National Toxicology Program

Selected toxicity information from HSDB, one of the National Library of Medicine's databases. ¹

Names (NTP)

• Dimethylarsinic acid (9CI)
• CACODYLIC ACID
• HYDROXYDIMETHYLARSINE OXIDE
• DIMETHYLARSONIC ACID
• DMAA

Human Toxicity Excerpts

• CACODYLIC ACID IS: HARMFUL IF SWALLOWED. AVOID INHALATION OF SPRAY MIST. [Farm Chemicals Handbook 1993. Willoughby, OH: Meister Publishing Co., 1993., p. C-62]**PEER REVIEWED**
  
• To analyze the mechanisms of arsenic induced gene damage, found previously in lungs of mice and rats orally administered dimethylarsinic acid, a major metabolite of inorganic arsenics, an in vitro system with human alveolar type II (L-132) cells was used. The exposure to 10 mM dimethylarsinic acid for 10 hr caused significant single-strand breaks in DNA of the cells. At an earlier period of the exposure, the replicative DNA synthesis was markedly suppressed, and the chain length of the nascent DNA was shorter than that of the control, suggesting that the template DNA received some modification other than strand breaks. The modification, being repairable, was sensitive to UV irradiation to cause strand breaks. [Tezuka M et al; Biochem Biophys Res Commun 191 (3): 1178-83 (1993)]**PEER REVIEWED**
  
• Ingestion of 77 mg/kg arsenic (as dimethyl arsenic acid and dimethyl arsenate) induced vomiting, abdominal pain, hyperactive bowel, and diarrhea ... . [DHHS/ATSDR; Toxicological Profile for Arsenic p. 107 (2000)]**PEER REVIEWED**
  
• Support for sensitization to DMA is provided in a case control study of a 26-yr-old woman who was occupationally exposed to DMA and experienced eczema on her face ... . Patch testing confirmed an allergic reaction to DMA, and avoidance of DMA resulted in disappearance of the symptoms. [DHHS/ATSDR; Toxicological Profile for Arsenic p. 131 (2000)]**PEER REVIEWED**
  
• ... FORESTRY WORKER ... INJECTING TREES WITH SILVICIDE, CHIEFLY CONTAINING CACODYLIC ACID, COMPLAINED OF ANOREXIA, NAUSEA, ABDOMINAL PAIN & ... /HAD/ ELEVATED ARSENIC URINE LEVEL. FREE OF EXPOSURE ... SYMPTOMS GRADUALLY SUBSIDED. /ARSENIC SILVICIDE/ [Hamilton, A., and H. L. Hardy. Industrial Toxicology. 3rd ed. Acton, Mass.: Publishing Sciences Group, Inc., 1974., p. 34]**PEER REVIEWED**
  

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Non-Human Toxicity Excerpts

• 100 & 1000 PPM BY WT ... CACODYLIC ACID /IN 60% SUCROSE SYRUP IS/ ... EXTREMELY TOXIC TO NEWLY EMERGED WORKER BEES ... MODERATELY TOXIC @ 10 PPM BY WT. ... NO DIFFERENCES IN TOXICITY ... OBSERVED BETWEEN PURIFIED & COMMERCIALLY FORMULATED HERBICIDES. [Kearney, P.C., and D. D. Kaufman (eds.) Herbicides: Chemistry, Degredation and Mode of Action. Volumes 1 and 2. 2nd ed. New York: Marcel Dekker, Inc., 1975., p. 761]**PEER REVIEWED**
  
• PRIMARY DERMAL IRRITATION INDEX--RABBITS--0.3. ESSENTIALLY NONIRRITATING TO THE SKIN WHEN ACCIDENTALLY APPLIED TOPICALLY. ... OCULAR IRRITATION SCORE--RABBITS--2.0. ESSENTIALLY NON-IRRITATING TO THE EYE WHEN ACCIDENTALLY EXPOSED. [Weed Science Society of America. Herbicide Handbook. 5th ed. Champaign, Illinois: Weed Science Society of America, 1983., p. 88]**PEER REVIEWED**
  
• ... EFFECT ON CELL DIVISION /IN PLANTS WAS STUDIED/. CACODYLIC ACID ... ACTED ON SPINDLES (COLCHINIC EFFECT). CACODYLIC ACID & CYCLOHEXYLARSINIC ACID WERE THE MOST POWERFUL ARSENICALS EXAMINED IN ACTING ON CHROMOSOMES. AS A RESULT, THEY ARE CONSIDERED MITOTIC POISONS. [Kearney, P.C., and D. D. Kaufman (eds.) Herbicides: Chemistry, Degredation and Mode of Action. Volumes 1 and 2. 2nd ed. New York: Marcel Dekker, Inc., 1975., p. 766]**PEER REVIEWED**
  
• FETUSES FROM PREGNANT HAMSTERS TREATED IP WITH 1000 MG CACODYLIC ACID ON DAYS 8, 11, OR 12 OF GESTATION WERE RESORBED. TREATMENT WITH 900 MG/KG CAUSED A HIGH DEGREE OF FETAL WASTAGES, WITH THE GREATEST EFFECTS BEING DUE TO TREATMENT ON DAYS 8 OR 9. GROWTH WAS REDUCED FOLLOWING ALL TREATMENTS EXCEPT DAY 8 & GROSS MALFORMATIONS WERE OBSERVED FOLLOWING ALL TREATMENTS EXCEPT DAY 12. [HOOD RD ET AL; BULL ENVIRON CONTAM TOXICOL 29 (6): 679-87 (1982)]**PEER REVIEWED**
  
