01 - 2,4-D Technical Fact Sheet
01 - 2,4-D Technical Fact Sheet
01 - 2,4-D Technical Fact Sheet
2,4-D has been used in the United States since the 1940s, and it was evaluated for re-registration in 2005 by the United States Environmental Protection Agency (U.S. EPA).3 The U.S. EPA determined that 2,4-D was eligible for re-registration, but re- Laboratory Testing: Before pesticides are registered by the quired certain changes to labeled uses to mitigate risk.3 See the U.S. EPA, they must undergo laboratory testing for shortterm (acute) and long-term (chronic) health effects. Labotext box on Laboratory Testing.
ratory animals are purposely given high enough doses to cause toxic effects. These tests help scientists judge how these chemicals might affect humans, domestic animals, and wildlife in cases of overexposure.
Active Ingredient
CASRN
Form
Vapor pressurea
Molecular Weight
Log Kow 0.001 M soln pH 5: 2.14 pH 7: 0.177 pH 9: 0.102 Salt dissociates to acid in water 2.24 x 10-2 -1.65 See values for 2,4-D acid above
Koc
2,4-D acid
94-75-7
1.9 x 10-5 Pa 1.4 x 10-7 mmHg Salt dissociates to acid in water 9.98 x 10-8 mmHg
atmm3/mol
221
20-136
2702-72-9 5742-19-8
243.03 326.18
45,000 mg/L 806,000 mg/L pH 5: 320,632 3645 pH 7: 729,397 86,400 pH 9: 663,755 94,647
2008-39-1
-5
1.4 x 10
-16
atmm3/mol
266.13
72-136
2,4-D
Active Ingredient 2,4-D isopropylamine (IPA) salt 2,4-D tri isopropanolamine (TIPA) salt 2,4-D BEE 2,4-D 2-ethylhexyl ester (EHE) 2,4-D isopropyl ester (IPE)
a
CASRN
Form Amber aqueous liquid Amber aqueous liquid Dark amber liquid Dark amber liquid Pale amber liquid
Vapor pressurea Salt dissociates to acid in water Salt dissociates to acid in water 3.2 x 10-4 Pa 2.4 x 10-6 mmHg 4.8 x 10-4 Pa 3.6 x 10-6 mmHg 1.87 Pa 5.3 x 10 mbar
-6
Henrys constant
Solubility In water (mg/L)b pH 5: 174,000 mg/L pH 7: 436,000 mg/L pH 9: 331,000 mg/L pH5: 461,000 mg/L pH 7: 461,000 mg/L pH 9: 104,000 mg/L Practically insoluble in water 0.0867 mg/L Practically insoluble in water
Log Kow Salt dissociates to acid in water Salt dissociates to acid in water 4.1
Koc
5742-17-6
32341-80-3
412.31
1929-73-3
321.2
1928-43-4
5.78
94-11-1
263.12
b
253.8 44.4
600
Uses:
2,4-D is used for broadleaf weed control in agricultural and nonagricultural settings, and it is registered for use in both terrestrial and aquatic environments. Major sites include pasture and rangeland, residential lawns, roadways, and cropland. Crops treated with 2,4-D include field corn, soybeans, spring wheat, hazelnuts, sugarcane, and barley.3 Uses for products containing 2,4-D vary widely. Always read and follow the label when applying pesticide products. Approximately 46 million pounds are used each year in the United States, based on data from 1992-2000.3 Signal words for products containing 2,4-D may range from Caution to Danger.10 The signal word reflects the combined toxicity of the active ingredient and other ingredients in the product. See the pesticide label on the product and refer to the NPIC fact sheets on Signal Words and Inert or Other Ingredients. To find a list of products containing 2,4-D which are registered in your state, visit the website http://npic.orst.edu/reg/state_agencies.html and search by active ingredient.
