1,3- AND 1,4-CYCLOHEXANDICARBOXYALDEHYDE

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2015

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: The study was conducted according to OECD TG 417, EPA, OPPTS 870.7485, EEC, Guideline B.36, JMAFF and in accordance with the Principles of Good Laboratory Practice (GLP)

Cross-reference

Cross-reference 1

Reason / purpose for cross-reference:

reference to same study

Cross-reference 2

Reason / purpose for cross-reference:

reference to other study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2015

Report date:

2015

Materials and methods

Objective of study:

other: pharmacokinetics and metabolism

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 417 (Toxicokinetics)

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.7485 (Metabolism and Pharmacokinetics)

Deviations:

no

Test guideline 3

Qualifier:

according to guideline

Guideline:

EU Method B.36 (Toxicokinetics)

Deviations:

no

Test guideline 4

Qualifier:

according to guideline

Guideline:

other: JMAFF

Deviations:

no

Principles of method if other than guideline:

not applicable

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

-

EC Number:

482-020-3

EC Name:

-

Molecular formula:

C8H12O2

IUPAC Name:

cyclohexane-1,3-dicarbaldehyde; cyclohexane-1,4-dicarbaldehyde

Test material form:

other: solution in corn oil

Details on test material:

- Name of test material (as cited in study report): 1,3- and 1,4-Cyclohexanedicarboxaldehyde
- Analytical purity: Non-Radiolabeled - The purity of the test material was determined to be 98.24 ± 0.44% area by gas chromatography (corrected for water) with identification by proton and carbon-13 nuclear magnetic resonance and gas chromatography mass spectrometry. Radiolabeled ([Hexyl-UL-14C]-Cyclohexane-1,3-dicarbaldehyde) - Non-GLP radiochemical purity is listed as >97% by high performance liquid chromatography and Radiolabeled ([Hexyl-UL-14C]-Cyclohexane-1,4-dicarbaldehyde) - Non-GLP radiochemical purity is listed as >94% by high performance liquid chromatography
- Lot/batch No.: Non-Radiolabeled - Lot# 201200123-WFE 2-3Mr and Radiolabeled ([Hexyl-UL-14C]-Cyclohexane-1,3-dicarbaldehyde) - (Lot# ES767-011-6 and Radiolabeled ([Hexyl-UL-14C]-Cyclohexane-1,4-dicarbaldehyde) - Lot# 08-39-55
- Radiochemical purity (if radiolabelling): [Hexyl-UL-14C]-Cyclohexane-1,3-dicarbaldehyde and [Hexyl-UL-14C]-Cyclohexane-1,4-dicarbaldehyde
- Specific activity (if radiolabelling): Radiolabeled ([Hexyl-UL-14C]-Cyclohexane-1,3-dicarbaldehyde) in ethanol: 6.34 mCi/mmol and Radiolabeled ([Hexyl-UL-14C]-Cyclohexane-1,4-dicarbaldehyde) in ethanol: 5 mCi/mmol

Radiolabelling:

yes

Test animals

Species:

rat

Strain:

Fischer 344

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Taconic (Germantown, New York)
- Age at study initiation: 9-10 weeks
- Fasting period before study: 16 hours prior to the administration of test material and was returned about 4 hours post-dosing with the exception of animals in the repeated exposure
- Housing: Non-cannulated animals were housed two per cage in stainless steel solid bottom cages with corncob bedding Following administration of test material the animals were housed singly in glass Rothtype metabolism cages, which were designed for the separation and collection of urine, feces, CO2, and organic volatiles
- Individual metabolism cages: yes
- Diet: ad libitum):
- Water: ad libitum
- Acclimation period: at least one week prior to use, including at least two days in metabolism cages and jugular vein cannulated rats (surgery performed by the supplier) were acclimated in metabolism cages for at least five days prior to use

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22°C with a range of 20°C-26°C
- Humidity (%): 54% with a range of 32-73%
- Photoperiod (hrs dark / hrs light): 12 hours light/dark cycle

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on exposure:

