Crotonaldehyde

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: GLP status unknown

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1985

Materials and methods

Objective of study:

other: adsorption, disposition, metabolism and excretion

Test guideline

Qualifier:

no guideline available

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Crotonaldehyde

EC Number:

224-030-0

EC Name:

Crotonaldehyde

Cas Number:

4170-30-3

Molecular formula:

C4H6O

IUPAC Name:

but-2-enal

Details on test material:

radiolabeled Lot no. 83-127-16-30 from Midwest Research Institute
Source: 14C labeled crotonaldehyde was supplied by NIEHS it was prepared by Midwest Research Institute, Lot No. 83-127-16-a30
Aqueous solution containing 4.74 mCi of [14C] Crotonaldehyde
The radiochemical purity was calcultated at 83%.purified to > 96%
Stated concentration was 3.64 mCi/mL (1.58 mM/mL, 11% w/v)
Unlabelled crotonaldehyde was obtained from Aldrich Chemical Company Lot no. 1217PH as an aqueous solution. Purity determined to be 93% crotonaldehyde and 7% water.
C4H6O
Specific activity: 2.31 mCi/mM
Storage: < 0C in dark

UNlabeled rfrom Aldrich Chemical company lot # 1217PH

Test animals

Species:

rat

Strain:

Fischer 344

Sex:

male

Details on test animals or test system and environmental conditions:

Purchased from Charles River Breeders (kingston ny)
quarantined for 2 weeks before use in study
Feed: certified purina rat chow
Water: ad libitum
fasted overnight prior to oral dosins
glass metabolism chambers the day before they were used in the experiment
These chambers provided for separate collection of urine and feces and for trapping 14C in exhaled breath

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

ethanol

Details on exposure:

one time

Duration and frequency of treatment / exposure:

one time

Doses / concentrations

Remarks:

Doses / Concentrations:
35, 3.1 and 0.67 mg/kg bw

No. of animals per sex per dose / concentration:

4

Control animals:

no

Positive control reference chemical:

No

Details on study design:

At the end of each experiment, the animal was anesthetized with an ip injection of 60 mg/kg ketamine and 8.6 mg/kg xylazine. Blood was then withdrawn via cardiac puncture until death occurred. Tissue samples were collected and stored in the dark at -20C until analzyed.

Details on dosing and sampling:

Animals were fasted 24 overnight prior to oral dosing.
The specifi activity of the [14C] crotonaldehyde was adjusted by combining appropriate amounts of unlabeled crotonaldehyde with purified [14c] crotonaldehyde (in HPLC mobile phase consisting of 10% ethanol in water) so that the correct dose was contained in ca. 1 mL of the sode formulation.
Oral doses were prepared in argon-purged vials sealed with teflon-faced silicone septum caps adn wrapped in aluminum foil. Dosing solutions were administered within 2 hrs of their preparation. Dose was calculated as the difference between the weights of the filled and empty dosing apparatus.
An aliquot of the dose formulation was removed after each 1ml dose was administered in order to determine the amount of 14C crotonaldeyde in each dose. This was necessary beacuase of the volatility of crotonaldehyde. The purity of the dosing solution was assayed by HPLC after all the animals had been dosed.

Urine and feces were collected separately over the time intervals (12, 24, 36, 48 and 72 hours). Urine was collected in round bottom flasks over dry ice. Feces were collected in tail cups secured to the rats with surgical adhesive. Urine and feces were stored in the dark at -20C until analyzed.

Breath was collected by two different trapping methods. in method A, which trapped volatile organics and CO2, air was pulled through the metabolism cages at 200-500 mL/min and then through a series of 3 traps. The first contained ca. 75ml of 9% ethanol in water maintained in ice water. The second contained ca 75 ml of 1% crotonaldehyde in 2-propanol (w/v) maintained in a dry ice-acetone bath. The thrid trap contained 400 mL of 1N sodium hydroxide maintained at ambient temp.

In Method B, which trapped only 14CO2, air was pulled through the metabolism cage at 200-500 ml/min and then through a series of two traps each containing 400 ml of 1N sodium hydroxide maintained at ambient temp. Breath trap solutions were stored at room temp until analyzed

Statistics:

Not available

Results and discussion

Preliminary studies:

None

Toxicokinetic / pharmacokinetic studies

Details on absorption:

The amount excreted in the feces is the amount that was not absorbed the systemic circulation since no excretion in feces by IV dosing (in same study). > or equal to 93% absorption from oral gavage administration. The percent dose excreted in feces (6-7% was consistent with the small percentage of the 14C that in the in vitro study (same study) was bound to stomach contents.