Mode of Action:
Target Organisms
2,4-D is used on a wide variety of terrestrial and aquatic broadleaf weeds. It has little effect on grasses.12 It appears to work by causing uncontrolled cell division in vascular tissue.12 Abnormal increases in cell wall plasticity, biosynthesis of proteins, and production of ethylene occur in plant tissues following exposure, and these processes are responsible for uncontrolled cell division.3,12 The ester forms of 2,4-D penetrate foliage, whereas plant roots absorb the salt forms.12 2,4-D appears to be similar in action to other auxin-type herbicides.12
Non-target Organisms
The modes of toxicity to animals from the acid, ester and salt forms of 2,4-D are similar. The primary exception is that the salt and acid forms can be extreme eye irritants.3 2,4-D is actively secreted by the proximal tubules of the kidney, and toxicity appears to result when renal clearance capacity is exceeded.3 Dose-dependent toxic effects include damage to the eye, thyroid, kidney, adrenals, and ovaries or testes.3 In addition, researchers have observed neurotoxicity, reproductive toxicity, and developmental toxicity.3 Chlorophenoxy herbicides exhibit a variety of mechanisms of toxicity, including dose-dependent cell membrane damage leading to central nervous system toxicity,13 interference with cellular metabolism involving acetyl-coenzyme A (CoA),13 and uncoupling of oxidative phosphorylation due to either the disrupted CoA activity or cellular membrane damage.13 2
2,4-D
Oral
Dermal
Acute dermal LD50s ranged from 1829 mg/kg to greater than 2000 mg/kg in rabbits depending on the chemical form of 2,4-D. All chemical forms of 2,4-D are considered low in toxicity11 for acute dermal exposure based on studies using rabbits.3 The acid and salt forms of 2,4-D are highly toxic to eye tissue, causing severe eye irritation. This is reflected in the signal word of the formulated product. The ester forms are not considered eye irritants, and have Iow to very low ocular toxicity.3 The ester and salt forms of 2,4-D are considered slight skin irritants.3
LD50/LC50: A common measure of acute toxicity is the lethal dose (LD50) or lethal concentration (LC50) that causes death (resulting from a single or limited exposure) in 50 percent of the treated animals. LD50 is generally expressed as the dose in milligrams (mg) of chemical per kilogram (kg) of body weight. LC50 is often expressed as mg of chemical per volume (e.g., liter (L)) of medium (i.e., air or water) the organism is exposed to. Chemicals are considered highly toxic when the LD50/LC50 is small and practically non-toxic when the value is large. However, the LD50/LC50 does not reflect any effects from long-term exposure (i.e., cancer, birth defects or reproductive toxicity) that may occur at levels below those that cause death.
Inhalation
All chemical forms of 2,4-D are of low to very low toxicity via inhalation based on studies using rats. Acute inhalation LC50s for rats ranged from 0.78 mg/L to greater than 5.4 mg/L depending on the chemical form.3 Most forms of 2,4-D are very low in toxicity, and the parent acid and TIPA salt forms are low in toxicity.3
2,4-D
The highlighted boxes relfect the values in the Acute Toxicity section of this fact sheet. Modeled after the U.S. Environmental Protection Agency, Office of Pesticide Programs, Label Review Manual, Chapter 7: Precautionary Labeling. http://www.epa.gov/oppfead1/labeling/lrm/chap-07.pdf
Always follow label instructions and take steps to minimize exposure. If any exposure occurs, be sure to follow the First Aid instructions on the product label carefully. For additional treatment advice, contact the Poison Control Center at 1-800222-1222. If you wish to report an incident to the National Pesticide Information Center, please call 1-800-858-7378.
Chronic Toxicity:
Animals
Subchronic oral exposure to 2,4-D caused damage to the eye, thyroid, kidney, adrenals, and the ovaries and testes of laboratory animals.3,19 A subchronic NOEL was established at 15 mg/kg/day based on studies in rats.19 See the text box on NOAEL, NOEL, LOAEL, and LOEL.
NOAEL: No Observable Adverse Effect Level NOEL: No Observed Effect Level LOAEL: Lowest Observable Adverse Effect Level LOEL: Lowest Observed Effect Level
The chronic toxicity NOEL in rats and mice was determined to be 5 mg/kg/day in two-year studies.12,20 The maximum tolerated dose in the two-year rat study was 150 mg/kg/day in male rats and 75 mg/kg/day in females.20 Additional NOEL and NOAEL doses were 15 mg/kg for rats in a 90-day study, and 1 mg/kg for dogs in a 12-month study, respectively.12,21 Rabbits exhibited toxicity following dosing with either acid, salt, or ester forms of 2,4-D at doses of 30 mg/kg/day or greater.4 Chronic NOAELs and LOELs in dogs, however, varied for different parameters studied and by chemical form.21 Rats showed no outward signs of toxicity following exposure to 200 mg/L of 2,4-D in drinking water for 30 and 100 days, but biochemical analysis suggested hepatic and muscle damage.17 Researchers fed rats 2,4-D at doses of 1, 15, 100, and 300 mg/kg/day acid equivalents (ae). Changes in blood and thyroid parameters, organ weight ratios, and body weight gain were noted at 100 and 300 mg/kg/day doses.19 Chronic toxicity in the eye, kidney, thyroid and liver of the rat were similar to effects found in subchronic studies.20 Eye lesions were associated only with high doses of 150 mg/kg/day.20
Humans
No human data were found on chronic effects of 2,4-D other than epidemiological studies of cancer occurrence. Although pesticide use has been linked to Parkinsons disease and to respiratory disease in farmers, 2,4-D was not implicated in any relationships between pesticide exposure and subsequent disease.22,23 See the Carcinogenicity section below for more information on 2,4-D and cancer in humans. See the text box on Exposure (page 5).