The appropriate quantity of radiolabeled and non-radiolabeled test articles was added to corn oil to prepare the dose solution. The amount of dose solution was administered at a target volume of ~5 mL/kg body weight; the target radioactivity was ~400 μCi/kg. Appropriate amounts of 14C-labeled and/or non-radiolabeled 1,3-and 1,4-cyclohexanedicarboxaldehyde were added to obtain the target doses of 20 or 400 mg 1,3- and 1,4-cyclohexanedicarboxaldehyde/kg body weight.
The dose confirmation and homogeneity were conducted concurrently with the study to determine the concentration of 1,3- and 1,4-cyclohexanedicarboxaldehyde and chemical homogeneity of the test material in all dose solutions using Gas Chromatography with Mass Spectrometry Detection (GC/FID) A previous study had shown 1,3- and 1,4-cyclohexanedicarboxaldehyde to be stable for 8 days at 1 and 250 mg/mL dose levels in corn oil

Duration and frequency of treatment / exposure:

Group 1 - 20 mg/kg (Single oral gavage dose of the mixture of 14C-1,3- and 1,4-cyclohexanedicarboxaldehyde)
Group 2 - 400 mg/kg - (Single oral gavage dose of the mixture of 14C-1,3- and 1,4-cyclohexanedicarboxaldehyde)
Group 3 - 20 mg/kg - (Group 3 rats were dosed for 14 days with non-radiolabeled 1,3- and 1,4-cyclohexanedicarboxaldehyde and dosed with 14C-1,3- and 1,4-cyclohexanedicarboxaldehyde on Day 15 and excreta collected for 7 days post-dosing the radiolabeled test material)

Doses / concentrations

Remarks:

Doses / Concentrations:
20 mg/kg and 400 mg/kg

No. of animals per sex per dose / concentration:

4 males

Control animals:

no

Positive control reference chemical:

not applicable

Details on study design:

Initially, a small pilot study was conducted prior to the definitive portion of this study according to the OECD 417 guideline in order to determine radioactivity absorption, distribution, toxicokinetics and metabolite profiling, with the individual 1,3 and the 1,4 isomer of the test material. In this pilot study, two male and two female rats were administered a nominal dose of 200 mg 14C-1,4-isomer/kg bw via oral gavage. and two additional male and female rats were administered 200 mg 14C-1,3-isomer/kg bw via oral gavage




- Dose selection rationale: According to the pilot study results, similar rates of absorption distribution, and elimination were observed between male and female rats for either 1,3-cyclohexanedicarboxaldehyde or 1,4 cyclohexanedicarboxaldehyde. Based on these data and the lack of gender differences in toxicity between male and female rats for 1,3- and 1,4-cyclohexanedicarboxaldehyde, this final definitive ADME study was conducted in male rats only with a mixture of 1,3- and 1,4-cyclohexandedicarboxaldehyde

Details on dosing and sampling:

