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Toxicological information

Basic toxicokinetics

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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: Acceptable well-documented study which meets basic scientific principles

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1979
Report Date:
1979

Materials and methods

Objective of study:
toxicokinetics
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Determination and quantification of exhaled and excreted radioactivity after oral application of single doses of [1-14C]isobutyric acid to rats
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): isobutyric acid
- Analytical purity: 97%
- Impurities (identity and concentrations): no data
- Purity test date: no data
- Radiochemical purity (if radiolabelling): no data
- Specific activity (if radiolabelling): 20 mCi/mmol
- Locations of the label (if radiolabelling): C-1 carbon atom
- Expiration date of radiochemical substance (if radiolabelling): no data
- Stability under test conditions: no data
- Storage condition of test material: no data
Radiolabelling:
yes
Remarks:
1-14C

Test animals

Species:
rat
Strain:
other: Charles River CD
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories Inc.,Wilmington, MA, USA
- Age at study initiation: no data
- Weight at study initiation: 250 to 300 g
- Fasting period before study: yes, 18 hrs
- Housing: no data
- Individual metabolism cages: yes, glass Delmar Roth metabolism chambers
- Diet (e.g. ad libitum): no data
- Water (e.g. ad libitum): yes
- Acclimation period: no data

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: original radioactive test substance ([1-C14]sodium isobutyrate) was purchased from ICN Pharmaceuticals with a specific activity of 20 mCi/mmol. This substance was diluted with unlabelled isobutyric acid and dissolved in distilled water prior to application.
Duration and frequency of treatment / exposure:
single dose
Doses / concentrations
Remarks:
Doses / Concentrations:
4, 40, and 400 mg/kg bw; radioactivity between 0.64 and 5.8 µCi per animal
No. of animals per sex per dose:
male: 4 animals per dose
females: 4 animals at a dose of 400 mg/kg
Control animals:
no
Details on dosing and sampling:
PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: expired air, urine, faeces, blood
- Time and frequency of sampling: expired air: 4, 8, 12, 24, and 48 hr; urine: daily; faeces: at the end of experiment (48 hr); blood: at 0.5, 1, 2, 4, 6, 8 hr.

TREATMENT FOR CLEAVAGE OF CONJUGATES (if applicable): urine was treated with urease to determine the amount of 14CO2 excreted as [14C]urea.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:
isobutyric acid was readily absorbed after oral application as demonstrated by the fast excretion in expired air and peak plasma levels after 0.5 to 1 hr.
Peak concentrations of isobutyric acid in plasma were 11.4 ± 2.4 µg/mL. Plasma levels decrease to 3.3 µg/mL at 2 hr. By 4 hr, plasma isobutyric acid was below the limit of detection.
Details on excretion:
In the first 4 hours after dosing, 67 to 83% of the administered dose was excreted as CO2 in expired air. Unchanged isobutyric acid was less than 0.1%. The recovery of radioactivity in the breath at 48 hr was 90.1, 96.7, and 90.8% for male rats dosed witn 4, 40, and 400 mg/kg, respectively and 86.2% for female rats dosed with 400 mg/kg. There was no difference between sexes.
Radioactivity excreted in urine (48hr) ranged from 3.21 to 4.61%. Faecal radioactivity was less than 1.0% of the dose.

Metabolite characterisation studies

Details on metabolites:
Isobutyric acid is rapidly metabolised and excreted as CO2. In plasma, metabolites of isobutyric acid could not be detected.

Any other information on results incl. tables

Excretion of radioactivity [%] by Charles River CD rats 48 hr after the administration of [1-14C]isobutyric acid (IBA)

(values are mean ± S.D.; n = 4, four animals per group)

Dose

[mg/kg]

Sex

 

Breath radioactivity

Urine

Faeces

Total accounted for

IBA

CO2

Total

4

Male

0.011 ± 0.004

90.11 ± 0.93

90.12

3.21 ± 0.40

0.41 ±0.04

93.74 ± 0.90

40

Male

0.08 ± 0.01

96.4 ± 0.35

96.48

3.26 ± 0.26

0.20 ± 0.03

99.94 ± 0.31

400

Male

0.029 ± 0.01

90.72 ± 1.36

90.75

4.15 ± 0.42

0.285 ± 0.04

95.18 ± 1.62

400

Female

0.008 ± 0.001

86.14 ± 1.48

86.15

4.61 ± 0.47

0.45 ± 0.06

91.21 ± 1.38

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): no bioaccumulation potential based on study results
After oral administration, isobutyric acid is readily absorbed, metabolised and excreated predominantly as CO2. 67 to 83% of the administered dose are excreted within 4 hours.
Executive summary:

The metabolic fate of isobutyric acid (IBA) was investigated by oral (gavage) administration of radiolabelled [1-14C]isobutyric acid to groups of 4 male CD rats at doses of 4, 40, and 400 mg/kg bw and to 4 female CD rats at 400 mg/kg bw. IBA was eliminated rapidly in the breath of the dosed animals as expired 14CO2. At 4 hr 67 to 83% and at 48 hr 85 to 90% of the dose was eliminated in the breath. There were no differences between sexes .

Urinary radioactivity averaged 3.5% of the dose with about 2/3 of the radioactivity present as urea.

Faecal radioactivity was less than 1% of the dose.

 

Isobutyric acid disappeared rapidly from the plasma of rats dosed by gavage with 400 mg/kg bw. Plasma levels peaked between 0.5 and 1 hr (11.4 ± 2.4µg/ml), decreased to 3.3 µg/mL at 1 hr and were below the limit of detection at 4 hr (DiVicenzo, 1979).