2,4-D
Endocrine Disruption:
Because 2,4-D has demonstrated toxic effects on the thyroid and gonads following exposure, there is concern over potential endocrine-disrupting effects.3 2,4-D is included in the U.S. EPA June 2007 Draft List of Chemicals for Tier 1 Screening.24
Carcinogenicity:
Animals
No oncogenic effects were observed in rats or mice following 2 years of dietary exposure of 2,4-D with concentrations ranging from 5-150 mg/kg/day or 5-300 mg/kg/day, respectively.20 Similarly, researchers did not observe immunotoxic or oncogenic responses in dogs dosed with 1.0-7.5 mg/kg/day for either 13 weeks or 1 year.21 A case-control study in companion dogs concluded that there was a modest association between malignant lymphoma in the dogs and the use of 2,4-D in their owners yards after accounting for other home and yard pesticide use.25 Other investigators have questioned the epidemiological association reported in that study.5,26 Overall, there has been no consistent association between exposure to 2,4-D and tumor induction in animals.27 More recently, non-cytotoxic concentrations of 2,4-D were correlated to DNA damage and altered expression of some genes in hamster embryo cells.28
Humans
The U.S. EPA evaluated 2,4-D for carcinogenic effects in 1988, 1992, and again in 2004. Each evaluation has concluded that the data are not sufficient to conclude that there is a cause and effect relationship between exposure to 2,4-D and nonHodgkins Lymphoma.3 2,4-D was categorized as Group D - not classifiable as to human carcinogenicity in 2004.3 See the text box on Cancer.
Cancer: Government agencies in the United States and abroad have developed programs to evaluate the potential for a chemical to cause cancer. Testing guidelines and classification systems vary. To learn more about the meaning of various cancer classification descriptors listed in this fact sheet, please visit the appropriate reference, or call NPIC.
The International Agency for Research on Cancer (IARC), had not assigned 2,4-D a cancer rating as of June 2008. However, in 1987, IARC placed the family of chlorophenoxy herbicides in Group 2B, possibly carcinogenic to humans.29 A discussion of the history of classification decisions regarding the carcinogenicity of 2,4-D has been published. A confounding factor in determining the carcinogenicity of 2,4-D is the frequent simultaneous exposure of workers to 2,4-D in addition to 2,4,5-T and its contaminant TCDD (dioxin), or to other herbicides. However, other work examining incidents of exposure to 2,4-D without simultaneous exposure to 2,4,5-T has found some association between 2,4-D and non-Hodgkins lymphoma.26 Although the free acid form of 2,4-D did not damage chromosomes, there is limited evidence that commercial formulations may have the potential to do so.27 Overall, evidence for mutagenicity has been inconsistent.26,27,30
2,4-D
Fetal abnormalities were observed in rats following oral doses of 90 mg/kg/day or greater beginning at fertilization; these doses were toxic to the mothers as well.4 A NOEL of 25 mg/kg/day was derived for fetal rats in one study, and a NOAEL of 12.5 mg/kg/day for the mothers and a developmental NOAEL of 50 mg/kg/day for the young were derived in another study.7 The overall maternal NOEL in rats was determined to be 8-17 mg/kg/day and overall developmental NOEL was 30 mg/kg/day 2,4-D acid equivalents.4 Rabbit fetuses were unaffected at doses below 40 mg/kg/day administered to the dams although extra ribs were formed at doses above this threshold.4 In rabbits, the developmental NOEL was 30 mg/kg/day 2,4-D acid equivalents.4
Humans
No experimental data are available regarding the effects of 2,4-D exposure on reproduction or development in humans. There are some reports of reproductive effects following occupational exposure to chlorophenoxy herbicides,7 including reduced sperm motility and viability following occupational exposure. Although motility and viability recovered over a period of several months, malformations were still present.32 Exposure to multiple pesticides in epidemiological studies make inference difficult.26
Distribution
In laboratory animals, the primary target organs for 2,4-D toxicity were the eye, thyroid, kidney, adrenal glands, and ovaries or testes following subchronic oral exposure at doses above the threshold of saturation for renal clearance.3 Biochemical changes suggested that liver and muscle damage occurred in rats at acute, subchronic, and chronic doses.17 In humans, 2,4-D has a wide volume of distribution due to its water solubility, but it does not accumulate in any tissue.7
Metabolism
Metabolism of 2,4-D is minimal in humans, with nearly all of it excreted unchanged as the parent compound.36,7 The remainder is excreted as an unspecified 2,4-D conjugate.37 In animals, little 2,4-D is metabolized prior to excretion. Up to 3.2% of the applied dose in rats was excreted as an unspecified polar metabolite.26 In sheep and cattle, muscle, liver, kidney, and fat tissue contained the metabolite 4-chlorocatechol.38 Dogs must metabolize the parent compound prior to excretion, due to their reduced ability to excrete organic acids.39 No reactive intermediate metabolic products for 2,4-D have been identified in any species.26
2,4-D
Excretion
