Isobutyric anhydride

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

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

Adequacy of study:

supporting 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

Test material information

Constituent 1

Reference substance name:

Isobutyric acid

EC Number:

201-195-7

EC Name:

Isobutyric acid

Cas Number:

79-31-2

Molecular formula:

C4H8O2

IUPAC Name:

2-methylpropanoic acid

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 or test system 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 / concentration:

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).