Cyclohexanone

Basic toxicokinetics

Administrative data

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

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1987

Report date:

1987

Materials and methods

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.

Test material

Test material information

Constituent 1

Reference substance name:

Cyclohexanone

EC Number:

203-631-1

EC Name:

Cyclohexanone

Cas Number:

108-94-1

Molecular formula:

C6H10O

IUPAC Name:

cyclohexanone

Radiolabelling:

no

Test animals

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.

Administration / exposure

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

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

400 ppm

Remarks:

males

Doses / concentrations 2

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

Results and discussion

Toxicokinetic / pharmacokinetic studies

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.

Any other information on results incl. tables

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.