The rats of Groups 1 and 2 were fitted with indwelling jugular vein cannulae and plasma and red blood cell (RBC) 14C concentration-time course evaluated to determine peak (Cmax) and half-peak (½Cmax) 14C concentrations. Approximately 0.1-0.2-mL blood was collected at chosen times (0.08, 0.17, 0.25, 0.5, 1, 2, 3, 6, 12, 24 hours, and every 24 hours post-dosing thereafter from each animal) and plasma prepared by centrifugation. The RBC was oxidized and the plasma and RBC analyzed for radioactivity by LSS. Excreta were collected, counted by LSS and metabolite identification conducted.
Terminal tissue distribution was also conducted. Group 3 rats were dosed for 14 days with non-radiolabeled 1,3- and 1,4-cyclohexanedicarboxaldehyde and dosed with 14C- 1,3- and 1,4-cyclohexanedicarboxaldehyde on Day 15 and excreta collected for 7 days post-dosing the radiolabeled test material.
The oral dose was administered via a ball-tipped gavage needle attached to a glass syringe. Animals from Groups 1 and 2 received a single oral dose of radiolabeled and non-radiolabeled test material. Group 3 animals received 14-daily doses of non-radiolabeled test material. On day 15, each Group 3 animal received a single dose of radiolabeled and non-radiolabeled dose formulation. The volume of radiolabeled and non-radiolabeled dose formulation administered to
each animal was calculated based on the body weight taken on the day of dose administration, with the exception of Group 3 (repeat). The volume of dose
administered to each Group 3 animal was based on the body weight taken on day 1 (for dosing days 1-7) and day 8 (for dosing days 8-14) of dose administration. The volume of radiolabeled and non-radiolabeled dose administered on day 15 was based on individual body weights on either day 14 or 15. The actual amount of radiolabeled and non-radiolabeled test material administered to each animal was determined by weighing the dose syringe before and after dose administration. The targeted volume of the radiolabeled and non-radiolabeled dose formulation was 5 mL/kg bw. The amount of non-radiolabeled test material administered to Group 3 (days 1-14) animals was determined by target volume, not syringe weight.
Groups 1 and 2 rats were fitted with indwelling jugular vein cannulae, which was used to collect blood for the determination of time course 14C concentration of the test materials in plasma and RBC.
Blood (approximately 0.1-0.2 ml from animals in Groups 1 and 2) were collected from the jugular vein cannula and transferred into tubes containing sodium heparin anticoagulant at 0.08, 0.17, 0.25, 0.5, 1, 2, 3, 6, 12, 24, and every 24 hours post-dosing thereafter from each animal. Radioactivity was determined in appropriate aliquots of the plasma and RBC of each samples collected from each group. Weighed aliquots of RBC were oxidized and the plasma and RBC analyzed for radioactivity by LSS
Specimen Collection - Urine -
All urine voided during the study was collected in dry-ice cooled traps. The urine traps were changed at 12, 24 and 48 hours post-dosing followed by 24-hour intervals for the remainder of the study. (Historically, rats do not reproducibly void a sufficient volume of urine by 6 hours post-dosing to allow for radioactivity determination via LSS and for chemical analysis. Therefore, the first collection interval was 12 hours post-dosing). The cages were rinsed with water at the time the traps were changed and the rinse collected. Each urine specimen and urine/cage rinse was weighed, and a weighed aliquot of each sample was analyzed for radioactivity by LSS as described below. Equal volume aliquots of urine samples (per time and dose) from the 0-12-hour, 12-24-hour and 24-48-hour collection intervals were pooled and stored at -80 ºC.
Feces - Feces in the study were collected in dry-ice chilled containers at 24-hour intervals. An aqueous homogenate (~ 25% w/w) was prepared (shaken for > 4 hours) and weighed aliquots of these homogenates were oxidized, (OxiMate 80 Sample Oxidizer, PerkinElmer Life Sciences, Inc., Boston, Massachusetts) and quantitated for radioactivity by LSS. In addition, equal volume aliquots of fecal homogenates from each animal were taken from the 0-24-hour and 24-48-hour collection intervals and pooled (per dose and time). These pooled samples were stored at -80 ºC.
Expired Volatiles - Initially, air was drawn through the cage at approximately 850 mL/minute, but since collection of expired air and volatiles wasn’t needed, cages were just cracked for airflow. Because < 1% of the administered dose was detected in the charcoal traps in the first studied group (e.g., Pilot Groups A and B), charcoal traps were not used in the definitive study.
Expired CO2
Because < 1% of the administered dose was detected in the CO2 traps of the first studied group (e.g., pilot groups A and B), CO2 traps were not used in the definitive study.
Terminal Sacrifice - At the specified time post-dosing, the animals were anaesthetized with any combination of CO2/O2 , cervical dislocation and sacrificed by exsanguination. Following sacrifice the Roth cages were washed and the cage wash analyzed for radioactivity by LSS.
Tissues - The following tissues were collected at sacrifice from all groups: adrenal, bladder, blood (terminal), bone (femur), bone marrow (femur), brain, carcass (residual), fat (perirenal), GI tract (with contents), heart, kidney, liver, lung, lymph node, muscle (skeletal), pancreas, pituitary, plasma (terminal), RBC (red blood cells), skin, spleen, testis, thymus, and thyroid
The brain, carcass, GI tract with contents, kidney, liver, pancreas and testis were collected, homogenized (~ 33% homogenate), a weighed aliquot solubilized or oxidized, and analyzed for radioactivity by LSS. Bone was solubilized and analyzed for radioactivity by LSS. Blood was centrifuged to obtain plasma and the plasma analyzed for radioactivity by LSS. RBC was oxidized and analyzed for radioactivity by LSS. The skin was removed from the carcass and a representative skin sample oxidized and analyzed for radioactivity by LSS. The remaining tissues were directly oxidized without homogenization and analyzed for radioactivity by LSS.
Final CageWash - Following the terminal sacrifice of the animals, a final cage wash (FCW) was performed with water and detergent. The FCWwas collected and the weight of the sample was determined. The FCWwas shaken for > 4 hours and a weighed aliquot was analyzed for radioactivity by LSS.
Plasma and RBC - Blood was obtained at sacrifice via cardiac puncture. The blood was centrifuged to obtain plasma and RBC and analyzed for radioactivity via LSS.
Control Samples - A male rat was dosed with the appropriate carrier because the test vehicle was nonaqueous (i.e., corn oil). The carrier-control animal was sacrificed by the same procedure as the dosed animals. The control urine and feces were collected for 24 hours postdosing.

