Reaction mass of methyl chloroacetate and chloroacetic acid

Endpoint summary

Description of key information

Short description of key information on bioaccumulation potential result: 
Monochloroacetic acid: Supporting studies: several publications.

Additional information

Monochloroacetic acid:

Distribution:

Tissue distribution of [14C] Monochloroacetic acid was determined. Groups of 3 male Sprague-Dawley rats were treated with a subcutaneous LD90 dose of [2-14C] monochloroacetic acid (20 µCi/kg). Radioactivity from LD90 doses of 14C-labelled monochloroacetic acid distributed primarily to the liver and kidney where they were found in greater concentration than in plasma. Total radioactivity in heart and brain was similar to plasma. An LD 1 dose of [14C]monochloroacetic acid distributed similarly to an LD90 dose and peak plasma levels were reached 32 min after administration. Plasma disappearance of radioactivity was biphasic (approximate plasma half-life: rapid phase, 90 min; slow phase, 500 min). Kidney cortex and medulla had similar 14C-monochloroacetic acid levels. Approximately 50 % of the administered radioactive dose was recovered in urine by 1024 min after test substance administration. [14C] Monochloroacetic acid distributed primarily to liver and kidney.

In rats given 1.0 µCi of 1-14C-Monochloroacetic acid orally, radioactivity in plasma, liver, kidney, heart, testis, and spleen peaked at 1-2 hours, and declined rapidly (t1/2 = 2-7 hours). However, radioactivity in brain, although present in lower levels than other organs, continued to rise up to 8 hours and plateaued through 24 hours. Monochloroacetic acid may exert its lethal effect by a central mechanism.

Distribution of monochloroacetic acid was studied in male Sprague -Dawley rats given a single oral dose of 0.1 mmole/ kg body weight, by gavage. The animals were sacrificed at 4, 8, 12, 24 and 48 h following the treatment. The distribution of 14C-label, determined in different tissues, suggests that monochloroacetic acid is rapidly absorbed and eliminated from the body. The elimination phase appears to be fast for intestine and kidney as compared to other tissues. Maximum radioactivity was detected in intestine and kidney at 4 and 8 h following the treatment which was followed by liver, spleen, testes, lung, brain and heart in a decreasing order.

Distribution of monochloroacetic acid was studied in male Sprague -Dawley rats given a daily oral dose of 1 mmole/ kg body weight, by gavage for one or for three days. The animals were sacrificed at 24 h following the doses 1 and 3 and blood was withdrawn.

As compared to the number of doses given, the accumulation of 14C-label was not as large as expected. 14C-Label determined in the dialyzed plasma, suggests an in vivo binding of 14C-label to plasma proteins where albumin accounted for about 65% as determined by affinity chromatography.

Distribution, metabolism, and excretion of monochloroacetic acid were examined in adult male Sprague-Dawley rats at a subtoxic (10 mg/kg) and a toxic (75 mg/kg) dose. Rats were injected i.v. with [14C]-monochloroacetic acid. The distribution rate constant (K12) was greatly reduced at the toxic dose. Elimination of test substance from plasma required modeling by two compartments. Most of the radioactivity found in plasma was parent monochloroacetic acid. Elimination rate constant (K10) was greatly reduced at the toxic dose. Elimination of the toxic dose was further retarded due to increased retention of chloroacetic acid in the peripheral compartment as indicated by increased mean residence times in most tissues. A very large fraction of dose was found in the gastrointestinal tract, almost all of which was reabsorbed. A very large fraction of dose (73 and 59%) was found in urine, 55 to 68% of which was parent monochloroacetic acid. The rate-determining step in the toxicity of monochloroacetic acid was identified as its detoxification by the liver.

Interaction with sulfhydryl groups:

Monochloroacetic acid binding of in vitro sulfhydryl (SH) groups was examined as a possible mechanism of toxicity. The substance did not reduce significantly alkylate sulfhydryl groups of cysteine in vitro.

Monochloroacetic acid binding of in vivo sulfhydryl (SH) groups was examined as a possible mechanism of toxicity with male Sprague-Dawley rats. In vivo total sulfhydryl concentration in rat liver was affected significantly by LD90 dose of monochloroacetic acid at time corresponding to LT5. Brain and heart sulfhydryl values were not affected by test substance at LT5. Monochloroacetic acid inhibition of sulfhydryl groups in rat liver occurred in protein and nonprotein fractions. Test substance inhibition of total sulfhydryl groups in rat liver increased with time. Total sulfhydryl concentration was reduced to approximately 50 % of the control value by 120 min (LT 40). Rat kidney cortex and medulla also showed significant inhibition of total sulfhydryls from 84 (LT10) to 120 min (LT40) after monochloroacetic acid treatment. Brain and heart sulfhydryls were not affected at these times. Monochloroacetic acid reduced the SH concentration in the kidney and liver of treated rats.

Inhibition of enzymes:

The effect of monochloroacetic acid on in vitro [14C] acetate oxidation in liver homogenates was determined. The apparent km, for acetate oxidation by rat liver homogenate was 2.4 x 10E(-6) M and the Vmax was 30.5 x 10E2 dpm 14 -CO2 min(-1). 14 -CO2 production was linear for at least 16 min in the presence of the inhibitor. Monochloroacetic acid (1 µM) inhibited [1-14C]acetate oxidation at all substrate concentrations. Monochloroacetic acid was an uncompetitive inhibitor of acetate oxidation. The apparent Kt for test substance was 9.1 x 10E(-7) M.