National Toxicology Program

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

Names (NTP)

• DMA-4 herbicide
• 2,4-DIMETHYLAMINE SALT

Human Toxicity Excerpts

• A male suicide victim weighing 75 kg ingested 120 ml of 2,4-D, dimethylamine (80 mg/kg) experienced vomiting, congestion, pulmonary emphysema, CNS congestion, perivascular hemorrhages, severe degeneration of ganglion cells, and death within hours of ingestion. The 2,4-D concentration in tissues was 12.5-7700 mg/kg. [Nielsen K et al; Acta Pharmacol Toxicol 22: 224-34 (1965) as cited in WHO; Environ Health Criteria: 2,4-Dichlorophenoxyacetic Acid (2,4-D) p.85 (1984)]**PEER REVIEWED**
  
• A cohort of herbicide applicators was formed in 1972 from the personnel records of four main Finnish employers involved in chemical brushwood control. ... The cohort included 1971 male workers who had been exposed to chlorinated phenoxyacids for at least two weeks during 1955-1971. Forty-five individuals had died during the same period. Thus there were 1926 persons alive in the beginning of 1972 through 1980, and for cancer morbidity from 1972 through 1978. ... During the nine year prospective follow-up period ... 105 persons had died from natural causes versus 155 expected (observed/expected 0.68). ... The ... most common types of tumor ... lung and stomach ... cancers closely corresponded to the expected figures. ... When the ten year period of latency was taken into account there were no significant differences between the observed and expected figures although for some tumors greater numbers were found than expected: 9 cases of lung cancer (6.6 expected), 2 bladder tumors (0.9 expected) and 2 lip cancers (0.5 expected). ... After making allowance for 10 and 15 year periods of latency which restricted the relatively small number of person-years even more, no incr of cancer mortality was uncovered. ... This study /did not/ ... allow any assessment of the soft tissue sarcoma risk because the number of persons having a sufficiently long latency period is too small. /Chlorinated phenoxyacids/ [Riihimaki V et al; Chemosphere 12 (4/5): 79-84 (1983)]**PEER REVIEWED**
  
• SUBJECTIVE CLINICAL SYMPTOMS REPORTED AMONG WORKERS USING VARIOUS ESTERS & SALTS OF 2,4-D INCL RAPID FATIGUE, HEADACHE, LOSS OF APPETITE & PAIN IN THE REGION OF THE LIVER & STOMACH. SENSITIVITY TO TASTE & SMELL WAS LOWERED. /2,4-D ESTERS AND SALTS/ [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. V15 128]**PEER REVIEWED**
  
• The chlorophenoxy herbicides have produced contact dermatitis in man ... /Chlorophenoxy compounds/ [Doull, J., C.D.Klassen, and M.D. Amdur (eds.). Casarett and Doull's Toxicology. 3rd ed., New York: Macmillan Co., Inc., 1986., p. 554]**PEER REVIEWED**
  
• Recent epidemiologic studies showed increased frequency of birth defects in pesticide applicators & general population of the Red River Valley, Minnesota. These studies further indicated that this crop growing area used more chlorophenoxy herbicides & fungicides than elsewhere in Minnesota. Based on frequency of use & known biology, certain herbicides, pesticide additives, fungicides, & mycotoxins are suspect agents. To define whether these agents affect developmental endpoints in vitro, 16 selected agrochemicals were examined using the MCF-7 breast cancer cell line. In the flow cytometric assay, cell proliferation in this estrogen-responsive cell line indicates xenobiotic-mediated estrogenic effects. Cell viability, morphology, ploidy, & apoptosis were incorporated in this assay. Data showed that the adjuvants X-77 & Activate Plus induced significant cell proliferation at 0.1 & 1 microg/ml. The commercial-grade herbicides 2,4-D LV4 & 2,4-D amine induced cell proliferation at 1 & 10 microg/ml. The reagent-grade 2,4-D products failed to induce proliferation over the same concn range, suggesting that other ingredients in the commercial products, presumably adjuvants, could be a factor in these results. The fungicides triphenyltin & mancozeb induced apoptosis at concns of 4.1 microg/ml (10(-5) M) & 50 microg/ml, respectively. Triphenyltin also induced aneuploidy (C2/M arrest) at 0.41 microg/ml (10(-6) M). Data provide a mechanistic step to understanding human reproductive & developmental effects in populations exposed to these agrochemicals, & initiative to focusing limited resources for future in vivo animal developmental toxicity studies. [Lin N, Garry VF. J Toxicol Environ Health A 60 (6): 423-439. 2000.]**PEER REVIEWED**
  
