Dichloroacetic acid

Endpoint summary

Description of key information

When the physicochemical properties of Dichloroacetic acid were assessed for toxicokinetic properties, the substance was expected and studied to be easily absorbed from the gastro-intestinal tract. On the other hand, respiratory deposition and absorption was assessed to be very low.  Dermal absorption was considered to be possible based on physicochemical properties, and confirmed by calculation of the dermal flux (1.21 mg/(cm2.h)).

Distribution in the body is expected to take place rapidly, mainly based upon the low molecular weight, high water solubility and the clinical observations and target organs (liver, brains, testes) seen in the toxicity studies.  Experimental studies also demonstrated rapid distribution in various tissues.

Indication of rapid metabolism were already deduced from toxicological studies (e.g. increased liver weights rats, peroxisome proliferation).  Experimental studies in animals and humans showed an  oxidative dechlorination to form glyoxylate, which may then be routed through several different pathways leading to oxalate, glycine, serine, glycolate and even carbon dioxide.  Among humans there are known polymorphisms which may account for differences in the ability to metabolize DCA.

Based on the low molecular weight and high water solubility, rapid urinary excretion of parent substance and metabolites are expected. In experimental studies in animals and humans, only  a small fraction of DCA (-1-2%) was found in the feces , whereas in humans, the amount is a slightly higher Both in humans and animals, variable quantities of glyoxylate, glycolate, monochloracetic acid, and thiodiacetic acid are found in the urine. A fraction of the glyoxylate produced from DCA is oxidized to carbon dioxide and is exhaled.  

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

30

Absorption rate - inhalation (%):

10

Additional information

The assessment below is based on the ECHA Guidance on information requirements and chemical safety assessment (Chapter R.7c: Endpoint specific guidance, November 2012 Version 1.1), for which physicochemical and toxicological data may be used for a qualitative toxicokinetics assessment. In addition, experimental values were found in secondary and primary literature references.

Absorption of DCA was assessed as follows based on physicochemical/toxicological data. The substance is a liquid compound with a molecular weight of128.94g/mol and experimental water solubility of1e+006 mg/L. The logPow has a value of 0.52 (QSAR) or 0.92 (experimental) The vapour pressure is 0.19 hPA (20°C).Hydrolysis data showed that the substance is stable in water at at pH 4, 7 and 9.

-         Oral/GI absorption:
The substance is expected to be easily absorbed from the gastro-intestinal tract based on the physicochemical properties (low molecular weight and high water solubility) and toxicological data (toxicity in acute oral and subchronic toxicity studies indicate a good systemic availability of the substance underlining an oral absorption).
Studies in humans and animals also indicate that DCA is readily absorbed by the gastrointestinal tract. Following oral administration of radiolabeled DCA to rats and mice, only about 1-2% of the label was found in the faeces, indicating almost complete gastrointestinal absorption. In fasted human subjects, peak plasma DCA concentration occurs within 15 to 30 minutes of oral dosing.
Based upon this rationale, an absorption rate of 100% is considered.

-         Respiratory absorption:
Based on the low vapour pressure of DCA, inhalation and deposition in the respiratory tract is very unlikely. If any substance is deposited in the higher respiratory tract (e.g. by fluid particles) they will be easily removed from the aqueous fluid (mucus) lining the respiratory tract due to the high water solubility. Therefore systemic availability by inhalation is not expected to be a realistic exposure.
Based upon this rationale, an absorption rate of 10% is considered.

-         Dermal absorption:
The fact that DCA is a liquid substance with low molecular weight and high water solubility leads to favorable conditions to be absorbed by the skin. The corrosive properties might stimulate further penetration, however repair may also lead to decreased uptake.
When Dermwin was applied, the dermal penetration rate seems to be rather low. A dermal penetration rate of 0.00121cm/h was found. However because of the high water solubility, the value of the maximum ‘dermal flux’ is slightly higher: 1.21 mg/(h.cm2) Taking all this into account, it can be expected that the dermal absorption is realistic.
Based upon this rationale, an absorption rate of 30% is considered.

 

For the assessment of distribution, metabolism and excretion,physicochemical and toxicological properties are also taken into account according to ECHA guidanceChapter R.7c. 

-         Distribution:
Based upon the molecular weight below 200 g/mol and high water solubility, distribution in the body is expected to take place rapidly. This is further confirmed by the presence of clear target organs (e.g. liver , brain and testes findings) and clinical observations (including state of narcosis or seminarcosis) in the toxicity studies.
The distribution of DCA was also investigated in experimental animals (EPA, 2003). After 48 hours upon oral gavage DCA administration. 21 to 36% of the tracer [14C] was recovered from tissues; the majority of tracer was found in the liver, muscle, skin, blood and intestines. After 24 hours, all of the other tissues combined (kidney, adipose, stomach, testis, lung, spleen, heart, brain, and bladder) contained 10 to 15% of the label, while at 48 hours these tissues contained ~1-2% of the original dose given.

-         Metabolism and accumulation potential: 
Metabolism cannot be deduced from the data available, except for the increase in liver weights and hepatomegaly in male and female rats in the repeated dose toxicity studies, which may be indicative of enzyme induction. In addition, mechanistic toxicity studies were peformed, indicating peroxisome proliferation and induction of carnitine acetyl-transferase, palmityl-CoA oxidase and the PPA-protein in the liver of rats and mice.
The metabolism of DCA was also investigated in experimental animals and humans. The primary metabolic pathway for DCA involves oxidative dechlorination to form glyoxylate, which may be routed through several different pathways. Transamination by peroxisomal alanine-glyoxylate transaminase forms glycine, which can be incorporated into proteins, used in the synthesis of serine, or degraded releasing carbon dioxide. Glyoxylate can also be converted to glycolate by glyoxylate reductase. Data on DCA metabolism in humans support the hypothesis that DCA metabolism is similar in both humans and rodents. The occurrence of oxalic acid in the urine of DCA-treated patients indicates that DCA is oxidatively dechlorinated to glyoxylate, which is then converted to oxalate. Among humans there are known polymorphisms which may account for differences in the ability to metabolize DCA and other halogenated compounds.

-         Excretion:
Based on the low molecular weight and high water solubility, urinary excretion of parent substance and metabolites are assumed realistic. Excretion via the other routes are not expected based on the low logPow value.Accumulation is not expected.
The elimination of DCA was also investigated in experimental animals and humans. Only a small fraction of DCA (1-2%) was found in the feces in animal studies. In humans, the amount is a slightly higher fraction of the ingested dose than has been reported for animals. Oxalate is the primary urinary metabolite of DCA. Both in humans and animals, variable quantities of glyoxylate, glycolate, monochloracetic acid, and thiodiacetic acid are found in the urine. A fraction of the glyoxylate produced from DCA is oxidized to carbon dioxide and is exhaled.