Statistics:

Descriptive statistics were used, i.e., mean ± standard deviation. All calculations in the database were conducted using Microsoft Excel (Microsoft Corporation, Redmond, Washington) spreadsheets and databases in full precision mode (15 digits of accuracy). Certain pharmacokinetic parameters were calculated for RBC and plasma data, including AUC (area-under-the-curve), Cmax, ½Cmax, and elimination rate constants, using a pharmacokinetic computer modeling program using PK Solutions (v.2.0.6., Summit Research Services, Montrose, Colorado).

Results and discussion

Preliminary studies:

not applicable

Main ADME results

Main ADME results 1

Type:

absorption

Results:

rapidly absorbed

Main ADME results 2

Type:

metabolism

Results:

rapidly metabolised

Main ADME results 3

Type:

excretion

Results:

rapid excretion

Main ADME results 4

Type:

other: bioaccumulation

Results:

very low bioaccumulation potential

Toxicokinetic / pharmacokinetic studies

Details on absorption:

A conservative estimate of absorption of the oral doses was made from the percent of administered radioactivity recovered in urine (including the cage rinses and final cage wash) and tissues at sacrifice (except GI tract). This estimate may be low, since it does not account for net biliary elimination, which was not measured. The nominal 20 or 400 mg/kg dose group animals (Groups 1-3) showed high absorption of 14C-1,3- and 1,4-cyclohexanedicarboxaldehyde (at least 92-95% of the administered dose), based on recovery in urine, rinse, FCWand non-GI tissues. There was also some indication of enterohepatic recirculation in rats from both dose groups. Double peaks were observed in both the plasma and RBC concentration timecourse data in all high dosed rats and observed in 2 rats RBC in the low dose group.

Details on distribution in tissues:

After 168 hours post-dosing, only a few tissues from animals of all groups contained quantifiable radioactivity with ≤ 0.05% of the administered dose or ≤ 1.035 μg/g tissue, on average.

Details on excretion:

Urinary Elimination of the Administered 14C-1,3- and 1,4-cyclohexanedicarboxaldehyde -
Group 1. Single Oral Low Dose (20 mg/kg bw) 14C-1,3- and 1,4-cyclohexanedicarboxaldehyde - Following a single oral dose of 14C-1,3- and 1,4-cyclohexanedicarboxaldehyde, a mean total of 94% of the administered dose were recovered in urine (including the rinse) of male rats.Radioactivity was rapidly excreted with 95% of total urinary elimination occurring within 12 hours post-dosing.
Group 2. Single Oral High Dose (400 mg/kg bw) of 14C-1,3- and 1,4-cyclohexanedicarboxaldehyde - Following a single oral dose of 14C-1,3- and 1,4-cyclohexanedicarboxaldehyde, a mean total of 91% of the administered dose were recovered in urine (including the rinse) of male rats. Radioactivity was rapidly excreted with 92% of total urinary elimination occurring within 12 hours post-dosing.
Group 3. Repeat Oral Low Dose (20 mg/kg bw) 14C-1,3- and 1,4-
cyclohexanedicarboxaldehyde
Following a repeat (14 days) oral dose of 20 mg/kg 1,3- and 1,4-cyclohexanedicarboxaldehyde and single oral dose of 20 mg/kg 14C-1,3- and 1,4-cyclohexanedicarboxaldehyde, a mean total of 94% of the administered dose were recovered in urine (including the rinse) of male rats Radioactivity was rapidly excreted
with 91% of total urinary elimination occurring within 12 hours post-dosing
Fecal Elimination of the Administered 14C-1,3- and 1,4-cyclohexanedicarboxaldehyde -
Group 1. Single Oral Low Dose (20 mg/kg bw) 14C-1,3- and 1,4-cyclohexanedicarboxaldehyde - Following a single oral dose of 20 mg/kg 14C-1,3- and 1,4-
cyclohexanedicarboxaldehyde, a mean total of 13% of the administered dose was recovered in the feces of male rats Radioactivity was rapidly excreted with 91% of total fecal elimination occurring within 24 hours post-dosing
Group 2. Single Oral High Dose (400 mg/kg bw) of 14C-1,3- and 1,4-cyclohexanedicarboxaldehyde - Following a single oral dose of 400 mg/kg 14C-1,3- and 1,4-cyclohexanedicarboxaldehyde, a mean total of 9.4% of the administered dose was recovered in the feces of male rats. Radioactivity was rapidly excreted with 82% of total fecal elimination occurring within 24 hours post-dosing.
Group 3. Repeat Oral Low Dose (20 mg/kg bw) 14C-1,3- and 1,4-cyclohexanedicarboxaldehyde - Following a repeat oral dose of 20 mg/kg 1,3- and 1,4-
cyclohexanedicarboxaldehyde and single oral dose of 20 mg/kg 14C-1,3- and 1,4-cyclohexanedicarboxaldehyde, a mean total of 11% of the administered dose was recovered in the feces of male rats,. Radioactivity was rapidly excreted with 80% of total fecal elimination occurring within 24 hours post-dosing.