• The percutaneous penetration of 2,4-dichlorophenoxyacetic acid (2,4-D) and 2,4-D dimethylamine salt (DMA) was evaluated separately in five male volunteers who participated in both experiments. Urine samples collected for 144 h following dermal applications of 10 mg to the dorsum of the hand (9 cm2) were analyzed for 2,4-D. Following the acid application, an average of 4.46 +/- 0.849% was recovered in the urine and a significantly lower amount of 1.76 +/- 0.568% following the DMA application. Significantly higher amounts of 2,4-D DMA (7.68 +/- 0.493 mg) were washed off the hand 6 h following application as compared with 2,4-D acid (5.35 +/- 0.384 mg). These results indicate that, in addition to the differences in physical and chemical properties of the two compounds that will affect absorption, the amount of the chemical absorbed is related inversely to the amount of washed off. Urinary excretion of 2,4-D was not complete in all volunteers 144 h following either application, but in all cases it was approaching the limit of detection. An average of 84.8 +/- 2.55% and 76.8 +/- 8.05% of the total recovered in 144 h was recovered in the urine 96 h following 2,4-D acid and 2,4-D DMA application, respectively. Average, approximated half-lives for excretion were 39.5 +/- 8.1 h for the acid application and 58.5 +/- 13.2 h for the DMA application. [Harris SA, Solomon KR; J Toxicol Environ Health 36 (3): 233-240. 1992.]**PEER REVIEWED**
  
• Percutaneous absorption of the 14C-ring-labeled phenoxy herbicide 2,4-D-amine (2,4-dichlorophenoxyacetic acid dimethylamine) was examined following topical applications of the herbicide to the palm and forearm of human volunteers. The effect of two vehicles (water and acetone) and the mosquito repellent DEET (N,N-diethyl-m-toluamide) on dermal absorption of 2,4-D-amine also was investigated. The total percent dermal absorption was calculated from the mean percent urinary recoveries and was not corrected for nonurinary excretion. The data revealed 14 +/- 4.5% (standard deviation) and 10 +/- 11.5% palmar absorption of 2,4-D-amine applied in water, with and without DEET, respectively, and 7 +/- 6.2% and 13 +/- 5.0% forearm absorption of the herbicide applied in water or acetone, respectively. Soap-and-water skin washes conducted at 24 h posttreatment removed up to 34% of the applied dose. Successive tape strips of skin taken at 24 h posttreatment demonstrated generally decreasing herbicide levels in the outer layers. The data bring into question the complete validity of the rhesus monkey model to predict human dermal absorption. [Moody RP et al; J Toxicol Environ Health 36 (3): 241-250. 1992.]**PEER REVIEWED**
  
• Dimethylammonium salt of 2,4-dichlorophenoxyacetic acid (DMA-2,4-D) is a widely used herbicide that is considered moderately toxic. In the present study we found that DMA-2,4-D is able to cause apoptosis in peripheral blood lymphocytes of healthy individuals & Jurkat T cells. Apoptosis induced by DMA-2,4-D was dose & time dependent, independent of Fas, TNF receptor 1 or the aromatic hydrocarbon receptor, & involved disruption of the mitochondrial transmembrane potential & activation of caspase-9. ZVAD-FMK, a broad-spectrum inhibitor of caspases, blocked DMA-2,4-D-induced apoptosis completely. While an inhibitor of caspase-9, as well as caspase-9 & caspase-3 inhibitors in combination, strongly blocked DMA-2,4-D-induced apoptosis, an inhibitor of caspase-3 had a moderate inhibitory effect. Unlike Fas-mediated apoptosis, the initiator caspase, caspase-8, was not involved in DMA-2,4-D-induced apoptosis. Transfection of Jurkat cells with Bcl-2 prevented DMA-2,4-D-induced disruption of the mitochondrial transmembrane potential & led to a complete blockage of apoptosis. Our data indicate that DMA-2,4-D kills human lymphocytes by initiating apoptosis via a direct effect on mitochondria. The activation of caspases occurs downstream of mitochondrial damage, & the dysfunction of mitochondria appears to be sufficient for triggering all downstream events leading to apoptosis. [Kaioumova D, et al; Hum Immunol 62 (1): 64-74 (2001)]**PEER REVIEWED**
  