In humans, 2,4-D is rapidly excreted from the body, primarily in the urine.7 Much of the compound appears to be eliminated unchanged, although some 2,4-D is eliminated from the body as a conjugate.37 The percent of original dose excreted as a polar, acid-hydrolyzable metabolite was 4.8-27.0%.26 The elimination half-life from blood plasma in humans orally dosed with 5 mg/kg of 2,4-D was 11.6 hours.37 These human volunteers excreted more than 75% of 2,4-D in their urine within 96 hours of oral dosing.36 Concentrations in blood plasma paralleled concentrations excreted in urine.36 Some 2,4-D may be excreted in perspiration but this process appears to occur more slowly compared with urinary excretion.7 Excretion of 2,4-D in animals depends on the species, formulation, and dose.40 In rats, elimination of orally administered doses of 5 and 50 mg/kg 2,4-D took 24 hours, and the urine was composed almost entirely of unmetabolized 2,4-D.39 Dogs excreted a 5 mg/kg oral dose primarily in their urine with minor amounts detected in feces.39 Dogs dosed with 50 mg/kg excreted equal amounts in urine and feces and excretion was incomplete at 120 hours post-dose.39 Because dogs appear to be deficient in their ability to excrete organic acids, 2,4-D must be metabolized prior to excretion.39 Dogs orally dosed with 2,4-D excreted the parent compound, several conjugates and one unidentified compound in their urine.39 Excretion of 2,4-D in urine is dose-dependent but nonlinear, with percent excreted in urine declining at higher doses.7 In all of the species of animals studied, 2,4-D is excreted quickly and almost entirely in the urine.7
Environmental Fate:
Soil
2,4-D amine salts and esters are not persistent under most environmental conditions.3 Typically, the ester and amine forms of 2,4-D are expected to degrade rapidly to the acid form.3 Soil half-life values have been estimated at 10 days for the acid, diethylamine salt, and ester forms.44 Another study estimated a soil half-life for the ester form EHE ranging from 1-14 days with a median half-life of 2.9 days.3 In aerobic mineral soils, a half-life of 6.2 days was estimated.3 A granular formulation of the BEE form was detected in aquatic sediments for 186 days post-application, perhaps due to either the formulation or slow de-esterification of the sediment-bound chemical.3 See the text box on Half-life.
The half-life is the time required for half of the compound to break down in the environment. 1 half-life = 50% remaining 2 half-lives = 25% remaining 3 half-lives = 12% remaining 4 half-lives = 6% remaining 5 half-lives = 3% remaining Half-lives can vary widely based on environmental factors. The amount of chemical remaining after a half-life will always depend on the amount of the chemical originally applied. It should be noted that some chemicals may degrade into compounds of toxicological significance.
Microbial degradation of 2,4-D in soil involves hydroxylation, cleavage of the acid side-chain, decarboxylation, and ring opening.1 The ethyl hexyl form of the compound is rapidly hydrolyzed in soil and water to form the 2,4-D acid.1 Other comparative studies demonstrated that ester and amine salt forms of 2,4-D have similar soil dissipation rates because they are converted rapidly to the same anionic form.45
2,4-D
2,4-D has a low binding affinity in mineral soils and sediment, and in those conditions is considered intermediately to highly mobile.3 In sandy loam, sand, silty clay loam, and loam soil, Koc values of 70, 76, 59, and 117 mL/g, respectively, were obtained,3 indicating low binding affinity in these soil types. Although 2,4-D is highly mobile, rapid mineralization rates may reduce the potential of 2,4-D to affect groundwater.46 Microbes may play a major role in degradation.2 Break-down products of 2,4-D detected in laboratory experiments included 1,2,4-benzenetriol, 2,4-dichlorophenol (2,4DCP), 2,4-dichloroanisole (2,4-DCA), 4-chlorphenol, chlorohydroquinone (CHQ), volatile organics, bound residues, and carbon dioxide. These degradates are expected to be of low occurrence in the environment, of low toxicity, or both.3
Water
The half-life of 2,4-D in aerobic aquatic environments was estimated to be 15 days and in anaerobic aquatic laboratory studies, 41-333 days.3 A granular formulation of the BEE form degraded rapidly in the water column in alkaline conditions but was present in sediments for 186 days.3 The ethyl hexyl form is rapidly hydrolyzed in water to 2,4-D acid, with a degradation half-life (DT50) of less than one day.1 Ester forms of 2,4-D hydrolyze at rates that are pH dependent; the hydrolysis half-life of the butoxy ester increased from 9 hours at pH 8 to more than one year in more acidic conditions with a pH of 5.38 The acid form of 2,4-D is very resistant to abiotic hydrolysis.3 2,4-D has been detected in streams and shallow groundwater at low concentrations, in both rural and urban areas.3,47,48
Air
Volatility for most forms of 2,4-D is low (see table on page 1 and 2). However, the vapor pressure of some ester forms range from 1.1 x 10-3 to 2.3 x 10-3 mmHg,2 indicating that these forms readily volatilize. The Henrys Law Constant for 2,4-D acid is 3.5 x 10-4 at pH 7,49 indicating low potential for movement from water to air. No data were found regarding the degradation of 2,4-D in the atmosphere.
Plants
The ester forms of 2,4-D penetrate foliage, whereas plant roots absorb the salt forms.12 Ester forms are converted to the acid within the plant, then accumulate in cells due to passive diffusion down the concentration gradient.12 Active transport within the plant may also occur.12 Accumulation occurs primarily at the meristem tissue of roots and shoots.1 Forest dissipation studies indicated that the ethyl hexyl ester form of 2,4-D degraded slowly on foliage and in leaf litter.3 Residues of an ester form of 2,4-D were detected in samples of dead birch leaves for up to three years post-application.50
Indoor
No data were available on indoor persistence.