• CACODYLIC ACID WAS ADMIN BY GASTRIC INTUBATION (SOLN IN DISTILLED WATER) TO TIME-PREGNANT RATS & MICE ON DAYS 7-16 OF GESTATION. RATS RECEIVED 0, 7.5, 15, 30, 40, 50, OR 60 MG/KG/DAY IN 0.2 ML/DAY; MICE RECEIVED 0, 200, 400, OR 600 MG/KG/DAY IN 0.1 ML/DAY. FETUSES FROM MICE SACRIFICED ON DAY 18 & RATS ON DAY 21 WERE EXAM. IN MOUSE TERATOGENIC RESPONSE WAS CONFINED TO CLEFT PALATE AT 400 & 600 MG/KG/DAY. THE EFFECTIVE MATERNAL TOXIC DOSE IN RAT WAS 40 MG/KG/DAY. IN THIS SPECIES, THE INCIDENCE OF IRREGULAR PALATINE RUGAE, EG, RIDGES THAT WERE DISCONTINUOUS &/OR LYING IN APPOSITION AT THE PALATAL RAPHE, WAS SIGNIFICANTLY DOSE-RELATED. THE RESULTS SUGGEST AN APPARENT NO-EFFECT LEVEL FOR THIS ANOMALY BELOW 30 MG/KG/DAY. [ROGERS EH ET AL; DRUG CHEM TOXICOL 4 (1): 49-61 (1981)]**PEER REVIEWED**
  
• The genotoxicity of nine organic and three inorganic arsenic cmpd was examined in cultured Chinese hamster cells. V79 cells were incubated with 50 or 100 ul of various concn of the test cmpd for 8 hr at 37 deg C; mitotic indices were determined by counting metaphases in 500 cells. Chromosomes exposed to the test cmpd were stained in order to observe the chromosome numbers in a metaphase twice divided. The number of chromosomes in the V79 cells ranged from 20 to 25; metaphases which had 40 to 50 chromosomes were thus considered tetraploid cells. Observation of the metaphases in the sister chromatid exchange test revealed that only dimethylarsenic acid induced tetraploids and mitotic arrest. Tetraploid cells appeared to have low cell division ability or a slower cell cycle than diploid cells. Dimethylarsenic acid directly inhibited cell division and dimethylarsenic acid induced tetraploidy may be an important part of arsenic genotoxicity. This cmpd may be the ultimate carcinogen of arsenic. [Endo G et al; Bull Environ Contam Toxicol 48 (1): 131-7 (1992)]**PEER REVIEWED**
  
• The nephrotoxicity of dimethylarsinic acid (cacodylic acid, DMA) was examined in male and female F344/DuCrj rats. Dimethylarsinic acid administered perorally at doses of 113, 85, and 57 mg/kg for 4 weeks produced dose-related decreases in body weight and survival rate in both sexes. Mortality was higher and appeared more quickly in females than in males. Histopathological findings in the kidney were proximal tubular degeneration and necrosis, as well as papillary necrosis, and hyperplasia of the epithelium covering the papillae. Since extensive proximal tubular necrosis was observed only in dead animals of both sexes, and not in survivors or the controls, it was concluded that the main cause of death could be attributed to nephrotoxicity of dimethylarsinic acid. The results thus show that dimethylarsinic acid is nephrotoxic to both male and female rats. [Murai T et al; Toxicol Lett 66 (1): 53-61 (1993)]**PEER REVIEWED**
  
• Dimethylarsinic acid administration induced the preferential increase of the heterochromatic area forming the inside of the interphase nucleus. A histopathological study of the lung and liver in mice after dimethylarsinic acid administration was carried out by transmission electron microscopy. Ultrastructural alterations in the endothelial nuclei of the alveolar wall were observed 12-48 hr after administration. Heterochromatin tended to collect in a dense, compact mass lining the inner walls of the nucleus. A significant increase in heterochromatin induced by dimethylarsinic acid administration was observed by morphometric analysis. However, no substantial differences appeared in the sinusoidal endothelium of the liver. The much greater induction of morphological alterations, such as increased heterochromatin, in lung endothelial nuclei than in the liver might explain the high risk of lung cancer by arsenics, and that there may be a close relationship between heterochromatin alteration and DNA damages. [Nakano M et al; Carcinogenesis 13 (3): 391-3 (1992)]**PEER REVIEWED**
  
• An in vivo investigation of the effects of dimethylarsinic acid, a primary metabolite of arsenate and arsenite, was conducted. Male ICR mice were orally dosed with sodium dimethylarsinic acid at concn of 1500 mg/kg. Following dosing the mice were sacrificed and their organs homogenized for a fluorimetric determination of DNA content. Another group of five mice were placed in metabolic cages after dosing with 1500 mg/kg sodium dimethylarsinic acid in order to determine the arsenic content in expired air. Organ assays, 12 hr after dosing was applied, revealed significant DNA breaks in the lungs, but much less in the spleen, kidney or liver. The pH dependence of these DNA breaks indicated that the DNA damage caused by dimethylarsinic acid was not the result of alkylating agents. Data from the expired air of dimethylarsinic acid dosed mice indicated that dimethylarsine was probably a major metabolite of dimethylarsinic acid. A comparison DNA breakage evaluation, involving dimethylarsinic acid and dimethylarsine, demonstrated that dimethylarsinic acid did not result in DNA breakage while dimethylarsine did. The DNA breaks observed in the lungs of dimethylarsinic acid exposed mice are the result of dimethylarsine which is metabolically generated from dimethylarsinic acid. The active oxygen produced in the lung via the reaction of dimethylarsine with molecular oxygen is probably the source of the DNA damage. This active oxygen mechanism explains the lung specific DNA breakage resulting from dimethylarsinic acid administration. [Yamanaka K et al; Biochem Biophys Res Commun 165 (1): 43-50 (1989)]**PEER REVIEWED**
  