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Non-Human Toxicity Excerpts

• ONE 1000 MG/KG ORAL DOSE INCR PLASMA & ERYTHROCYTE SODIUM LEVELS IN CALVES WITHOUT AFFECTING POTASSIUM & ALDOSTERONE LEVELS. 400 MG/KG DOSE INCR PLASMA ALDOSTERONE & CAUSED HYPERKALEMIA WITHOUT HYPERNATREMIA. [GRITS MA; VESTSI AKAD NAVUK BSSR, SER BIYAL NAVUK 1: 129 (1978)]**PEER REVIEWED**
  
• PRENATAL STUDIES ON 2,4-D IN WISTAR RATS SHOWED THAT IT INDUCED FETOTOXIC EFFECTS & INCR INCIDENCE OF SKELETAL ANOMALIES AFTER SINGLE ORAL DOSES OF 100-150 MG/KG/DAY ON DAYS 6-15 OF GESTATION. AT HIGHEST DOSAGE OF 150 MG/KG/DAY ... BUTOXYETHANOL & DIMETHYLAMINE SALTS OF 2,4-D WERE ASSOC WITH SIGNIFICANTLY INCR TERATOLOGIC INCIDENCE. [National Research Council. Drinking Water & Health Volume 1. Washington, DC: National Academy Press, 1977., p. 499]**PEER REVIEWED**
  
• Lowest observed avoidance concn: Ephemerella walkeri (mayfly nymphs): > 10 mg/l [Verschueren, K. Handbook of Environmental Data of Organic Chemicals. 2nd ed. New York, NY: Van Nostrand Reinhold Co., 1983., p. 499]**PEER REVIEWED**
  
• Lowest observed avoidance concn: Salmo gairdneri (rainbow trout): 1.0 mg/l [Verschueren, K. Handbook of Environmental Data of Organic Chemicals. 2nd ed. New York, NY: Van Nostrand Reinhold Co., 1983., p. 499]**PEER REVIEWED**
  
• There was no evidence of peripheral neuropathy or other neurotoxicity in rats dermally treated with a 12% aqueous solution of the amine salt of 2,4-dichlorophenoxyacetic acid (2,4-D amine). Male and female Fischer 344 rats were treated on the skin of all four limbs with 2,4-D amine for 2 hr/day, 5 days/week, for 3 weeks. Measurements were: body weights, hindlimb grip strength, accelera ting rod performance, single and paired pulse electrophysiology of the caudal and sciatic nerve, hindfoot H-reflexes, light microscopy of brain, spinal cord, sciatic nerve, tibial nerve, digital nerve, and electron microscopy of the tibial nerve. The experiment continued for up to one month postexposure. Treatment caused a weight loss in both male and female rats and caused minor skin change during treatment in both sexes. No other treatment-related effects were found. [Mattson JL et al; Neurobehav Toxicol Teratol 8 (3): 255-63 (1986)]**PEER REVIEWED**
  
• Administration of the herbicide 2,4-DN (amine salt of 2,4-dichlorophenoxyacetic acid) to weanling rats in a dose of 1/20.000 and 1/2000 of the LD50 for 3 months brought about a 40-50% reduction of thiamine content in the organs and tissues of experimental animals as compared with control. ... In the liver of rats given 2,4-DA, there was a 2-fold decrease in the content of flavine adeninedinucleotide, whereas the content of flavine mononucleotide showed a 2-fold rise. Rats given a lesser herbicide dose manifested a reduced excretion of riboflavin in urine, and an inhibition of liver succinate dehydrogenase. The same animals demonstrated an increase in the relative mass of the adrenals with a concurrent diminution of ascorbic acid content. [Bogdan AS; Vopr Pitan 2: 59-62 (1983)]**PEER REVIEWED**
  
