Decene, hydroformylation products, low boiling

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

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

Adequacy of study:

key study

Study period:

1987

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable well-documented study report which meets basic scientific principles.

Data source

Reference

Reference Type:

publication

Title:

The metabolism of t-butylcyclohexane in Fischer-344 male rats with hyaline droplet nephropathy

Author:

Henningsen G.M., Yu K.O., Salomon R.A., Ferry M.J., Lopez I., Roberts J., Servè M.P.

Year:

1987

Bibliographic source:

Toxicology Letters 39: 313-318

Materials and methods

Objective of study:

metabolism

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 417 (Toxicokinetics)

GLP compliance:

not specified

Test material

Reference

Name:

Unnamed

Type:

Constituent

Details on test material:

t-butylcyclohexane

Radiolabelling:

no

Test animals

Species:

rat

Strain:

Fischer 344

Sex:

male

Details on test animals or test system and environmental conditions:

Fourteen Fischer-344 male rats weighing 307+/-10g. Feed (Purina Rat Chow, Ralston Purina Co., St. Louis, MO) and water were provided ad libitum.

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

not specified

Details on exposure:

Fourteen Fischer-344 male rats weighing 307±10 g were randomly divided into 2 groups (8 treated, 6 control). Doses (0.8 g/kg) of t-butylcyclohexane or water (0.8 g/kg) were administered by gavage on an every other day regimen for 2 weeks. Feed (Purina Rat Chow, Ralston Purina Co., St. Louis, MO) and water were provided ad libitum and animals were weighed daily.

Duration and frequency of treatment / exposure:

2 weeks

Doses / concentrations

Remarks:

Doses / Concentrations:
0.8 g/kg

No. of animals per sex per dose / concentration:

8 treated, 6 control

Control animals:

yes, concurrent no treatment

Details on study design:

Fourteen Fischer-344 male rats weighing 307±10 g were randomly divided into 2 groups (8 treated, 6 control). Doses (0.8 g/kg) of t-butylcyclohexane or water (0.8 g/kg) were administered by gavage on an every other day regimen for 2 weeks. Feed (Purina Rat Chow, Ralston Purina Co., St. Louis, MO) and water were provided ad libitum and animals were weighed daily. Following the 14-day exposure period, the rats were sacrificed by halothane.

Details on dosing and sampling:

During the first 48 h of the initial dosing period, the rats were placed in metabolism cages and the urine was collected. A 5.0 ml aliquot of each urine sample was adjusted to a pH of 4.0, and 0.2 ml glucuronidase/sulfatase was added. The sample was shaken for 16 h at 37°C, then cooled to room temperature and filtered through a diatomaceous earth column using methylene chloride as the eluent. The methylene chloride extracts of the hydrolyzed rat urine were analyzed on a gas-liquid chromatograph (GC) equipped with a flame ionization detector. A 25 m x 0.2 mm ID carbowax 20 M fused silica column was used with injection port and detector temperatures of 200 and 250°C, respectively. The oven temperature was programmed to rise from 60 to 170° C at a rate of 5°C/mm and helium was used as the carrier gas. Additional metabolite identification was accomplished using a Hewlett-Packard 5985 gas chromatography/mass spectrometer (GS/MS) system. The GC was equipped with a 15 m x 0.2 mm ID DX-4 capillary column and the injection port temperature and the oven temperature were the same as reported above. Helium was the carrier gas. The MS was a quadrupole instrument operated in the electron impact mode with a voltage of 70 eV and an ion source temperature of 200°C.

The relative abundance of the urinary metabolites was found by preparing a standard solution utilizing a weighed amount of each pure compound and dodecane as an internal standard and then comparing the integrated areas of the GC curve with the areas of the CC urinary metabolite curve containing added dodecane.

Results and discussion

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

The majority of the oxidative metabolism of t-butylcyclohexane occurred on the cyclohexane structure. Of the 2 products which were the result of metabolic oxidation of the t-butyl side chain, 2-methyl-2-cyclohexylpropanoic acid was formed in greater abundance. The formation of the other alkyl side chain, metabolite 2-methyl-2-cyclohexyl-1,3-propanediol can be envisioned as 2 separate monooxidation steps involving the t-butyl group. Each of the branched chain products could hypothetically originate from a common precursor: 2-methyl-2-cyclohexylpropanol. The GC showed no trace of this propanol precursor, suggesting that, if formed, it was rapidly metabolized.
The metabolic oxidation of the cyclohexane ring of t-butylcyclohexane preferentially occurred at the 4-position. The bulkiness of the t-butyl group apparently inhibited monooxidation at the 2- and 3-positions. Both cis- and trans-4-t-butyl- cyclohexanol are formed with the latter being the overall principle metabolic product. The remaining minor metabolites identified were the result of dioxidation on the cyclohexane ring at the 3-position. The least formed cyclohexanediol was the isomer in which all the ring substituents exist in the equatorial position of the cyclohexane chair conformation of 2- hydroxy-4-t-butylcyclohexanol. 2-Hydroxy-4-t-butylcyclohexanol has the t-butyl and the OH at C1 groups in the equatorial position, while the OH at C2 is in the axial position. The most abundant cyclohexanediol, 2-hydroxy-4-t-butylcyclohexanol, has the OH at C2 and the t-butyl groups in the equatorial positions while the OH at C1 is in the axial position. If one envisions that the starting materials for the cyclohexanediols were the corresponding 4-t-butylcyclohexanols, the small amount of cis-4-t-butylcyclohexanol found may be due to its facile conversion into the 2 most abundant t-butyl-1,2-cyclohexanediols isolated. The large amount of trans-4-t-butylcyclohexadiol found may be a reflection of its easier conjugation with glucuronic acid relative to cis-4-t-butylcyclohexanol. The difficulty in glucuronidation of the cis-4-t-butylcyclohexanol could then, conceivably, result in further hydroxylation to facilitate urinary excretion by creating more polar metabolites (diols).

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): no data
The major metabolites of t-butylcyclohexane were found to be: trans-4-t-butylcyclohexanol, 2c-hydroxy-4t-t-butylcyclohexanol, 2-methyl-2-cyclohexylpropanoic acid, 2c-hydroxy-4c-t-butylcyclohexanol, 2-methyl-2-cyclohexyl-1,3-propanediol, 2t-hydroxy-4t-t-butylcyclohexanol, and cis -4-t-butylcyclohexanol.

Executive summary:

The major metabolites of t-butylcyclohexane were found to be: trans-4-t-butylcyclohexanol, 2c-hydroxy-4t-t-butylcyclohexanol, 2-methyl-2-cyclohexylpropanoic acid, 2c-hydroxy-4c-t-butylcyclohexanol, 2-methyl-2-cyclohexyl-1,3-propanediol, 2t-hydroxy-4t-t-butylcyclohexanol, and cis -4-t-butylcyclohexanol.