• Cellular events in the lung caused by the administration of dimethylarsinic acid to mice were studied. Male ICR mice were given an oral dose of 1500 mg/kg of dimethylarsinic acid after fasting for several hr. Of the pulmonary enzymes directly participating in protective reactions against active oxygen species, dimethylarsinic acid elevated superoxide-dismutase and glutathione-peroxidase activities. The elevations suggested that breaks in pulmonary DNA strands were partially if not completely due to active oxygen species, probably superoxide anion radicals, produced from molecular oxygen by undergoing one electron reduction by dimethylarsine and also by hydroxyl radicals formed through a chain reaction. Superoxide anion radicals were produced mainly in Clara and alveolar type-II cells. No histopathological changes were noted in the lungs, liver, kidneys, or spleen of these mice, but there was a significant increase in heterochromatin content in alveolar endothelial cells. Glucose-6-phosphate-dehydrogen was activated by dimethylarsinic acid dosing, possibly to replenish the diminished NADPH level. Glutathione-reductase was not activated, despite the reduction in glutathione. Pulmonary cell damage, particularly DNA strand scission, induced by oral dosing is partially if not completely due to active oxygen species produced in the metabolism of dimethylarsinic acid. [Yamanaka K et al; Toxicol Appl Pharmacol 108 (2): 205-213 (1991]**PEER REVIEWED**
  
• DNA damage induced by administration of dimethylarsinic acid to rats and mice was investigated. At 12 hr after administration of dimethylarsinic acid, DNA single-strand breaks were induced markedly in lung. The majority of dimethylarsine, one of the main metabolites, in the expired air was excreted within 6-18 hr after administration of dimethylarsinic acid to rats. In vitro experiments using nuclei isolated from lung of mice indicated that DNA strand breaks were caused by dimethylarsine. Furthermore, the strand breaks after exposure to dimethylarsine were reduced in the presence of catalase and/or superoxide dismutase. These results suggest that the strand breaks are induced not by dimethylarsine itself but by active oxygen, eg, superoxide radical and hydroxyl radical produced both by dimethylarsine and molecular oxygen. When DNA was exposed to dimethylarsine, thiobarbituric acid reactive intermediates and cis-thymine glycol were produced. Dimethylarsine appears to induce DNA damage by the mechanism similar to the damage produced by ionizing radiation. [Yamanaka K et al; Biol Trace Elem Res 21: 413-7 (1989)]**PEER REVIEWED**
  
• Female rats exposed to DMA at 3746 mg As/cu m developed erythematous lesions on the feet and ears ... these lesions did not develop in females exposed at lower concn (2226 mg As/cu m) or males. [DHHS/ATSDR; Toxicological Profile for Arsenic p. 38 (2000)]**PEER REVIEWED**
  
• Mice exhibited respiratory arrest after a single oral dose of 489 mg/kg DMA ... and lung ornithine decarboxylase activity was reduced after ingestion of one or two doses of 720 mg DMA/kg ... . [DHHS/ATSDR; Toxicological Profile for Arsenic p. 105 (2000)]**PEER REVIEWED**
  
• ... effects on fetal development (malformed palate, reduced fetal weight, delayed ossification, incr fetal mortality) have been observed in rats and mice give repeated oral doses of DMA during gestation ... . [DHHS/ATSDR; Toxicological Profile for Arsenic p. 119 (2000)]**PEER REVIEWED**
  
• ... also evaluated the carcinogenic effects of DMA in rats in a multiorgan carcinogenesis bioassay. Male F344/DuCrj rats were treated sequentially with diethylnitrosamine (DEN) and N-methyl-N-nitrosamine (MNU), then 1,2-dimethylhydrazine (DMH). The animals were then sequentially admin N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in drinking water in weeks 1 and 2 and N-bis(2-hydroxypropyl)nitrosamine (DHPN) in drinking water during wk 3 and 4. This is refereed to as the DMBDD treatment. After a 2-wk interval, rats were give 50, 100, 200, or 400 ppm DMA in drinking water. DMA significantly enhanced the tumor induction in the urinary bladder, kidney, liver and thyroid gland in DMBDD-treated groups. Induction of preneoplastic lesions (glutathione S-transferase placental form-positive foci in the liver and atypical tubules in the kidney) was also significantly incr in DMA-treated groups. [DHHS/ATSDR; Toxicological Profile for Arsenic p. 127 (2000)]**PEER REVIEWED**
  
• SUBACUTE TOXICITY: TEN RATS EACH AT 226, 118, & 54 MG/KG OVER A FEEDING PERIOD OF 3 WK. /RATS FED AT/ THE 226 MG/KG LEVEL SHOWED EVIDENCE OF REDUCED ACTIVITY OF SPERMATOGONIA CELLS WITH SOME ATROPHIC CHANGES OF THE SEMINIFEROUS TUBULES. THE FINDINGS WERE /NOT/ OBSERVED IN...THE CONTROL OR 118 MG/KG GROUP. /CACODYLIC ACID/ [Weed Science Society of America. Herbicide Handbook. 4th ed. Champaign, IL: Weed Science Society of America, 1979. of America, 1979., p. 92]**PEER REVIEWED**
  
• CACODYLIC ACID WAS NONTUMORIGENIC IN MICE ADMIN 15-46 MG/KG/DAY ORALLY FOR 2 YEARS. /CACODYLIC ACID/ [Hayes, W.J., Jr., E.R. Laws Jr., (eds.). Handbook of Pesticide Toxicology Volume 1. General Principles. New York, NY: Academic Press, Inc., 1991., p. 176]**PEER REVIEWED**
  