• Mutagenic effects: Studies available at present are not adequate for the quantitive evaluation of the mutagenic effects of 2,4-D and its derivatives in short-term tests. However, the evidence does not suggest that 2,4-D derivatives are potent mutagens. /2,4-D and its derivatives/ [WHO; Environ Health Criteria: 2,4-Dichlorophenoxyacetic Acid (2,4-D) p.13 (1984)]**PEER REVIEWED**
  
• CARP FINGERLINGS EXPOSED TO 2,4-D AMINE SALT @ 25-100 MG/L FOR 30 DAYS SHOWED DYSTROPHIC & NECROBIOTIC LIVER & NERVE CELL CHANGES; PERIVASCULAR & PERICELLULAR EDEMA IN BRAIN, LIVER, KIDNEY, INTERCAPILLARY & SEROUS GLOMERULITIS, INTERSTITIAL NEPHRITIS, GLOMERULAR NECROSIS. /2,4-D AMINE SALT/ [SHCHERBAKOV YA; EKSP VODN TOKSIKOL 6: 164-71 (1976)]**PEER REVIEWED**
  
• CARP FINGERLINGS EXPOSED TO 2,4-D AMINE SALT 3-5 HR @ 400 MG/L OR 18-20 HR @ 200 MG/L CAUSED VASCULAR DISTURBANCES: HYPEREMIA & HEMORRHAGING IN ORGANS, MORE SEVERE IN MYOCARDIUM THAN IN BRAIN. /2,4-D AMINE SALT/ [SHCHERBAKOV YA; EKSP VODN TOKSIKOL 6: 156-63 (1976)]**PEER REVIEWED**
  
• DAILY ORAL ADMIN OF 0.1 MG 2,4-D AMINE SALT DURING PREGNANCY REDUCED LENGTH OF RAT EMBRYOS. IN MOST CASES WT & SURVIVAL OF EMBRYOS DECR; PRE- &/OR POSTIMPLANTATION MORTALITY INCR. SINGLE ORAL /DOSE AT/ 0.5 OF THE LD50 CAUSED INCR CEREBRAL VENTRICLES & PERITONEAL HEMORRHAGE. /2,4-D AMINE SALT/ [ALEKSASHINA ZA ET AL; GIG SANIT 4: 70-1 (1979)]**PEER REVIEWED**
  
• Of 6 detelocentric lines of the Chinese Spring wheat, three 2,4-D resistant lines showed incr DNAse activity 6 hr after spraying tillering plants with 1X10-2 molar 2,4-D amine, whereas in 3 susceptible lines the enzyme activity decr. DNA decr in the 3 resistant lines and in 1 susceptible line. Two days after the spray, the enzyme was inhibited in the 3 resistant lines and slightly stimulated in the 3 susceptible lines. However, in 2 resistant lines characterized by absence of the short shoulder in their chromosomes combined with a sharp decr of the RNA/DNA ratio, a greater decr in RNA levels 6 hr after the spray. In other lines the RNA content was not altered or incr. Two days after the 2,4-D amine spray the RNAse activity was decr in all lines with the exception of 1 of 2 resistant lines without the short chromosome shoulder. The short-term response of DNAse and DNA to 2,4-D amine was determined mainly by the degree of resistance, whereas the reactions observed 2 days after the 2,4-D amine spray were determined by chromosomal variations. /2,4-D Amine salt/ [Khotyleva LV et al; Dokl Akad Nauk BSSR 25 (7): 664-6 (1981)]**PEER REVIEWED**
  
• The mammalian pharmacology is not well characterized. ... Both acute & chronic toxicities in laboratory mammals are low. All species ... tested react similarly, & there seems to be only minor differences in potency between various salts & esters of 2,4-D, either as pure chemical or as commercial preparations. [Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984., p. III-130]**PEER REVIEWED**
  