Toxicokinetic parameters

Toxicokinetic parameters 1

Test no.:

#1

Toxicokinetic parameters:

Tmax: between 0.293 and 1.668 hours

Toxicokinetic parameters 2

Test no.:

#2

Toxicokinetic parameters:

half-life 1st: between 1.8 and 3.1 hours

Toxicokinetic parameters 3

Test no.:

#3

Toxicokinetic parameters:

half-life 2nd: ~6 hours

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

Metabolite profiling and quantitation were conducted on select samples for Groups 1-3.
A total of 11 radiochemical peaks were detected in the acidified urine and/or fecal samples across the profiles of all 3 definitive groups (groups 1-3). Only five major peaks (containing six major metabolites) of the 11 radiochemical peaks accounted for more than 5% of the administered dose. No
parent 1,3-CHDA and 1,4-CHDA was detected in the urine or fecal samples. Among these five major peaks, the most abundant metabolite Peak E, as well as the less abundant Peak D-1, accounting for 39 to 45% and 9% of the administered dose (respectively), were identified as the cis and trans isomers of 1,3-cyclohexanedicarboxylic acid (1,3-CHD acid) (isomer assignments unknown). Peaks B and F1 account for 17% and 10-12% of the administered dose (respectively) and were identified as the cis and trans isomers of 1,4-cyclohexanedicarboxylic acid (1,4-CHD acid) (isomer assignments unknown).
Two additional major peaks were tentatively identified as either the cis or trans isomer of 4-(hydroxymethyl)cyclohexanecarboxylic acid, which
comprised ~7 % to 11 % of the administered dose, and either the cis or trans isomer of 3-(hydroxymethyl)¬cyclohexane carboxylic acid which
comprised ~9 % of the administered dose.

Any other information on results incl. tables

The concentration of radioactivity in each of the dose solution was 84-85% of the target concentration. The slight deviations from the target concentrations were deemed to have no impact on the overall interpretation of the study. The measured concentration of total test material in each dose solution was 87-117% of the target concentration. The homogeneity analysis revealed acceptable homogeneity

with 0.4-3.3% relative standard deviation for all groups.

The mean dose of 14C-1,3- and 1,4 -cyclohexanedicarboxaldehyde administered to the groups was 17.0-24.5 and 391-405 mg/kg bw for the targeted 20 and 400 mg/kg dose groups, respectively. Though the doses administered were slightly above or below the target, this was deemed to have no impact on the overall interpretation of the study. A range of 322- 464 μCi/kg was administered to male rats for all dose groups. The actual radioactivity administered was 81-86% of the targeted dose of ~400 μCi/kg.

Total recovery of radioactivity from the animals averaged 107, 101 and 105% for Groups 1-3 male rats, respectively

There were no signs of toxicity observed in any animals following oral administration of 20 or 400 mg/kg bw 14C-1,3- and 1,4 -cyclohexanedicarboxaldehyde.

Time-Course Concentration of Radioactivity and Pharmacokinetics in Plasma - After an oral gavage dose of 20 or 400 mg/kg bw, 14C-1,3- and 1,4 -cyclohexanedicarboxaldehyde radioactivity was rapidly absorbed without any apparent lag time and achieved the highest measured concentration (Cmax), on average, at 0.17-3 hours (Tmax). As mentioned above, after Tmax, plasma concentrations declined in a biphasic manner. The mean half-life for the rapidly declining plasma alpha phase (t½α) was between 1.8 and 3.1 hours for male rats in Group 1 and Group 2, respectively. The more slowly declining beta phase plasma half-life (t½) was ~6 hours for both low and high dose groups. The Cmax and AUC parameters were greater than dose-proportional in male rats between the low and high dose groups.

