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EC number: 201-207-0 | CAS number: 79-43-6
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Developmental toxicity / teratogenicity
Administrative data
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 1992
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Although some details are missing, the study is consdired to be reliable, relevant and adequate.
Data source
Referenceopen allclose all
- Reference Type:
- publication
- Title:
- Developmental Toxicity of Dichloroacetate in the Rat
- Author:
- Smith et al.
- Year:
- 1 992
- Bibliographic source:
- TERATOLOGY 46: 217-223 (1992)
- Reference Type:
- secondary source
- Title:
- Unnamed
- Year:
- 2 003
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- GLP compliance:
- not specified
- Limit test:
- no
Test material
- Reference substance name:
- Dichloroacetic acid
- EC Number:
- 201-207-0
- EC Name:
- Dichloroacetic acid
- Cas Number:
- 79-43-6
- Molecular formula:
- C2H2Cl2O2
- IUPAC Name:
- 2,2-dichloroacetic acid
- Test material form:
- other: liquid
- Details on test material:
- - Name of test material (as cited in study report): Dichloroacetate; DCA
- Analytical purity: >99% purity
- Other: supplied by Sigma Chemical Co. (St. Louis, MO)
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Long-Evans
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Breeding Laboratories (Portage, MI)
- Age at study initiation: 65-80 days
- Housing: In groups of three in plastic cages with corn cob bedding (Bed O'Cobs, Anderson Cob Div., Maumee, OH). Sperm-positive females were considered to be in day 0 of pregnancy and were singly housed for the duration of the study.
- Diet (e.g. ad libitum): Purina Rodent Laboratory Chow No. 5001 (St. Louis, MO) ad libitum
- Water (e.g. ad libitum): distilled water ad libitum
- Acclimation period: Not provided
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.11 – 23.33°C
- Humidity (%):40-60%
- Photoperiod (hrs dark / hrs light): 12/12
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- other: distilled water
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS: The compound was dissolved in water and adjusted to pH 7 with sodium hydroxide, such that the desired dosage, adjusted daily, could be administered at 10 mL/kg body weight.
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Dosing solutions were prepared daily and their purity and stability confirmed using ion chromatography.
- Details on mating procedure:
- - Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1/1
- Length of cohabitation: At 2:00 PM and checked for the presence of sperm at 9:00 AM on the following morning.
- Proof of pregnancy: sperm in vaginal smearreferred to as day 0 of pregnancy - Duration of treatment / exposure:
- on gestational days 6 to 15
- Frequency of treatment:
- daily
Doses / concentrations
- Remarks:
- Doses / Concentrations:
0, 14, 140, or 400 mg/kg-day DCA (calculated as the free acid)
Basis:
actual ingested
on gestational days 6 to 15
- No. of animals per sex per dose:
- 19-20/group
- Control animals:
- yes, concurrent vehicle
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: The animals were observed daily for signs of toxicity.
DETAILED CLINICAL OBSERVATIONS: No data
BODY WEIGHT: Yes
- Time schedule for examinations: Weights were collected at the beginning and end of gestation and daily during treatment.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): No data
POST-MORTEM EXAMINATIONS: Yes
Females dying prematurely were subjected to gross necropsy
- Sacrifice on gestation day 20: On day 20 of gestation, the dams were killed using CO, asphyxiation.
- Organs examined: Their livers, spleens, and kidneys were removed and weighed. Corpora lutea were counted using a dissecting microscope. The uterine horns were examined for the number and location of fetuses or resorption sites. - Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes. Corpora lutea were counted using a dissecting microscope.
- Number of implantations: Yes
- Number resorptions: Yes . The uterine horns were examined for the number and location of fetuses or resorption sites. - Fetal examinations:
- - External examinations: Yes: all per litter: The fetuses were then removed, weighed, measured for crown-rump length, sexed, and evaluated for external abnormalities.
- Soft tissue examinations: Yes: Two-thirds of each litter were fixed in Bouin's solution for freehand razor blade sectioning (Wilson, '65).