• ... Essentially nontoxic to animals exposed to properly treated forage. When large doses are fed experimentally, general depression, anorexia, weight loss, general tenseness, and muscular weakness (particularly of the hindquarters) are noted. [Aiello, S.E. (ed). The Merck Veterinary Manual. 8th ed. Merck & Co., Inc., National Publishing Inc., Philadelphia, PA. 1998., p. 2059]**PEER REVIEWED**
  
• Large doses in cattle may interfere with rumen function. Dogs may develop myotonia, ataxia, posterior weakness, vomiting, diarrhea, and metabolic acidosis. [Aiello, S.E. (ed). The Merck Veterinary Manual. 8th ed. Merck & Co., Inc., National Publishing Inc., Philadelphia, PA. 1998., p. 2059]**PEER REVIEWED**
  
• Erythrocytes from Rana catesbeiana (bullfrog) tadpoles were evaluated for DNA damage following exposure to selected herbicides, using the alkaline single-cell gel DNA electrophoresis (SCG) or "comet" assay ... . This approach involves detection, under alkaline conditions, of DNA fragments that upon electrophoresis migrate from the nuclear care, resulting in a comet formation. The herbicides tested, along with their active ingredients, were AAtrex Nine-O (atrazine), Dual-960E (metalochlor), Roundup (glyphosate), Sencor-500F (metribuzin), & Amsol (2,4-D amine). Tadpoles were exposed in the lab for a 24 hr period to several concns of the herbicides dissolved in dechlorinated water. Methyl methanesulphonate was used as a positive control. The herbicides AAtrex Nine-O-, Dual-960E-, Roundup-, & Sencor-500F-treated tadpoles showed significant DNA damage when compared with unexposed control animals, whereas, Amsol-treated tadpoles did not. Unlike the other responding herbicides, Sencor-500F did not show a relationship between dosage & DNA damage. [Clements C et al; Environ Mol Mutagen 29 (3): 277-288. 1997.]**PEER REVIEWED**
  
• Forms of 2,4-dichlorophenoxyacetic acid ... are herbicides used to control a wide variety of broadleaf & woody plants. Subchronic toxicity studies in rats were conducted on 3 forms of 2,4-D: the parent form, 2,4-D acid; 2,4-D dimethylamine salt (DMA); & 2,4-D 2-ethylhexyl ester (2-EHE). Doses in the subchronic studies (on an acid equivalent basis) were 0, 1, 15, 100, & 300 mg/kg/day. Major treatment related findings in the 3 studies included decreases in red cell mass, decreases in T3 & T4 levels, decreases in ovary & testes weights, increases in liver, kidney, & thyroid weights, & cataracts & retinal degeneration (high-dose females). [Charles JM et al; Fundam Appl Toxicol 33 (2): 161-165. 1996.]**PEER REVIEWED**
  
• Subchronic toxicity studies in dogs were conducted on 3 forms of 2,4-D: the parent form, 2,4-D acid (ACID); 2,4-D dimethylamine salt (DMA); & 2,4-D 2-ethylhexyl ester (2-EHE). ... Doses in the subchronic studies, on an acid equivalent basis, were 0, 0.5 (ACID only), 1.0, 3.75, & 7.5 mg/kg/day. Treatment related findings in the 3 studies included reductions in body weight gain, & food consumption, & minor increases in blood urea nitrogen, creatinine, & alanine aminotransferase. The data from the 3 subchronic studies demonstrated the comparable toxicity of ACID, DMA, & 2-EHE & support a subchronic NOAEL of 1.0 mg/kg/day for all 3 forms. Due to the similarity in toxicity of the 3 forms of 2,4-D, a 1-yr chronic toxicity study was performed on the parent ACID to fully characterize the potential toxicity of 2,4-D in the dog. ACID was well tolerated at doses of 0, 1.0, 5.0, & 7.5 mg/kg/day. The clinical pathology alterations were similar to those seen in the subchronic studies & were not progressive. The histopathology alterations observed were not severe in nature & the no observed effect level in the chronic study was determined to be 1.0 mg/kg/day. There was no indication of any immunotoxic or oncogenic response in the studies. [Charles JM et al; Fundam Appl Toxicol 29 (1): 78-85. 1996.]**PEER REVIEWED**
  