• RATS & MICE INHALING CACODYLIC ACID EXHIBITED RESPIRATORY DISTRESS, RHINORRHEA, & PORPHYRIN-LIKE ENCRUSTATION OF EYES DURING EXPOSURE & DIARRHEA & DECREASED WT GAIN, POSTEXPOSURE. [STEVENS JT ET AL; THE ACUTE INHALATION TOXICOLOGY OF THE TECHNICAL GRADE ORGANOARSENICAL HERBICIDES, CACODYLIC ACID AND DISODIUM METHANEARSONIC ACID; BULL ENVIRON CONTAM TOXICOL 21(3) 304 (1979)]**PEER REVIEWED**
  

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Human Toxicity Values

• None found

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Non-Human Toxicity Values

• LD50 Rat oral 700 mg/kg [Farm Chemicals Handbook 1993. Willoughby, OH: Meister Publishing Co., 1993., p. C-62]**PEER REVIEWED**
  
• LC50 Rat male inhalation (exposure to dust): > 6.9 mg/l/2 hr [Verschueren, K. Handbook of Environmental Data of Organic Chemicals. 2nd ed. New York, NY: Van Nostrand Reinhold Co., 1983., p. 329]**PEER REVIEWED**
  
• LC50 Rat female inhalation (exposure to dust): > 3.9 mg/l/2 hr [Verschueren, K. Handbook of Environmental Data of Organic Chemicals. 2nd ed. New York, NY: Van Nostrand Reinhold Co., 1983., p. 329]**PEER REVIEWED**
  
• LC50 Mouse inhalation (exposure to dust): > 6.4 mg/l/2 hr [Verschueren, K. Handbook of Environmental Data of Organic Chemicals. 2nd ed. New York, NY: Van Nostrand Reinhold Co., 1983., p. 329]**PEER REVIEWED**
  
• LD50 Rat male ip 720 mg/kg [Verschueren, K. Handbook of Environmental Data of Organic Chemicals. 2nd ed. New York, NY: Van Nostrand Reinhold Co., 1983., p. 329]**PEER REVIEWED**
  
• LD50 Rat female ip 520 mg/kg [Verschueren, K. Handbook of Environmental Data of Organic Chemicals. 2nd ed. New York, NY: Van Nostrand Reinhold Co., 1983., p. 329]**PEER REVIEWED**
  
• LD50 Mouse male ip 520 mg/kg [Verschueren, K. Handbook of Environmental Data of Organic Chemicals. 2nd ed. New York, NY: Van Nostrand Reinhold Co., 1983., p. 329]**PEER REVIEWED**
  
• LD50 Mouse female ip 600 mg/kg [Verschueren, K. Handbook of Environmental Data of Organic Chemicals. 2nd ed. New York, NY: Van Nostrand Reinhold Co., 1983., p. 329]**PEER REVIEWED**
  
• LD50 Rat ip 1350 mg/kg /Technical cacodylic acid/ [Verschueren, K. Handbook of Environmental Data of Organic Chemicals. 2nd ed. New York, NY: Van Nostrand Reinhold Co., 1983., p. 329]**PEER REVIEWED**
  
• LD50 Rat oral 644 mg/kg [Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996., p. 1862]**PEER REVIEWED**
  
• LC50 Rat female inhalation 2117 mg As/m3/2 hr [DHHS/ATSDR; Toxicological Profile for Arsenic p. 19 (2000)]**PEER REVIEWED**
  
• LD50 ddy male mouse oral (in water) 652 mg/kg. /From table/ [DHHS/ATSDR; Toxicological Profile for Arsenic p. 88 (2000)]**PEER REVIEWED**
  

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Absorption, Distribution and Excretion

• ... ABSORPTION RATES ... FROM RAT SMALL INTESTINE ... WATER PARTITION COEFFICIENT SUGGEST THAT THESE CMPD /INCL CACODYLIC ACID/ MAY BE ABSORBED PREDOMINANTLY BY PASSIVE DIFFUSION. [The Chemical Society. Foreign Compound Metabolism in Mammals Volume 3. London: The Chemical Society, 1975., p. 189]**PEER REVIEWED**
  
• IN 5 HEALTHY FOREST WORKERS EXPOSED TO CACODYLIC ACID DURING 2 MO PERIOD, URINARY ARSENIC WAS USED AS INDEX OF EXPOSURE. [WAGNER SL, WESWIG P; ARCH ENVIRON HEALTH 28 (2): 779 (1974)]**PEER REVIEWED**
  
• ... ROOT ABSORPTION OF THE MONOSODIUM SALT OF METHANEARSONIC ACID (MSMA), CACODYLIC ACID, ARSENATE, & ARSENITE FROM NUTRIENT SOLN (1X10-4 M) /WAS STUDIED/. THE ORDER OF CONCN IN ROOTS WAS ARSENATE /HIGHEST, THEN/ ARSENITE, METHANEARSONIC ACID, CACODYLIC ACID. HOWEVER ... IF THE RATIO OF ARSENICAL CONCN IN TOPS TO THAT IN THE ROOTS WAS A MEASURE OF TRANSPORT, CACODYLIC ACID WAS TRANSPORTED TO THE TOPS 5 TO 10 TIMES MORE RAPIDLY THAN METHANEARSONIC ACID, ARSENITE, OR ARSENATE. TOXICITY OF ARSENICALS WAS DIRECTLY PROPORTIONAL TO ROOT CONCN. [Kearney, P.C., and D. D. Kaufman (eds.) Herbicides: Chemistry, Degredation and Mode of Action. Volumes 1 and 2. 2nd ed. New York: Marcel Dekker, Inc., 1975., p. 764]**PEER REVIEWED**
  