Food Residue
2,4-D was not included in the list of pesticides detectable in regulatory monitoring.51 Traces of 2,4-D were detected in 49.3% of finished drinking water samples and 53.7% of untreated water samples (365 and 367 samples taken, respectively), with detections between 1.1 and 2416.0 parts per trillion (ppt). These concentrations are well below the maximum contaminant level (MCL) of 70,000 ppt set by the U.S. EPA for finished drinking water.52 In bottled water, only 2 of 367 samples contained 2,4-D, with residues of 3.2 and 4.2 ppt.52 See the text box on Maximum Contaminant Level (MCL).
Maximum Contaminant Level (MCL): The MCL is the highest level of contaminant that is legally allowed in drinking water. The MCL is enforceable. The MCL is typically measured in milligrams (mg) of contaminant per liter (L) of water.
U.S. Environmental Protection Agency, Region 5, Water, Underground Injection Control Terms, 2011. http://epa.gov/r5water/uic/glossary.htm#mcl
2,4-D
Birds
2,4-D
A mesocosm study indicated that an unspecified form of 2,4-D applied at 0.117 mL/m2 had no negative effects on species richness, biomass, or survival on algae and 25 species of aquatic animals, including frog larvae, salamanders, snails, and a range of other invertebrates.53 Ninety-six-hour LC50 concentrations for several species of amphibian larvae exceeded 100 mg/L for the amine salt forms.2 2,4-D acid, 2,4-D EHE, and 2,4-D DMA are considered practically non-toxic to amphibian larvae based on tests with Rana pipiens.3 Bioavailability and uptake of 2,4-D by organisms are strongly influenced by pH, temperature, and other environmental factors.2 The sensitivity of aquatic invertebrates to 2,4-D increases with temperature; concentrations below those associated with short-term toxic effects impaired reproduction when ambient temperature was elevated.2 Although some aquatic invertebrates appear to sense and avoid 2,4-D in the water, others do not, even when exposed to lethal concentrations.2 Fish appear to avoid 2,4-D in a dose-dependent manner until the onset of toxic effects.2 Toxicity of 2,4-D was increased when fish were simultaneously exposed to 2,4-D and carbaryl or picloram.2
Terrestrial Invertebrates
LC50 values for 24-hour exposures in honey bees were estimated to be 104 and 115 g per bee. Researchers estimated the LD50 at greater than 10 g/bee, so 2,4-D is considered practically non-toxic.3 Effects on bee longevity varied according to dose and 2,4-D form.2 2,4-D is not considered hazardous to beneficial insects due to its low insecticidal activity and an adequate safety margin when products containing 2,4-D are used at recommended levels.2,3 Carabid beetles exposed to sand dosed with 1 g/m2 exhibited greater than 50% mortality after 4 days.2 The calculated 48-hour LC50 concentration for earthworms exposed to filter paper treated with 2,4-D was 61.6 g/cm.22 Effects of 2,4-D on soil microorganisms were species-dependent.2
Regulatory Guidelines:
The referance dose (RfD) for 2,4-D is 0.01 mg/kg/day.54 See the text box on Reference Dose (RfD). The U.S. EPA has classified 2,4-D as Group D - not classifiable with regard to human carcinogenicity in 2004.3 IARC had not assigned 2,4-D a cancer rating as of December 2007. However, the chlorophenoxy herbicides as a group were classified in Group 2B, meaning that they are considered to be possibly carcinogenic to humans, by IARC in 1987.29 See the text box on Cancer (page 5).
Reference Dose (RfD): The RfD is an estimate of the quantity of chemical that a person could be exposed to every day for the rest of their life with no appreciable risk of adverse health effects. The reference dose is typically measured in milligrams (mg) of chemical per kilogram (kg) of body weight per day.
U.S. Environmental Protection Agency, Technology Transfer Network, Air Toxics Health Effects Glossary, 2009. http://www.epa.gov/ttnatw01/hlthef/hapglossaryrev.html#RfD
The threshold limit value, or TLV, for 2,4-D is 10 mg/m3 for an 8-hour time weighted average exposure.55 This limit is based on results of animal feeding experiments.43 This same dose was selected by the Occupational Safety and Health Administration (OSHA) for the permissible exposure limit (PEL) for an 8 hour time weighted average exposure and by the National Institute for Occupational Safety and Health (NIOSH) for the recommended exposure limit (REL) for a 10-hour workday and a 40-hour workweek.43 The MCL for 2,4-D in drinking water is 0.07 mg/L.56 See the text box on Maximum Contaminant Level (MCL) (page 8).
10
2,4-D
References
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4. 5.
6. 7.
