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Toxicological information

Specific investigations: other studies

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Administrative data

Endpoint:
biochemical or cellular interactions
Type of 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: Mechanistic study; no study according to guidelines

Data source

Reference
Reference Type:
publication
Title:
Inhibition of pyruvate carboxylase by chloropyruvic acid and related compounds
Author:
Doedens D, Ashmore J
Year:
1972
Bibliographic source:
Biochem. Pharmacol. 21(12), 1745-1751

Materials and methods

Test guideline
Qualifier:
no guideline available
Principles of method if other than guideline:
Effects on CO2 fixation in rat liver slices with lactate and pyruvate as substrate was measured. Mitochondrial CO2 fixation was investigated. Further, effects on incorporation of 14C from [U-14C]L-alanine into glucose and CO2 and on production of ketone bodies was investigated and the inhibition of CO2 fixation in acetone powder extracts.
GLP compliance:
not specified
Type of method:
in vitro

Test material

Constituent 1
Chemical structure
Reference substance name:
Chloroacetic acid
EC Number:
201-178-4
EC Name:
Chloroacetic acid
Cas Number:
79-11-8
Molecular formula:
C2H3ClO2
IUPAC Name:
2-Chloro-ethanoic acid
Details on test material:
Chloroacetic acid was supplied by Pfaltz and Bauer.

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals or test system and environmental conditions:
Rats weighing 200-350 g were used. Animals in liver slice experiments were fasted overnight; others were fed ad lib. Rats were sacrificed by stunning and exsanguination.

Administration / exposure

Route of administration:
other: not applicable
Vehicle:
other: not applicable
Details on exposure:
Liver slices were incubated with chloroacetic acid.
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
N.A.
Frequency of treatment:
N.A.
Post exposure period:
N.A.
Doses / concentrations
Remarks:
Basis: nominal conc. 0.1, 1-10 mM
No. of animals per sex per dose:
Not specified
Control animals:
no

Examinations

Examinations:
Effects on CO2 fixation in rat liver slices with lactate and pyruvate as substrate was measured. Mitochondrial CO2 fixation was investigated. Further, effects on incorporation of 14C from [U-14C]L-alanine into glucose and CO2 and on production of ketone bodies was investigated and the inhibition of CO2 fixation in acetone powder extracts.
Positive control:
No

Results and discussion

Details on results:
Incorporation of 14CO2 into glucose in slices incubated with lactate or pyruvate was inhibited by chloropyruvic acid. At 0·1 mM, chloropyruvic acid (CPA) and related compounds, including chloroacetic acid, inhibited incorporation into glucose of label from [U-14C]alanine without affecting production of ketone bodies or 14CO2. Inhibition was not observed in similar preparations using succinate as substrate. In mitochondria, concentrations of 1-10 mM CPA inhibited CO2 fixation by 56-95 per cent. In acetone powder extracts, CPA at 1-10 mM reduced CO2 fixation by 21-86 per cent. Interconversion between CPA and chlorolactate was not catalyzed by lactic dehydrogenase, nor did these compounds inhibit this enzyme.

Applicant's summary and conclusion

Conclusions:
The data from this mechanistic study in rat liver indicate that CPA and related acids (e.g. monochlororacetic acid) may inhibit gluconeogenesis by specific inhibition of pyruvate carboxylase. Whether or not this metabolic effect is involved in the development of sterility after administration of CPD remains to be determined.

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