• CACODYLIC ACID HAS ERYTHROCYTE AFFINITIES AS FOLLOWS: RAT HIGHEST, THEN RABBIT, THEN HUMAN. [STEVENS JT ET AL; TOX APPL PHARM 41 (1): 221 (1977)]**PEER REVIEWED**
  
• UPTAKE, ACCUMULATION & TRANSLOCATION OF ARSENIC FROM DIFFERENT ARSENICAL COMPOUNDS WAS INVESTIGATED IN COTTON PLANTS. WHEN CACODYLIC ACID WAS APPLIED IN THE RANGE OF 0-40 UG(AS)/ML, ARSENIC WAS FOUND NOT ONLY IN THE ROOTS BUT ALSO IN THE LEAVES & REPRODUCTIVE STRUCTURES. THE DEFOLIANT, CACODYLIC ACID, WAS APPLIED AS FOLIAR SPRAY AT THE COMMERCIALLY RECOMMENDED RATE OF 1.4 KG/HA OF CACODYLIC ACID EQUIVALENTS TO COTTON PLANTS WITH GREEN & MATURE BOLLS. COTTONSEED FROM THE TREATED BOLLS DID NOT ACCUMULATE ARSENIC ABOVE 2.6 UG(AS)/G, THE TOLERANCE LIMIT. HOWEVER, AT HIGHER APPLICATION RATES, THE ARSENIC CONCENTRATIONS INCREASED IN THE COTTONSEED. COTTON PLANTS WERE GROWN IN GREENHOUSE IN YOLO CLAY LOAM (FINE SILTY, MIXED, NONACIDIC, THERMIC TYPIC XERORTHENTS) WITH SOIL BACKGROUND LEVEL OF 6 UG/G, WERE GROWN WITH COTTON GIN TRASH CONTAINING CACODYLIC ACID AT 0 TO 53.5 UG(AS)/G MIXED INTO THE SOIL. ANALYZED PLANT SAMPLES CONTAINED LESS THAN 0.05 UG(AS)/G & DID NOT ACCUMULATE OR CONCENTRATE ARSENIC FROM THE SOIL. [MARCUS-WYNER L, RAINS DW; J ENVIRON QUAL 11 (4): 715-9 (1982)]**PEER REVIEWED**
  
• URINARY ELIMINATION OF ARSENIC METABOLITES WAS FOLLOWED UP AS A FUNCTION OF TIME IN VOLUNTEERS WHO INGESTED A SINGLE DOSE (500 UG) AS SODIUM ARSENITE, MONOMETHYLARSONATE OR CACODYLATE. EXCRETION RATE INCREASED IN THE ORDER: ARSENIC, CACODYLATE, MONOMETHYLARSENATE AFTER 4 DAYS, ARSENIC EXCRETED IN URINE REPRESENTED 46, 78, & 75% OF THE INGESTED DOSE IN THE CASE OF SODIUM ARSENITE, MONOMETHYLARSENATE & CACODYLATE RESPECTIVELY. CACODYLATE WAS EXCRETED UNCHANGED. [BUCHET JP ET AL; INT ARCH OCCUP ENVIRON HEALTH 48 (1): 71-80 (1981)]**PEER REVIEWED**
  
• WEANLING RATS WERE FED 1 OF 5 DIETS FOR 42 DAYS EITHER AD LIBITUM OR ON A RESTRICTED-EQUALIZED FEEDING REGIMEN. THE 5 DIETS INCLUDED A LOW ARSENIC CONTROL & A MEDIUM OR HIGH LEVEL OF ARSENIC FROM EITHER WITCH FLOUNDER (GLYSTOCEPHALUS CYNOGLOSSUS) TISSUE OR CACODYLIC ACID. DIETARY ARSENIC IN EITHER FORM DID NOT INFLUENCE ANY OF THE BIOLOGICAL INDICES EXPOSUREEXAMINED EXCEPT TISSUE ARSENIC LEVELS. RETENTIONS OF ARSENIC IN THE LIVERS & SPLEENS OF RATS FED THE HIGHEST LEVEL OF FISH ARSENIC (28.8 PPM) WERE ABOUT 7 AND 2 TIMES HIGHER, RESPECTIVELY, THAN CONTROLS. RETENTIONS OF ARSENIC IN THE LIVERS AND SPLEENS OF RATS FED THE HIGHEST LEVEL OF ARSENIC FROM CACODYLIC ACID (22.1 PPM) WERE ABOUT 30 AND 110 HIGH TIMES HIGHER, RESPECTIVELY, THAN CONTROLS. RETENTION OF ARSENIC WITHIN ERYTHROCYTES OF RATS FED THE HIGHEST LEVEL OF FISH ARSENIC WERE EQUAL TO CONTROLS WHEREAS IT WAS ABOUT 130 TIMES HIGHER THAN CONTROLS AMONG RATS FED THE HIGHEST LEVEL OF ARSENIC AS CACODYLIC ACID. A PPARENTLY THE CHEMICAL FORM OF ARSENIC IN THE EDDIBLE TISSUE OF THE WITCH FLOUNDER IS UNIQUELE METABOLIZED BY THE RAT COMPARED TO OTHER ARSENIC FORMS. [SIEWICKI TC; J NUTR 11 (4): 602-9 (1981)]**PEER REVIEWED**
  