- Skeletal examinations: Yes: 1/3 of each litter were fixed in alcohol, double stained with alizarin red S for ossified bone and Alcian blue for cartilage, and cleared in 2% KOH and glycerine (Inouye, '76; Kimmel and Trammell, '81).
- Head examinations: No data - Statistics:
- Maternal body and organ weights (first study), mean fetal weights and crown-rump lengths, and litter sizes (first study) were analyzed for overall treatment differences using the one-way analysis-of-variance (ANOVA) procedure. Differences between the dose groups and the control group were examined using pairwise contrasts (Winer, '71). The presence of a significant dose response was tested with linear regression. The proportions of maternal deaths and pregnancies were compared using the Z-test for differences between proportions (Walpole and Myers, '78). Organ weights (second study), litter sizes (second study), sex ratios, and percentages of resorptions and fetuses with abnormalities were evaluated with the Kruskal-Wallis test for overall differences, with pairwise Mann-Whitney tests to compare each treatment with the control (Lehmann, ’75), and Jonckheere's test to analyze for a dose-related response (Lehmann, '75).
Results and discussion
Results: maternal animals
Maternal developmental toxicity
- Details on maternal toxic effects:
- Maternal toxic effects:yes
Details on maternal toxic effects:
Secondary source: A significant decrease in maternal weight gain, adjusted for gravid uterine weight, was found in the mid- and high-dose dams (63 and 77% of control, respectively), as well as an increase in spleen and kidney weights at the highest dose. Absolute liver weight was significantly elevated for all dose groups compared to the control group, with 3, 8, and 14% increases observed, respectively. Dose-related hypertrophy in the liver, spleen and kidneys was reported in the two high-dose groups (no incidence data).
Effect levels (maternal animals)
open allclose all
- Dose descriptor:
- NOAEL
- Effect level:
- 14 mg/kg bw/day (actual dose received)
- Basis for effect level:
- other: other:
- Dose descriptor:
- LOAEL
- Effect level:
- 140 mg/kg bw/day (actual dose received)
- Basis for effect level:
- other: other:
Results (fetuses)
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:yes
Details on embryotoxic / teratogenic effects:
Secondary source: Reduced fetal crown-rump length (5% decrease) and fetal body weight (7% decrease) were significant in the high-dose group. A dose-related increase in soft 40 tissue anomalies, primarily cardiovascular, was reported in the 140 and 400 mg/kg-day groups.
The increase in soft tissue abnormalities was significant for the two highest dose groups and the cardiac abnormalities for the highest dose. An intraventricular septal defect between the ascending (bilateral hydronephrosis and renal papilla) and defects of the orbit also reported.
Effect levels (fetuses)
- Dose descriptor:
- NOAEL
- Effect level:
- 14 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- not specified
- Basis for effect level:
- other: soft tissue anomalies
- Remarks on result:
- other: see remarks
- Remarks:
- Reduced fetal crown-rump length (5% decrease) and fetal body weight (7% decrease) were significant in the high-dose group. A dose-related increase in soft 40 tissue anomalies, primarily cardiovascular, was reported in the 140 and 400 mg/kg-day groups. The increase in soft tissue abnormalities was significant for the two highest dose groups and the cardiac abnormalities for the highest dose. An intraventricular septal defect between the ascending aorta and the right ventricle was most commonly observed with less frequent urogenital defects (bilateral hydronephrosis and renal papilla) and defects of the orbit also reported. Collectively, these studies determined a NOAEL of 14 mg/kg-day and a LOAEL of 140 mg/kg-day DCA for developmental effects (soft tissue anomalies).
Fetal abnormalities
- Abnormalities:
- not specified
Overall developmental toxicity
- Developmental effects observed:
- not specified
Any other information on results incl. tables
The principal fetal target for DCA was the heart and major vessels, with most affected fetuses displaying, after Wilson sectioning, a defect between the ascending aorta and the right ventricle. More detailed histopathological examination of this defect revealed it as a high interventricular septal defect (H-IVSD), with a range of tissue involvement (Epstein et al., '91). Overt interventricular septal defects were found to bethe second most common anomaly. Otherless frequently affected systems were the kidneys (bilateral hydronephrosis, renal papilla, stage one) and the orbit.