No blood samples were collected from male rat 14A5681 (Group 1) at the 120- and 144- hr time-points and no blood sample was collected from male rat 14A5682 (Group 2) at the 0.17 hr timepoint.

Time-Course Concentration of Radioactivity and Pharmacokinetics in RBC - The RBC 14C-1,3- and 1,4 -cyclohexanedicarboxaldehyde concentrations of Groups 1 and 2 were approximately 3-5x lower than their plasma concentrations. The RBC Tmax and Cmax data were very similar to that of plasma. The mean half-life elimination was similar between the low and high dose groups, except that only the high dose group was biphasic with t½ β. The Cmax and AUC parameters were greater than dose-proportional in male rats between the low and high dose groups.

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): no bioaccumulation potential based on study results
Under the conditions of the study, administered 14C-1,3- and 1,4-cyclohexanedicarboxaldehyde-derived radioactivity was quickly absorbed and eliminated in urine and feces from the rat, with almost no tissue residues. Similar rates of absorption distribution, and elimination were observed between male rats for either dose group.

Executive summary:

A pharmacokinetic study was conducted in F344/NTac rats for 168 hours (7 days) postdosing to determine absorption, distribution and excretion of 14C-1,3- and 1,4 -cyclohexanedicarboxaldehyde following oral exposure (single dose of 20 or 400 mg/kg bw or repeat dose of 20 mg/kg bw).

Orally administered 14C-1,3- and 1,4-cyclohexanedicarboxaldehyde was absorbed rapidly without any apparent lag time. The percent absorption of the orally administered dose in the low and high dose groups was at least 92-95%, based on recovery in urine and non-GI tissues. The total recovery of radioactivity from all animals was an average of 104 ±4%.

Similar pharmacokinetic parameters were observed in rats for either dose level. The time-course of 14C-1,3- and 1,4 -cyclohexanedicarboxaldehyde-derived radioactivity in plasma exhibited a biphasic decline after reaching Cmax and was therefore fit to a twocompartment pharmacokinetic model. Plasma radioactivity declined rapidly during the α phase (t½ α = ~1.8-3 hours), followed by a slower decline during the terminal β phase (t½ β = ~6 hours).

Less than 0.06% of the orally administered 14C-1,3- and 1,4 -cyclohexanedicarboxaldehyde remained in the tissues after 168 hours (7 days) postdosing in all of the groups, indicating the very low bioaccumulation potential 14C-1,3 - and 1,4 -cyclohexanedicarboxaldehyde in rats.

The majority (91-94%) of the administered 14C-1,3- and 1,4 -cyclohexanedicarboxaldehyde derived radioactivity was rapidly excreted in urine without any difference between the dose levels. The majority of the urinary elimination (91-95%) occurred within the first 12 hours post-dosing. Most of the remaining oral dose (9-13%) was eliminated in feces, with the majority of the fecal elimination (80-91%) occurring within the first 24 hours post-dosing.

A total of 11 radiochemical peaks were detected in the acidified urine and/or fecal samples across the profiles of all 3 definitive groups (groups 1-3). Only five major peaks (containing six major metabolites) of the 11 radiochemical peaks accounted for more than

5% of the administered dose. No parent 1,3 -CHDA and 1,4-CHDA was detected in the urine or fecal samples. Among these five major peaks, the most abundant metabolite Peak E, as well as the less abundant Peak D-1, accounting for 39 to 45% and 9% of the

administered dose (respectively), were identified as the cis and trans isomers of 1,3-CHD acid (isomer assignments unknown). Peaks B and F1 account for 17% and 10-12% of the administered dose (respectively) and were identified as the cis and trans isomers of 1,4- CHD acid (isomer assignments unknown).

Two additional major peaks were tentatively identified as either the cis or trans isomer of 4-(hydroxymethyl)cyclohexanecarboxylic acid (Peak C), which comprised ~7 % to 11 % of the administered dose, and either the cis or trans isomer of 3-(hydroxymethyl)-

cyclohexane carboxylic acid (Peak D-2) which comprised ~9 % of the administered dose.

In summary, administered 14C-1,3- and 1,4-cyclohexanedicarboxaldehyde-derived radioactivity was quickly absorbed and eliminated in urine and feces from the rat, with almost no tissue residues. Similar rates of absorption distribution, and elimination were

observed between male rats for either dose group.