• After human ingestion of arsenite rich wine, 10% of the arsenic was excreted as methylarsonic acid and dimethylarsinic acid. Ingestion of arsenate-rich water produced elevated levels of arsenate and dimethylarsinic acid. However, when crab meat containing organoarsenic was ingested, none of these compounds was observed at elevated levels until after digestion of the urine with hot sodium hydroxide. Then high levels of dimethylarsinic acid were observed. [Menzie, C.M. Metabolism of Pesticides-Update III. Special Scientific Report- Wildlife No. 232. Washington, DC: U.S.Department of the Interior, Fish and Wildlife Service, 1980., p. 34]**PEER REVIEWED**
  
• The sum of concn of inorganic arsenic, methylarsonic acid and dimethylarsinic acid in urine from adults and children living in an unpolluted area was compared with the corresponding sum measured in urine from adults and children living in an area polluted with arsenic and in urine from persons occupationally exposed to arsenic. The median values for 22 adults and 10 children aged 3-10 years living in the unpolluted area were 9.3 and 19.8 nmol arsenic/mmol creatinine, respectively. The corresponding ranges were 3.2-27.9 and 7.7-57.8 nmol arsenic/mmol creatinine, respectively. The difference between adults and children was tested by Mann-Whitney's non-parametric test and found to be significant (p < 0.0025). No significant difference was found in arsenic concn in urine from 73 adults and 10 children living in the polluted area compared with the arsenic concn in urine from those living in the unpolluted area. The arsenic level in urine from adult workers handling arsenic-treated wood was approximately four fold higher (p < 0.001), with a maximum recorded concn corresponding to 814.9 nmol arsenic/mmol creatinine. The arsenic levels in urine from two glass workers were nine and two fold higher, respectively. No significantly increased arsenic levels were found in urine from workers impregnating wood and in urine from lead accumulator workers. [Jensen GE et al; Sci Total Environ 107: 169-77 (1991)]**PEER REVIEWED**
  
• The amount of arsenic in the urine, feces and in duplicate diets of two couples who had eaten customary Japanese meals were monitored for 7 days by atomic absorption spectrophotometry. For the four volunteers, the mean daily intake of arsenic from their diets was 182 ug (range 27 to 376 ug). The dietary arsenic was composed of 5.7% inorganic arsenic, 3.6% methylarsonic acid, 27.4% dimethylarsinic acid and 47.9% trimethylarsenic cmpd. The mean amounts of arsenic eliminated daily in urine and feces were 148 ug (50-416 ug) and 46 ug (0-138 ug), respectively. The urinary arsenic was composed of 1.4% inorganic arsenic, 3.5% methylarsonic acid, 33.6% dimethylarsinic acid and 61.4% trimethylarsenic cmpd. The daily intake of arsenic influenced the total amount of arsenic excreted in the urine (r = 0.7302, p < 0.01) and the amount eliminated in the feces (r = 0.5900, p < 0.01) the next day. Specifically, there was also a significant correlation between the daily intakes of trimethylarsenic cmpd and dimethylarsinic acid and the amounts of these cmpd found in the urine the following day (r = 0.6833, p < 0.01 and r = 0.6630, p < 0.01, respectively). Considering the amounts of arsenic cmpd present in seafood and in other components of the diet together with the urinary elimination patterns of arsenic cmpd, it seemed probable that the trimethylarsenic cmpd in the urine originated largely from fish and shellfish, which contain mainly arsenobetaine. Trimethylarsenic cmpd in the urine should therefore be the preferred indicator of arsenic arising from the ingestion of seafood, especially fish and shellfish. In this study, the mean daily intake of inorganic arsenic from the diet (0.18 ug/kg) did not exceed the FAO/WHO JECFA Tolerable Daily Intake of 2 ug inorganic arsenic/kg. [Mohri T et al; Food Chem Toxicol 28 (7): 521-30 (1990)]**PEER REVIEWED**
  
• The concn and chemical species of arsenic in the human body were monitored by measurements on urine and hair. Urine samples were taken from 94 male and eight female students of a Japanese medical school. Hair samples were taken from 100 of the teaching staff of the medical school. Four species of arsenic were assayed by liquid nitrogen trapping arsine generation atomic absorptiometry. Mean concn of four arsenic cmpd (ug arsenic/l) in the urine samples after adjustment for differences in specific gravity were: inorganic, 11.9; methylarsonic acid, 3.66; dimethylarsinic acid, 35.1; trimethylarsenic cmpd, 70.5; and total arsenic, 121. Thus methylarsenic cmpd made up about 90% of the arsenic in urine. The mean concn (ug arsenic per g) in hair were inorganic 0.056; dimethylarsinic acid, 0.020; total arsenic 0.075. No methylarsonic acid or trimethyl arsenic cmpd were detected in hair. It was noted that although man ingested large amounts of trimethyl arsenic cmpd from seafood (indicated by the trimethyl arsenic cmpd content of urine), no trimethyl arsenic cmpd was found in the hair, suggesting that it was rapidly eliminated from the body. It was concluded that inorganic arsenic detected in the urine derives from a portion of the dietary inorganic arsenic being excreted in unchanged form in the urine, and that the inorganic arsenic concn in the urine of people on a normal diet is important when inorganic arsenic is used as an indicator for occupational exposure arsenic. [Yamato N; Bull Environ Contam Toxicol 40 (5): 633-640 (1988)]**PEER REVIEWED**
  
• Admin of (14)C and/or (74)As-dimethylarsenic acid to rats by oral, iv, or intratracheal routes at doses of 120 ug/kg bw to 200 mg/kg bw shoed that lung absorption was 9%, in comparison with 66% in the GI tract. Highest concn were observed in blood, muscle, kidney, liver and lung. Total urinary excretion of either labelled form at 24 hr was found to be 71%, 60% and 25% when give by iv, intratracheal and oral routes, respectively ... . [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V23 91 (1980)]**PEER REVIEWED**
  