Tomlin, C. D. S. The Pesticide Manual: A World Compendium, 14th ed.; British Crop Protection Council: Surrey, UK, 2006. WHO. Environmental Health Criteria 84, Environmental Aspects - 2,4-Dichlorophenoxyacetic acid (2,4-D); International Programme on Chemical Safety, World Health Organization: Geneva, Switzerland, 1989. Reregistration Eligibility Decision (RED) 2,4-D; EPA 738-R-05-002; U.S. Environmental Protection Agency, Office of Prevention, Pesticides and Toxic Substances, Office of Pesticide Programs, U.S. Government Printing Office: Washington, DC, 2005. Charles, J. M.; Hanley, T. R.; Wilson, R. D.; Van Ravenzwaay, B.; Bus, J. S. Developmental Toxicity Studies in Rats and Rabbits on 2,4-Dichlorophenoxyacetic Acid and its Forms. Toxicol. Sci. 2001, 60, 121-131. Carlo, G. L.; Cole, P.; MIller, A. B.; Munro, I. C.; Solomon, K. R.; Squire, R. A. Review of a Study Reporting an Association between 2,4-Dichlorophenoxyacetic Acid and Canine Malignant Lymphoma: Report of an Expert Panel. Regul. Toxicol. Pharmacol. 1992, 16, 245-252. Kamrin, M. A. Pesticide Profiles: Toxicity, Environmental Impact, and Fate; Lewis Publishers: New York, 1997, p 306. Munro, I. C.; Carlo, G. L.; Orr, J. C.; Sund, K. G.; Wilson, R. M.; Kennepohl, E.; Lynch, B. S.; Jablinske, M.; Lee, N. L. A Comprehensive, Integrated Review and Evaluation of the Scientific Evidence Relating to the Safety of the Herbicide 2,4-D. J. Am. Coll. Toxicol. 1992, 11, (5), 559-664. FAO. Pesticide Residues in Food - Evaluations Part 1: Residues; FAO Plant Production and Protection Paper 152/1, Food and Agriculture Organization of the United Nations and World Health Organization: Rome, 1988; Vol. 1, pp 179-189. Hazardous Substances Databank (HSDB), 2,4-D; U.S. Department of Health and Human Services, National Institutes of Health, National Library of Medicine. http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?HSDB (accessed June 2008), updated June 2005. Pesticide Products. Pest-Bank [CD-ROM] 2007. Label Review Manual; U.S. Environmental Protection Agency, Office of Prevention, Pesticides and Toxic Substances, Office of Pesticide Programs. http://www.epa.gov/oppfead1/labeling/lrm/chap-07.pdf (accessed June 2008), updated Sept 2007. Herbicide Handbook, 8th ed.; Vencill, W.K. Ed.; Weed Science Society of America: Lawrence, KS, 2002; pp 113-115. Bradberry, S. M.; Proudfoot, A. T.; Vale, J. A. Poisoning Due to Chlorophenoxy Herbicides. Toxicol. Rev. 2004, 23 (2), 65-73. Peterson, M. E.; Talcott, P. A. Small Animal Toxicology, 2nd ed.; Saunders Elsevier: St. Louis, 2006; pp 734-735. Campbell, A.; Chapman, M. Handbook of Poisoning in Dogs and Cats; Blackwell Science Ltd.: Oxford, England, 2000; pp 220-221. Arnold, E. K.; Lovell, R. A.; Beasley, V. R.; Parker, A. J.; Stedelin, J.R. 2,4-D Toxicosis III: An Attempt to Produce 2,4-D Toxicosis in Dogs on Treated Grass Plots. Vet. Hum. Toxicol.1991, 33 (5), 457-461. Paulino, C. A.; Guerra, J. L.; Oliveira, G. H.; Palmero-Neto, J. Acute, Subchronic and Chronic 2,4-Dichlorophenoxyacetic Acid (2,4-D) Intoxication in Rats. Vet. Hum. Toxicol. 1996, 38 (5), 348-352. Reigart, J. R.; Roberts, J. R. Chlorophenoxy Herbicides. Recognition and Management of Pesticide Poisonings, 5th ed.; U.S. Environmental Protection Agency, Office of Prevention, Pesticides and Toxic Substances, Office of Pesticide Programs, U.S. Government Printing Office: Washington, DC, 1999; pp 94-96. Charles, J. M.; Cunny, H. C.; Wilson, R. D.; Bus, J. S. Comparative Subchronic Studies on 2,4-Dichlorophenoxyacetic Acid, Amine, and Ester in Rats. Fundam. Appl. Toxicol. 1996, 33, 161-165. Charles, J. M.; Bond, D. M.; Jeffries, T. K.; Yano, B. L.; Stott, W. T.; Johnson, K. A.; Cunny, H. C.; Wilson, R. D.; Bus, J. S. Chronic Dietary Toxicity/ Oncogenicity Studies on 2,4-Dichlorphenoxyacetic Acid in Rodents. Fundam. Appl. Toxicol. 1996, 33, 166-172. Charles, J. M.; Dalgard, D. W.; Cunny, H. C.; Wilson, R. D.; Bus, J. S. Comparative Subchronic and Chronic Dietary Toxicity Studies on 2,4-Dichlorophenoxyacetic Acid, Amine, and Ester in the Dog. Fundam. Appl. Toxicol. 1996, 29, 78-85. Hoppin, J. A.; Umbach, D. M.; London, S. J.; Alavanja, M. C. R.; Sandler, D. P. Chemical Predictors of Wheeze among Farmer Pesticide Applicators in the Agricultural Health Study. Am. J. Respir. Crit. Care Med. 2002, 165, 683-689. Kamel, F.; Tanner, C. M.; Umbach, D. M.; Hoppin, J. A.; Alavanja, M. C. R.; Blair, A.; Comyns, K.; Goldman, S. M.; Korell, M.; Langston, J. W.; Ross, G. W.; Sandler, D. P. Pesticide Exposure and Self-reported Parkinsons Disease in the Agricultural Health Study. Am. J. Epidemiol. 2006, 165 (4), 364-374. Draft List of Initial Pesticide Active Ingredients and Pesticide Inerts to be Considered for Screening Under the Federal Food, Drug, and Cosmetic Act. Fed. Regist. June 18, 2007, 72 (116), 33486-33503.
