2-ethylbutyric acid

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

basic toxicokinetics, other

Type of information:

other: review article or handbook

Adequacy of study:

supporting study

Study period:

Not available

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Objective of study:

not specified

Principles of method if other than guideline:

Not available

GLP compliance:

not specified

Details on excretion:

The innocuous polar metabolites that result from metabolism are predominantly excreted in urine.

Metabolites identified:

yes

Details on metabolites:

The β-oxidation of aliphatic alcohols, aldehydes, and carboxylic acids is inhibited by the 2-ethyl substituent. These compounds undergo ω- and ω-1-oxidation.

Conclusions:

The 2-ethyl substituent of 2-ethylbutyric acid has the capacity to inhibit the β-oxidation of aliphatic alcohols, aldehydes, and carboxylic acids. These compounds are oxidised (ω- and ω-1-) to innocuous polar metabolites that are predominantly excreted from the body via the urine.

Reference 2

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1948

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Objective of study:

metabolism

Principles of method if other than guideline:

No guideline was available at the time the study was undertaken. Young male rabbits (2 - 4 kg) were housed in metabolism cages and were provided with a uniform diet of commercial rabbit chow or oat and cabbage. The sodium salt of the registered substance was injected subcutaneously or provided orally on day 0 at 1 g and urine was collected at 24-hour intervals (for at least 4 days). 0.1 g of the sodium salt of the registered substance was administered to rats. Standard procedures were used to analyse the urine, including modified Kjeldahl (total nitrogen), Folin (creatinine), Folin and Benedict-Denis (partition of urinary sulfur), and the procedure of Maughan, Evelyn, and Browne (1938). See Dominic, Dziewiatkowski, and Howard (1945) for a detailed description of the methodology.

GLP compliance:

no

Radiolabelling:

no

Species:

rabbit

Sex:

male

Route of administration:

other: Oral and subcutaneous injection

Vehicle:

water

Duration and frequency of treatment / exposure:

Daily administration for a period of 4 days.

Dose / conc.:

0 mg/kg bw/day (nominal)

Remarks:

Control

Dose / conc.:

0.1 other: g

Remarks:

As sodium salt / rats

Dose / conc.:

1 other: g

Remarks:

As sodium salt / rabbits

Control animals:

yes

Details on dosing and sampling:

Urine collected in 24-hour periods for analysis.

Metabolites identified:

yes

Details on metabolites:

Large amounts of glucuronic acid were excreted in rabbit urine that corresponded to 25 - 52 % of the 1 g 2-ethylbutyric acid ingested. Ketone derivatives, such as methylpropyl ketone, were not isolated in urine in increased amounts. At 0.1 g, glucuronic acid excretion in rats was increased by 22 to 49 %.

Conclusions:

The sodium salt of 2-ethylbutyric acid was administered to male rabbits and rats orally or by subcutaneous injection in a 4-day in vivo experiment. 2-Ethylbutyric acid was discovered to be excreted unchanged in the urine in combination with glucuronic acid at 22 - 52 % of the total amount ingested. This result is suggestive of the registered substance being somewhat difficult to oxidise. Ketone derivatives such as methylpropyl were not identified, however, the possibility of catabolism occurring by such pathways was not ruled out.

Reference 3

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

1911

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: Insufficient information for an assessment of reliability.

Objective of study:

metabolism

Principles of method if other than guideline:

Not available

GLP compliance:

no

Species:

dog

Route of administration:

subcutaneous

Duration and frequency of treatment / exposure:

One day

Dose / conc.:

11.6 other: g

Metabolites identified:

yes

Details on metabolites:

2-ethylbutyric acid undergoes β-oxidation and decarboxylation, which results in 2-pentanone (methyl-propyl-ketone).

Conclusions:

An in vivo experiment in dogs involving a subcutaneous injection 11.6 g 2-ethylbutyric acid determined that the substance undergoes β-oxidation and decarboxylation to yield 2-pentanone (methyl-propyl-ketone). This metabolite is excreted from the body via the urine.

Description of key information

The 2-ethyl substituent of 2-ethylbutyric acid has been reported by the WHO (1999) (secondary source) to have the capacity to inhibit the β-oxidation of aliphatic alcohols, aldehydes, and carboxylic acids. These compounds are oxidised (ω- and ω-1-) to innocuous polar metabolites that are predominantly excreted from the body via the urine. An in vivo experiment with dogs that involved a subcutaneous injection of 11.6 g 2-ethylbutyric acid similarly demonstrated that the registered substance undergoes β-oxidation and decarboxylation to yield 2-pentanone (methyl-propyl-ketone). This metabolite was excreted from the body in the urine. In contrast to the supporting information, an in vivo key study (Klimisch score = 2) that was undertaken over a 4 -day period, in which the sodium salt of 2-ethylbutyric acid was administered to male rabbits and rats at 1 g and 0.1 g, respectively, determined that 2-ethylbutyric acid was largely non-metabolised and instead excreted unchanged in the urine as the glucuronic conjugate (increases of 22 - 52 %). This result infers that the capacity of the registered substance to be metabolised is limited. Ketone derivatives such as methylpropyl were not identified. It was concluded in the study, however, that the possibility of catabolism occurring by such pathways could not be eliminated.