Details on distribution in tissues:

the percent of oral dose in tissues 72 h after dosing was essentially the same for doses of 35 and 0.67 mg/kg, except for that of the stomach which contained 0.2% and 0.8% of the doses, respectively. Tissue-blood ratios (TBR) were higher than in IV administration. Tissues with TBR values between 1 and 2 included skin, intestines, seminal vesicles, prostate, lungs, spleen, kidney and heart. Higher TBR values were observed in teh adrenals(3.4 and 4.6), trachea (2 and 2.3), stomach (3.9 and 14), esophagus (3 and 4.4) and liver (2.9 and 7.1),

Details on excretion:

Urine and exhaled air were major routes of excretion of [14c] crotonaldehyde. 38-39% excreted in urine, 44-49% in breath as CO2 and 6-7% in feces in 72 hours. No change in excretion pattern over the dose range (0.67, 3,3 and 35 mg/kg bw). Essentially no unmetabolized crotonaldehyde was excreted via the urine. Excretion of 14C in breath was essentialy entirely 14CO2. The very small amounts of (<1.5% of dose) of 14C trapped in the cryogenic (organic vapors) trap may also be 14CO2 dissolved in the 2-propanol trapping solution.

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

3-hydroxy-1-methylpropylmercapturic acid and 2-carboxy-1-methylethylmerpaturic acid as urinary metbaolite

Any other information on results incl. tables

Recovery of Total Radioactivity After Administration of [14C]Crotonaldehyde to Male Fischer 344 Rats (% Dose)^a
Time (hours)	Dose (mg/kg)	Urine	Breath CO2	Breath volatiles	feces	Major selected tissues and blood^b,c	total
72	0.67	39 ± 4^b	47 ± 5^b		6.6 ± 0.9^b	6.2 ± 0.7	99 ± 8^b
72	3.3	34 ± 2^b	49 ± 7^b		5.6 ± 3.8^b	n/a
72	35	38 ± 3	55 ± 5	0.26 ± 0.19	6.9 ± 0.2	4.7 ± 0.2	93 ± 4^b

^aMean ± SD for four animals except where noted

^bMean ± SD for 3 animals

^cMajor tissues are considered to be skin, muscle, adipose, and liver. Skin is assumed to be 15% of total body weight; muscle, 50% and adipose 10%.

Cumulative Excretion of Total^14C After Oral Administration of [^14C]Crotonaldehyde to Male Fischer 344 Rats (% Dose)

Dose (mg/kg)

35

3.3

0.67

Excreta

Urine

Breath

Feces

Total

Urine

Breath

Feces

Total

Urine

Breath

Feces

Total

Time (h)

12

27 ± 10

33 ± 5

^d

60 ± 11

32.8 ± 5.6

43.6 ± 5.5

^d

76.5 ± 9.6

37.0 ± 4.7

41.0 ± 4.6

^d

78.0 ± 7.7

24

35 ± 4

39 ± 4

2.9 ± 2.6

77 ± 7

32.9 ± 2.3

^e

5.1 ± 3.7

81.8 ± 5.0

38.7 ± 4.9

44.7 ± 5.2

5.8 ± 1.2

87.4 ± 9.9^c

36

37 ± 3

42 ± 4

81 ± 4

33.3 ± 2.1

45.4 ± 6.7

83.7 ± 4.9

39.0 ± 4.0

45.0 ± 4.6

89.8 ± 7.1

48

37 ± 3

43 ± 5

5.6 ± 1.1

86 ± 3

33.4 ± 2.1

47.9 ± 6.7

5.5 ± 3.8

86.7 ± 4.8

39.1 ± 4.0

45.7 ± 4.7

6.4 ± 0.9

91.2 ± 7.2

72

38 ± 3

44 ± 5

6.9 ± 0.2

89 ± 3

34.0 ± 1.6

49.1 ± 6.9

5.6 ± 3.8

88.7 ± 4.6

39.4 ± 4.1

46.8 ± 5.0

6.6 ± 0.9

92.8 ± 7.5

^aValues are mean ± SD for four animals

^bValues are mean ± SD for three animals, except where noted otherwise.

^cValues are mean ± range for two animals

^dFirst feces collection was 0-24 h

^eThe 12-24 h and the 36-48 h breath samples were accidentally combined before analysis. The percent dose excreted for this combined sample is recorded as one sample, 36-48 h.

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): no bioaccumulation potential based on study results
no bioaccumulation potential based on study results

Executive summary:

[14C]Crotonaldehyde of greater than 96% radiochemical purity was obtained as a 1:9 ethanol:water solution by high performance liquid chromatography of commercial [14C]crotonaldehyde.

Orally administered [14C] crotonaldehyde at doses of 0.7, 3 and 35 mg/k was greater than 90% absorbed. Within 12 h of dosing, 78, 74 adn 60 percent of the dose, respectively, had been excreted in breath and urine. In 3 days, 86, 83 and 82%, respectively, had been excreted by these routes. An additional 7% off the dose was excreted in feces.