• The toxic effects of repeated, increasing oral doses of Dikamin D (72% 2,4-D-amine Na), a broad leave herbicide product used world-wide, were evaluated on rats by the method of Lim et al. (1961). A comparison of the determined acute oral LD50 and the calculated subchronic oral LD50 values revealed a definite tolerance of the experimental animals to the test compound. This finding indicates that repeated oral treatment is capable of increasing the test animal's metabolizing capacity, which accounts for the development of tolerance. [VARNAGY L et al; ACTA VETERINARIA HUNGARICA; 43 (2-3): 355-358. 1995.]**PEER REVIEWED**
  
• Ambush, Treflan, Blazer, Roundup, 2,4-D Amine, Crossbow, Galecron, Pramitol, and Pondmaster were tested for their mutagenicity using the Drosophila sex-linked recessive lethal mutation assay. ... Unlike adult feeding and injection assays, the larvae were allowed to grow in medium with the test chemical, thereby providing long and chronic exposure to the sensitive and dividing diploid cells, i.e., mitotically active spermatogonia and sensitive spermatocytes. All chemicals induced significant numbers of mutations in at least one of the cell types tested. Some of these compounds were found to be negative in earlier studies. An explanation for the difference in results is provided. It is probable that different germ cell stages and treatment regimens are suitable for different types of chemicals. [Kale PG et al; Environ Mol Mutagen 25 (2): 148-53. 1995.]**PEER REVIEWED**
  
• Absorption & urinary excretion of 2,4-dichlorophenoxyacetic acid sodium (sodium 2,4-D) & 2,4-dichlorophenoxyacetic acid dimethylammonium (2,4-DMA) salts were examined after single oral & mid-dorsal skin applications of the herbicides to male rats. Doses of 2.6 mg 2,4-D/kg body wt (sodium 2,4-D) & 1.9 mg 2,4-D/kg bw (2,4-DMA) were applied. Quantitatively, with both salts, most of the orally administered herbicide (over 90%) was excreted in urine within 28 hr. However, 2,4-D urinary peak concns were measured 4.5 & 20.5 hr after dosing with 2,4-DMA & sodium 2,4-D, respectively. Additionally, the volume of urine in the oral study was significantly increased with both salts when compared with the controls or the dermal exposure. After topical application, 2,4-D absorption was much lower than in the oral study. Urinary excretion only reached about 10 & 15% of the applied dose for sodium 2,4-D & 2,4-DMA, respectively, by 5 days post-treatment. Further, we found some elevations in hepatic cytochrome P-450 activities. Ethylmorphine N-demethylase was only slightly induced by the herbicides while ethoxyresorufin O-deethylase activity was increased nearly 2-fold by sodium 2,4-D. [Knopp D, Schiller F; Arch Toxicol 66 (3): 170-174. 1992.]**PEER REVIEWED**
  
• ... 2,4-D DMA was given orally combined with rat food to pregnant albino rats. Each group consisted of 2 pregnant rats &, 0 (control, group A), 25 ppm (group B), 50 ppm (group C), & 100 ppm (group D) 2,4-D DMA was given to each pregnant rat as daily intake. 2,4-D DMA affected young rat's dental development & dose-related findings were found in experimental groups. The odontoblast layer was irregular & globular dentin formation was present in Groups B, C, & D but not in the control group. Thickness of enamel decreased in Groups C & D. The results of the study have shown that 2,4-D DMA could disturb dental development in rats even in relatively low doses. [Alpoz AR, et al; Environ Int 26 (3): 137-142 (2001)]**PEER REVIEWED**
  