8.
9.
10.
11. 12.
13. 14. 15. 16. 17. 18.
24.
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2,4-D
25. Hayes, H. M.; Tarone, R. E.; Cantor, K. P.; Jessen, C. R.; McCurnin, D. M.; Richardson, R. C. Case-Control Study of Canine Malignant Lymphoma: Positive Association With Dog Owners Use of 2,4-Dichlorphenoxyacetic Acid Herbicides. J. Natl. Cancer Inst. 1991, 83, 1226-1231. 26. Garabant, D. H.; Philbert, M. A. Review of 2,4-Dichlorophenoxyacetic Acid (2,4-D) Epidemiology and Toxicology. Crit. Rev. Toxicol. 2002, 32 (4), 233-257. 27. Gandhi, R.; Wandji, S.-A.; Snedeker, S. Critical Evaluation of Cancer Risks from 2,4-D. Rev. Environ. Contam. Toxicol. 2000, 167, 1-33. 28. Maire, M. A.; Rast, C.; Landkocz, Y.; Vasseur, P. 2,4-Dichlorophenoxyacetic Acid: Effects on Syrian Hamster Embryo (SHE) Cell Transformation, c-Myc Expression, DNA Damage, and Apoptosis. Mutat. Res. 2007, 631, 124-136.
29. IARC Monographs on the Evaluation of Carcinogenicity Risks to Humans. Overall Evaluations of Carcinogencity: An Updating of IARC Monographs, Volumes 1 to 42; International Agency for Research on Cancer: Lyon, France, 1987; Supplement 7.
30. Madrigal-Bujaidar, E.; Hernandez-Ceruelos, A.; Chamorro, G. Induction of sister chromatid exchanges by 2,4-dichlorophenoxyacetic acid in somatic and germ cells of mice exposed in vivo. Food Chem. Toxicol. 2001, 39, 941-946. 31. Collins, T. F. X.; Williams, C. H. Teratogenic Studies with 2,4,5-T and 2,4-D in the Hamster. Bull. Environ. Contam. Toxicol. 1971, 6 (6), 559-567. 32. Lerda, D.; Rizzi, R. Study of reproductive function in persons occupationally exposed to 2,4-dichlorophenoxyacetic acid (2,4-D). Mutat. Res. 1991, 6 (6), 1, 47-50. 33. Brand, R. M.; McMahon, L.; Jendrzejewski, J. L.; Charron, A. R. Transdermal absorption of the herbicide 2,4-dichlorphenoxyacetic acid is enhanced by both ethanol consumption and sunscreen application. Food Chem. Toxicol. 2007, 456, 93-97. 34. Brand, R. M.; Spaulding, M.; Mueller, C. Sunscreens Can Increase Dermal Penetration of 2,4-Dichlorphenoxyacetic Acid. J. Toxicol. Clin. Toxicol. 2002, 40 (7), 827-832. 35. Pont, A. R.; Charron, A. R.; Brand, R. M. Active ingredients in sunscreens act as topical penetration enhancers for the herbicide 2,4-dicholorphenoxyacetic acid. Toxicol. Appl. Pharmacol. 2004, 195, 348-354. 36. Kohli, J. D.; Khanna, R. N.; Gupta, B. N.; MDhar, M. M.; Tandon, J. S.; Sircar, K. P. Absorption and Excretion of 2,4-Dichlorophenoxyacetic Acid in Man. Xenobiotica 1974, 4 (2), 97-100. 37. Sauerhoff, M. W.; Braun, W. H.; Blau, G. E.; Gehring, P. J. The Fate of 2,4-Dichlorophenoxyacetic Acid (2,4-D) Following Oral Administration to Man. Toxicology 1977, 8, 3-11. 38. Roberts, T. R. Metabolic Pathways of Agrochemicals - Part 1: Herbicides and Plant Growth Regulators; The Royal Society of Chemistry: Cambridge, UK, 1998; pp 66-74. 39. Van Ravenzwaay, B.; Hardwick, T. D.; Needham, D.; Pethen, S.; Lappin, G. J. Comparative metabolism of 2,4-dichlorophenoxyacetic acid (2,4-D) in rat and dog. Xenobiotica 2003, 33 (8), 805-821. 40. Arnold, E. K.; Beasley, V. R. The Pharmacokinetics of Chlorinated Phenoxy Acid Herbicides: A Literature Review. Vet. Hum. Toxicol. 1989, 31 (12), 121-125. 41. CDC. Third National Report on Human Exposure to Environmental Chemicals; U.S. Department of Health and Human Services, Centers for Disease Control and Prevention: Atlanta, 2005; pp 390-394. 42. Olsson, A. O.; Baker, S. E.; Nguyen, J. V.; Romanoff, L. C.; Udunka, S. O.; Walker, R. D.; Flemmen, K. L.; Barr, D. B. A liquid chromatographytandem mass spectrometry multiresidue method for quantification of specific metabolites of organophosphorus pesticides, synthetic pyrethroids, selected herbicides, and DEET in human urine. Anal. Chem. 2004, 76 (9), 2453-2461. 43. OSHA. Occupational Safety and Health Guideline for 2,4-D (Dichlorophenoxyacetic Acid); U.S. Department of Labor, Occupational Safety and Health Administration. http://www.osha.gov/SLTC/healthguidelines/2_4d-dichlorophenoxyaceticacid/ recognition.html (accessed May 2008), updated April 1999.
