ppm for 6 hours. The animals lost weight and appeared sedated. The material was rapidly eliminated from the blood; concentrations of free cyclohexanone and cyclohexanol in the blood immediately after exposure were about 26.01 and 20.48 µg/mL, respectively, at the low dose and 121.76 and 140.43 µg/mL, respectively at the high dose. Only trace quantities of free cyclohexanol were seen at 24 hours. Total 72-hour urinary excretion volumes of free cyclohexanone and cyclohexanol were 16.16 and 14.55 µg, respectively, at the high dose. By 72 hours, the total excretion of conjugated cyclohexanol (primarily excreted during the first 24 hours) and another conjugated product, tentatively cyclohexanone, was 13,306.15 and 546.69 µg at the low dose and 72,446.56 and 890.94 µg at the high dose.

Martis et al. investigated the metabolism of Cyclohexanone in beagle dogs after intravenous application. After dosing with 285 mg/kg bw, 74 - 100% of Cyclohexanone had been reduced to Cyclohexanole . Approximately 60% was excreted as the glucuronidated form of Cyclohexanole. The elimination half-time (t½) was determined to be approximately 80 minutes.

Mraz et al. studied the metabolism and kinetics of cyclohexanone in a group of volunteers (four men and four women) during and after 8-h exposures to 101, 207 and 406 mg/m3. After exposure to 207 mg/m3, the metabolic yields of urinary cyclohexanol, 1,2- and 1,4 -cyclohexanediol and their glucuronide conjugates were 1%, 39% and 18%, respectively. The elimination half-times (t½) of the 1,2- and 1,4-diols, respectively, were 16 h and 18 h. Consequently, after repeated exposure over five days, there was no cumulation of urinary cyclohexanol, whereas there was cumulative excretion of the diols. The permeation rate of cyclohexanone liquid through the skin was 37 - 69 mg/cm2 per hour (Mráz et al., 1994).

Dennerlein et al. (2012) as well as Schenk et al. (2018) investigated the dermal absorption of Cyclohexanonein vitro by using human skin samples or piglet skin samples, respectively. The flux rates determined during both experiments suggest an overestimation of absorption by in vitro methods when compared to the in vivo findings by Mraz et al. (1994).

Conclusion:

In the rat, the major part of Cyclohexanone is reduced to Cyclohexanol which is then glucoronidated and excreted. In humans, the glucuronidation pathway seems to be less important; the major part of Cyclohexanone gets ring-hydroxylated to 1.2- and 1.4 -diols which are excreted in glucuronidated and non-glucuronidated form. Hence, the rat model has in the case of Cyclohexanone some limitations in terms of human relevance.

Considering the absorption of Cyclohexanone, the results of the studies available suggest that Cyclohexanone is readily absorbed by all routes of exposure.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information