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Metabolism/Metabolites

• ... METAB OF CACODYLIC ACID IN BLACK VALENTINE BEANS /WAS STUDIED/. ANALYSIS OF THE EXTRACT REVEALED AS, PRESUMED TO BE CACODYLIC ACID /CA/, IN THE CHROMATOGRAM WHERE CA SHOULD HAVE BEEN. THE ABSENCE OF AS3+ & MSMA /MONOSODIUM METHANEARSONATE/ WAS DEMONSTRATED. IN SEPARATE EXPT, NO ARSINE ... DETECTED EVEN THOUGH SEVERE TOXICITY DEVELOPED ... . IN CONCLUSION, APPARENTLY NO DEGRADATION OF CACODYLIC ACID OCCURS IN PLANTS BASED ON LIMITED STUDIES. VARIOUS ORGANISMS, HOWEVER, ARE CAPABLE OF REDUCING CACODYLIC ACID TO DI- OR TRIMETHYLARSINE. [Kearney, P.C., and D. D. Kaufman (eds.) Herbicides: Chemistry, Degredation and Mode of Action. Volumes 1 and 2. 2nd ed. New York: Marcel Dekker, Inc., 1975., p. 755]**PEER REVIEWED**
  
• INGESTION OF WINE CONTAINING 50 UG AS3+ & 13 UG AS5+ INCR URINE LEVELS OF AS3+, AS5+, & DIMETHYLARSINIC ACID IN HUMAN. AS3+ & 5+ LEVELS WERE NORMAL AFTER 20 HR, BUT DIMETHYLARSINIC ACID LEVELS WERE NOT NORMAL UNTIL 85 HR LATER. [CRECELIUS EA; ERDA SYMP SER 42 (BIOL IMPLIC MAT ENVIRONMENT PROC ANNU HANFORD LIFE SCI SYMP 15TH): 63-8 (1977)]**PEER REVIEWED**
  
• METHANOBACTERIUM SPECIES (STRAIN M.OH) IN AN INCUBATION MIXTURE UNDER ANAEROBIC CONDITIONS REDUCED CACODYLIC ACID TO DIMETHYLARSINE IN ABSENCE OF A C-1 DONOR. [MCBRIDE BC ET AL; ACS SYMP SER 82 (ISS ORGANOMETALS ORGANOMETALLOIDS: OCCURRENCE FATE ENVIRON): 94-115 (1978)]**PEER REVIEWED**
  
• AFTER IV ADMIN OF INORG ARSENIC TO DOGS, METABOLITE DIMETHYLARSINIC ACID APPEARED RAPIDLY IN ERYTHROCYTES, THEN IN PLASMA. WITHIN 6 HR MOST ARSENIC REMAINING WAS DIMETHYLARSINIC ACID. BOTH INORG ARSENIC & DIMETHYLARSINIC ACID WERE RAPIDLY EXCRETED IN URINE. [CHARBONNEAU SN ET AL; TRACE SUBST ENVIRON HEALTH 12: 276 (1978)]**PEER REVIEWED**
  
• Urinary excretion of trimethylarsenic and its metabolites was studied in a subject following ingestion of food containing the compound. On two occasions 2 weeks apart, the subject was fed seafood containing 756 to 759 ug of arsenic, 98.8% as trimethylarsenic. During the study periods, the subject refrained from eating other seafoods. Urine and blood were collected at intervals from 24 hr before to 72 hr after seafood ingestion and analyzed for trimethylarsenic and other arsenic compounds. Trimethylarsenic output in urine peaked 2 hr after ingestion and totalled 50% of the ingested amount after 6 hr and 86 to 89% after 72 hr. About 2 to 5% of the injested dose was excreted as inorganic arsenic, dimethylarsenic acid, and methylarsonic acid. The trimethylarsenic taken by the blood was distributed in plasma rather than erythrocytes, peaked at 2.7 ng [Yamauchi H, Yamamura Y; Bull Environ Contam Toxicol 32 (6): 682-87 (1984)]**PEER REVIEWED**
  
• The metabolism and excretion of orally administered arsenic trioxide were investigated in the hamster. Syrian golden hamsters were maintained on food containing inorganic arsenic at 0.32 ug/g and 0.1 ug/g of trimethyl arsenic compounds. The hamsters consumed about 8 g of the feed daily. These hamsters were than treated with a single oral dose of arsenic trioxide at 4.5 mg/kg. They were killed before and 1, 6, 12, 24, 72, and 120 hr after administration of arsenic trioxide. Urine and feces samples were collected every 24 hr individually for each hamster. Arsenic content and metabolites of arsenic trioxide were determined in hair, blood, brain, kidneys, liver, lung, muscle, skin, and spleen by atomic absorption spectrophotometry. Urine and feces samples were analyzed for arsenic metabolites. The chief metablites identified in all of the tissues were methylarsenic acid and dimethylarsenic acid. Inorganic arsenic accounted for the major portion of total arsenic in tissues, follwed by the two metabolites. Only traces of trimethyl arsenic compounds occurred in the liver but none were present in other tissues tested. Inorganic arsenic and methylarsenic acid were chiefly present in blood cells while dimethylarsenic acid was mainly present in the plasma. Dimethylarsenic acid accounted for a major portion of compounds in urine and feces; excretion pattern showed 49% was in urine and 11% in feces, equivalent to 60% of the administered dose. [Yamauchi H, Yamamura Y; Toxicol 34 (2): 113 (1985)]**PEER REVIEWED**
  