• The possibility that urinary thioethers concn might be a marker for detecting exposure to herbicide containing 2,4-dichlorophenoxyacetic acid dimethylamine (2,4-DMA) was investigated in animals. Mice were treated with the herbicide containing 2,4-DMA consecutively for 4 days. Urinary concns of thioethers related either to body weight or creatinine concn in urine in the group of animals treated with herbicide were significantly higher compared to control group. Results suggest that thioethers determination in urine might be a noninvasive & simple method for detecting exposure to herbicide containing 2,4-DMA. [Mikov I, et al; Ann Agric Environ Med 7 (1): 61-3 (2000)]**PEER REVIEWED**
  
• Concentrated solns of 2,4-D (>12%) have been shown to cause severe skin burns in rats & rabbits. Topical application of 24% soln of 2,4-D amine over a 3 wk period produced ulcerative dermatitis, decreased body weight, & increased kidney size. A 12% soln of 2,4-D resulted in minimal skin changes. The dermal effect was thought to be due to a direct effect of the 2,4-D, as both the 12 or 24% solns had a pH= 10. Additionally, these animals at necropsy revealed no neuropathologic changes. [Sullivan, J.B. Jr., G.R. Krieger (eds.). Hazardous Materials Toxicology-Clinical Principles of Environmental Health. Baltimore, MD: Williams and Wilkins, 1992., p. 1065]**PEER REVIEWED**
  
• Pregnant CD-1 mice were administered a commercial 2,4-dichlorophenoxyacetic acid (2,4-D) formulation on days 6-16 days of gestation, in drinking water at concentrations ranging from 0 to 1.0% of the formulated product, equivalent to approximately 0-650 mg/kg per day expressed as the amine derivative. The effect of 2,4-D on immune function was evaluated in offspring 7 weeks after birth. The dams tolerated repeated 2,4-D exposure in drinking water without difficulty. The offspring exhibited decreased body weight with minor reductions in the kidney weights in the 0.1 and 1.0% 2,4-D treatment groups. A generalized suppression of lymphocyte stimulation by concanavalin A (Con A) was observed at high dose of commercial 2,4-D formulation (1.0%). Cytometric studies of the lymphocyte subpopulations demonstrated an increased relative count of B cells and reduced T cytotoxic or suppressor cells in the 1.0% formulation. The humoral immune response, antibody production against sheep red blood cells and peritoneal macrophage phagocytic function, were not altered by 2,4-D. Since the immune alterations in the offspring were observed many weeks after exposure, it appears as though 2,4-D exposure during gestation causes permanent changes in cell types associated with immune function. Since 2,4-D is not considered a persistent chemical, it is unlikely that 2,4-D residues are contributing significantly to the observed immune alterations. The immune alterations were observed only in the higher treatment groups. Therefore, the impact on human and animal health from an immune perspective, which would be encountered following normal application in the environment, would be minimal. [Lee K, et al; Toxicology 165 (1): 39-49 (2001)]**PEER REVIEWED**
  
• The effects of the herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) on the central nervous system (CNS) were studied in rats. Behavioural and neurochemical studies were performed. Results show that acute and oral administration of dimethylamine 2,4-D was able to decrease locomotion and rearing frequencies and to increase immobility duration of rats observed in an open-field test. Treatment of rats with p-chlorophenylalanine (PCPA) was unable to change rat's open-field behaviour; 5-hydroxytryptophan (5-HTP) administration not only increased locomotion and rearing frequencies but also decreased immobility duration. Pretreatment of the rats with PCPA and 5-HTP decreased and increased dimethylamine 2,4-D effects, respectively. The herbicide was not able to change the striatal levels of dopamine and homovanilic acid but decreased the striatal levels of serotonin (5-HT), as observed for the doses of 100 and 200 mg/kg and increased those of 5-hydroxyindoleacetic acid (5-HIAA) as measured after the 200 mg/kg dose treatment. When the levels of serotonin and 5-HIAA were measured at the brain stem level, only those of 5-HIAA were modified, being increased by diethylamine 2,4-D (60; 100 and 200 mg/kg); this increment on 5-HIAA levels was observed even 1 hr after pesticide administration. Further analysis showed that 2,4-D concentrations chromatographically detected both in serum and brain of the intoxicated animals were dose-dependent, being found as early as 1 hr after the smaller dose of the herbicide used (10 mg/kg). The results suggest that diethylamine 2,4-D modify 5-HT functional activity within the CNS. [Oliveira GH, Palermo-Neto J; Pharmacol Toxicol 73 (2): 79-85 (1993)]**PEER REVIEWED**
  