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NPIC is a cooperative agreement between Oregon State University and the U.S. Environmental Protection Agency (U.S. EPA, cooperative agreement # X8-83458501). The information in this publication does not in any way replace or supersede the restrictions, precautions, directions, or other information on the pesticide label or any other regulatory requirements, nor does it necessarily reflect the position of the U.S. EPA.
2,4-D
44. Vogue, P.A.; Kerle, E.A.; Jenkins, J.J. OSU Extension Pesticide Properties Database; Oregon State University: Corvallis, OR, 2004. 45. Wilson, R. D.; Geronimo, J.; Armbruster, J. A. 2,4-D Dissipation in Field Soils After Applications of 2,4-Dimethylamine Salt and 2,4-D Ethylhexyl Ester. Environ. Toxicol. Chem. 1997, 16 (6), 1239-1246. 46. Boivin, A.; Amellal, S.; Schiavon, M.; van Genuchten, M. T. 2,4-dichlorophenoxyacetic acid (2,4-D) sorption an ddegradation dynamics in three agricultural soils. Environ. Pollut. 2005, 138, 92-99.
47. Pesticides in Surface and Groundwater of the United States: Summary of Results of the National Water Quality Assessment Program (NAWQA); U.S. Geological Survey: Reston, VA, 1998. 48. McPherson, A. K.; Moreland, R. S.; Atkins, J. B. Occurrence and Distribution of Nutrients, Suspended Sediment, and Pesticides in the Mobile River Basin, Alabama, Georgia, Mississippi, and Tennessee, 1999-2001; Water-Resources Investigations Report 0349. 50. 4203, U.S. Geological Survey: Montgomery, AL, 2003; pp 1-2, 44, 57. Rice, C. P.; Chernyak, S. M.; McConnell, L. L. Henrys Law Constants for Pesticides Measured as a Function of Temperature and Salinity. J. Agric. Chem. 1997, 45, 2291-2298. Torstensson, N. T. L.; Lundgren, L. N.; Stenstrom, J. Influence of Climatic and Edaphic Factors on Persistence of Glyphosate and 2,4-D in Forest Soils. Ecotoxicol. Environ. Saf. 1989, 18, 230-239. Food and Drug Administration Pesticide Program Residue Monitoring 2003; U.S. Food and Drug Administration, Center for Food Safety and Applied Nutrition, Office of Plant and Dairy Foods: Washington, DC, 1993-2003. Pesticide Data Program Annual Summary, Calendar Year 2006; U.S. Department of Agriculture, Agricultural Marketing Service: Washington, DC, 2007. Relyea, R. A. The Impact of Insecticides and Herbicides on the Biodiversity and Productivity of Aquatic Communities. Ecolo. Appl. 2005, 15 (2), 618-627. Intergrated Risk Information System, 2,4-Dichlorphenoxyacetic Acid (2,4-D) (CASRN 94-75-7); U.S. Environmental Protection Agency. http://epa.gov/ncea/iris/subst/0150.htm (assessed April 2008), updated Jan 2008. ACGIH. TLVs and BEIs, Based on the Documentation of the Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices; American Conference of Governmental Industrial Hygienists Worldwide: Cincinnati, 2003; p 24. Drinking Water Contaminants; U.S. Environmental Protection Agency. http://www.epa.gov/safewater/contaminants/index.html (accessed May 2008), updated Feb 2008.
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For more information contact: NPIC Oregon State University, 310 Weniger Hall, Corvallis, OR 97331-6502 Phone: 1-800-858-7378 Email: [email protected] Fax: 1-541-737-0761 Web: npic.orst.edu
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