• The genotoxic effects of DMAA, one of the main metabolites of inorganic arsenics in mammals and its further metabolites were investigated using Escherichia coli B tester strains. When H/r30R (wild-type; Exc+Rec+) and Hs30R (uvrA-; Exc-Rec+) cells were incubated with dimethylarsenic acid for 3 hr in liquid NB medium, many more revertants appeared in sealed tubes than in the control, but this was not the case in unsealed tubes, suggesting that volatile metabolites of dimethylarsenic acid caused the mutagenesis. By GC-MS, dimethylarsine and trimethylarsine, known to be volatile metabolites in microorganisms, were detected in the gas phase of dimethylarsenic acid added tester strain cell suspensions in sealed tubes. Among these arsines, dimethylarsine was mutagenic in WP2 (wild-type Exc+Rec+) and WP2uvrA (uvrA-; Exc-Red+), while trimethylarsine was not. The mutagenesis induced by dimethylarsine required oxygen gas in the assay system; the number of revertants markedly increased in an oxygen-replaced system and diminished in a nitrogen-replaced one. [Yamanaka K et al; Chem Pharm Bull 37 (10): 2753-6 (1989)]**PEER REVIEWED**
  
• ... The major metabolite in urine of experimental animals exposed to inorganic arsenic is dimethylarsinic acid. The marmoset monkey is the only species to date which has been found to be unable to methylate inorganic arsenic. In man the urinary excretion at low levels consists of about 20% inorganic arsenic, 20% methylarsonic acid and 60% dimethylarsinic acid. [Friberg, L., Nordberg, G.F., Kessler, E. and Vouk, V.B. (eds). Handbook of the Toxicology of Metals. 2nd ed. Vols I, II.: Amsterdam: Elsevier Science Publishers B.V., 1986., p. V2 53]**PEER REVIEWED**
  
• Rat liver, kidney and lung slices methylate trivalent inorganic arsenic As(III) to monomethylarsonic acid and dimethylarsinic acid; the liver has the greatest methylating capacity. As(III) enters the liver cells by a diffusion process followed by extensive binding to intracellular components which favors its extensive accumulation. Reduced glutathione regulates As(III) metabolism through several mechanisms: facilitation of As(III) diffusion into the cells, stimulation of the first methylation reaction and increase of dimethylarsinic acid excretion by the cells. An excess of As(III) inhibits dimethylarsinic acid production by liver cells but this inhibition is reversible; mercuric ions inhibit both monomethylarsonic acid and dimethylarsinic acid production probably by decreasing inorganic arsenic uptake and the second methylation reaction. Dimethylarsinic acid can be produced from monomethylarsonic acid by rat liver slices and this methylation step is stimulated by GSH. In contrast to As(III), As(V) is not extensively taken up by the hepatocyte and is thus poorly methylated. [Georis B et al; Toxicology 63 (1): 73-84 (1990)]**PEER REVIEWED**
  
• Inorganic arsenic isan established human carcinogen. Methylation to monomethylarsonate and dimethylarsinate is believed to be th detoxification mechanism for inorganic arsenic. Urinary measurement of inorganic arsenic, monomethylarsonic acid, and dimethylarsinate is considered a good biological marker of internal dose to inorganic arsenic, since it excludes other ingested forms of arsenic which are much less toxic, and because urinary excretion is the main form of elimination of inorganic arsenic. A methylation threshold hypothesis for inorganic arsenic has been proposed, stating that after exposure to inorganic arsenic reaches a certain level or threshold, methylation capacity begins to decline, thus increasing the toxic effects of inorganic arsenic. The validity of this hypothesis was investigated by analyzing the data from studies which measured urinary inorganic arsenic, monomethylarsonic acid, and dimethylarsinate in different populations, ranging from background to high occupational and environmental exposure groups. Analysis focused on the proportion of urinary inorganic arsenic remaining in the unmethylated form (inorganic arsenic/(inorganic arsenic + monomethylarsonic acid + dimethylarsinate)). The results indicate that epidemiological and experimental human data do not support the methylation threshold hypothesis. On average, 20-25% inorganic arsenic remains unmethylated regardless of the exposure level. [Hopenhayn-Rich C et al; Environ Res 60 (2): 161-77 (1993)]**PEER REVIEWED**
  
• Effects of a low dietary intake of choline on the biosynthesis of dimethylarsinic acid and on the tissue retention of arsenic were studied in New-Zealand white rabbits exposed to arsenate. Rabbits were given a choline deficient diet or a standard diet containing 600 mg/kg choline for 10 weeks. One hour before administration of labeled arsenic, animals in one of the standard diet groups were given an ip injection of 100 umol/kg periodate oxidized adenosine. Labeled arsenate was injected iv. Inhibition of methyltransferase activity by injection of peroxidate oxidized adenosine resulted in a marked decrease in the production of arsenic-dimethylarsinic acid following exposure to labeled arsenicV. Rabbits given peroxidate oxidized adenosine excreted only about 50% as much labeled arsenic-dimethylarsinic acid as did the rabbits given labeled arsenic only. Thus, they retained a significantly higher percentage of labeled arsenic in the liver, lungs, and skin. In rabbits given a choline deficient diet, there was a similar decrease in urinary excretion of labeled arsenic-dimethylarsinic acid, and an increased retention of labeled arsenic in the tissues. These effects were probably caused by interaction of unmethylated arsenic with tissue constituents. Choline deprivation gave rise to an increased concn of labeled arsenic in the liver microsomes, whereas peroxidate oxidized adenosine treatment did not. Nutritional factors and agents interacting with transmethylase activity in the liver, may be important for the toxic response following exposure to inorganic arsenic. [Marafante E, Vahter M; Acta Pharmacologica et Toxicologica 59 (Suppl 7): 35-8 (1986)]**PEER REVIEWED**
  

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Footnotes

¹ Source: the National Library of Medicine's Hazardous Substance Database, 10/28/2007.