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Human Toxicity Values

• None found

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Non-Human Toxicity Values

• LD50 Rat oral 625 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. 1118]**PEER REVIEWED**
  
• LD50 Rabbit skin 2115 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. 1118]**PEER REVIEWED**
  

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Absorption, Distribution and Excretion

• The dimethylamine salt of (14)C-ring-labeled 2,4-D was administered to Fisher 344 rats orally (1 and 0.4 mg/kg body weight) and dermally (10 mg/kg body weight). Absorption, distribution, and elimination were determined from (14)C-labeled 2,4-D in blood, tissues, and excreta. Most of the orally administered dose (94-96%) became systemically available within 6 hr. Following dermal administration 10% of the dose became systemically available over 72 hr. However, peak concentrations in blood and kidney were achieved within 30 min of dosing by either route. By 1.5 hr after dosing, 2,4-D concentrations in blood, muscle, liver, and kidneys had decreased in both the orally dosed and dermally dosed animals. Between 2 and 8 hr, the blood, muscle, liver, and kidney concentrations in dermally dosed animals maintained a plateau while urinary excretion increased, presumably due to continued absorption 2,4-D from the skin. The concentrations in orally dosed animals continued to decrease. Following 7 hr of dermal exposure, skin cleansing removed about 63% of the applied dose; about 17% of the applied dose remained at the site of dermal dosing. At 8 hr, 2,4-D concentrations in blood, muscle, liver, and kidneys of dermally dosed animals began to decrease, most likely a result of the removal of the reservoir on the skin. However, 2,4-D continued to be absorbed from skin site, resulting in a slower decline of the 2,4-D concentrations in these tissues over remainder of the 72 hr study period. In animals that had been orally dosed, the absorbed dose was almost completely excreted within 24 hr. [Pelletier O et al; J Toxicol Environ Health 28 (2): 221-34 (1989)]**PEER REVIEWED**
  
• Plant roots absorb polar (salt) forms /of 2,4-D/ most readily. ... Following root absorption, it may move upward in the transpiration stream. Translocation is influenced by the growth status of the plant. Accumulation of the herbicide occurs principally at the meristematic regions of shoots and roots. /2,4-D salt/ [Weed Science Society of America. Herbicide Handbook. 5th ed. Champaign, Illinois: Weed Science Society of America, 1983., p. 132]**PEER REVIEWED**
  

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Metabolism/Metabolites

• HERBICIDAL ACTIVITY OF ESTERS, NITRILES, AMINES (&, OF COURSE, SALTS) APPEARS SIMILAR IF NOT IDENTICAL TO PARENT ACID. THIS IS APPARENTLY DUE TO PRESENCE OF HYDROLYTIC ENZYMES IN PLANTS & IN SOIL MICROORGANISMS THAT CONVERT THESE DERIVATIVES TO PARENT ACID. [Casarett, L.J., and J. Doull. Toxicology: The Basic Science of Poisons. New York: MacMillan Publishing Co., 1975., p. 57]**PEER REVIEWED**
  
• Chlorophenoxy acid derivatives are metabolized via participation of the hepatic microsomal mixed-function oxidase system. Thus, administration of 2,4-D amine salt and its butyl ester ... to rats induced the enzyme system (aminopyrine demethylase ... and aniline hydroxylase) ... although the degree of induction was substantially lower than that from phenobarbital. Prolonged administration of 2,4-D amine salt (0.1 LD50) showed cumulative effects reflected by both clinical and biochemical changes. Stimulation of mixed-function oxidase system may be one of the methods for reducing toxicological effects of this type of compounds. [Buslovich YS et al; Gig Sanit Issue 10: 76-7 (1982)]**PEER REVIEWED**
  

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TSCA Test Submissions

• None found

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Footnotes

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