The developmental toxicity of DCA has not previously been reported, nor have there been developmental studies of the major metabolites, glyoxylate and oxalate. A related compound, trichloroacetic acid (TCA), induces a range of heart malformations in the developing rat, although not with the predominance of H-IVSD seen with this compound (Smith et al., '89).
The metabolic effects of DCA are widespread and very complex (Crabb et al., '81, Stacpoole, '89). Many of the actions of DCA in intermediary metabolism are thought to be the direct or indirect consequence of its activation of the mitochondrial pyruvate dehydrogenase complex (Whitehouse and Randle, '73). Its effects are not localized, and oral administration causes striking changes in plasma metabolite levels, including reductions in the levels of lactate. Of possible interest to this study may be the observation that DCA concentrates in rat myocardial mitochondria (Kerbey et al., '76) and also activates myocardial branched chain α- keto acid dehydrogenase, promoting leucine
oxidation (Sans et al., '80).The mammalian embryo during early organogenesis relies almost exclusively on glycolysis for energy, a process presumably disturbed by DCA and therefore a candidate for consideration as part of its mechanism of action. It is difficult to hypothesize, however, just how a compound with such widespread metabolic effects as DCA would, by this process, target
the embryonic heart almost exclusively. Clinical applications of DCA have been hindered by its known toxicity in the testes, the lens and in the nervous system, all tissues also depending heavily on glycolysis as an energy source.
Preliminary data from this laboratory suggest that DCA has free and rapid access to the fetus following oral administration. The half-life of the parent compound has been reported as 0.5 h in humans and 3 h in the (nonpregnant) rat (Lukas et al., '80), although the metabolic effects in humans evidently persist for considerable time following DCA withdrawal (Stacpoole et al., '78).
We have not yet measured the accumulation of DCA or its metabolites in the rat fetus, but we have found that repeated dosing appears to be necessary to produce the characteristic heart malformations (Epstein et al., '91). The effects of chronic DCA administration have been noted by others to differ from those following acute doses (Searle et al., '76). Thus, given the current source of inadvertent chronic human exposure, our present efforts center on estimating the extent and influence of cumulative toxicity in the embryo.
Applicant's summary and conclusion
- Conclusions:
- Collectively, these studies determined a NOAEL of 14 mg/kg-day and a LOAEL of 140 mg/kg-day DCA for developmental effects (soft tissue anomalies) and maternal effects (reduced body weight and organ hypertrophy).
- Executive summary:
In an experiment by Smith et al. (1992), pregnant Long-Evans rats (19-20/group) were administered 0, 14, 140, or 400 mg/kg-day DCA by gavage on gestational days 6 to 15. A significant decrease in maternal weight gain, adjusted for gravid uterine weight, was found in the mid- and high-dose dams (63 and 77% of control, respectively), as well as an increase in spleen and kidney weights at the highest dose. Absolute liver weight was significantly elevated for all dose groups compared to the control group, with 3, 8, and 14% increases observed, respectively.
Dose-related hypertrophy in the liver, spleen and kidneys was reported in the two high-dose groups (no incidence data). Reduced fetal crown-rump length (5% decrease) and fetal body weight (7% decrease) were significant in the high-dose group. A dose-related increase in soft
40 tissue anomalies, primarily cardiovascular, was reported in the 140 and 400 mg/kg-day groups.
The increase in soft tissue abnormalities was significant for the two highest dose groups and the cardiac abnormalities for the highest dose. An intraventricular septal defect between the ascending aorta and the right ventricle was most commonly observed with less frequent urogenital defects (bilateral hydronephrosis and renal papilla) and defects of the orbit also reported. Collectively, these studies determined a NOAEL of 14 mg/kg-day and a LOAEL of 140 mg/kg-day DCA for developmental effects (soft tissue anomalies) and maternal effects (reduced body weight and organ hypertrophy).
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