Response to the NRCD Petition 

 • Title 

 • Executive Summary 

 • Introduction 

 • Not an Endrocrine Disruptor 

 • Neurodevelopmental 

 • Mutagenic Effects 

 • Exposures 

 • Conclusion 

 • References 

         

References

  1. Alexander, B.H., Mandel, J.S., Baker, B.A., Burns, C.J., Bartels, M.J., Acquavella, J.F., Gustin, C. 2007. Biomionitoring of 2,4-dichlorophenoxyacetic acid exposure and dose in farm families. Environmental Health Perspectives 115(3):370-376.
  2. Arbuckle, T. E., Burnett, R., Cole, D., Teschke, K., Dosemeci, M., Bancej, C., Zhang, J. 2002. Predictors of herbicide exposure in farm applicators. Int Arch Occup Environ Health 75, 406-414.
  3. Blair, R.M., Fang, H., Branham, W.S., Hass, B.S., Dial, S.L., Moland, C.L., Tong, W., Shi, L., Perkins, R., Sheehan, D.M. 2000. The estrogen receptor relative binding affinities of 188 natural and xenochemicals: Structural diversity of ligands. Toxicological Sciences 54:138-153.
  4. Bon, E., Barbe, U., Nunez Rodriguez, J., Cuisset, B., Pelissero, C, Sumpter, J.P., LeMenn, F. 1997. Plasma vitellogenin levels during the annual reproductive cycle of the female rainbow trout (Oncorhynchus mykiss): Establishment and validation of an ELISA. Comp. Biochem. Physiol. 117B(1):75-84.
  5. Bortolozzi, A., Evangelista de Duffard, A.M., Dajas, F., Duffard, R., Silveira, R. 2001. Intracerebral administration of 2,4-dichlorophenoxyacetic acid induces behavioral and neurochemical alterations in the rat brain. Neurotoxicolgy 22(2):221-232
  6. Charles, J.M., Cunny, H.C., Wilson R.D., and Bus, JS. 1996. Comparative Subchronic Studies on 2,4-Dichlorophenoxyacetic Acid, Amine and Ester in Rats. Fund. Appl. Toxicol. 33: 161-165. MRID No. 45761213
  7. Charles, J.M., Cunny, H.C., Wilson, R.D., Bus, J.S., Lawlor, T.E., Cifone, M.A., Fellows, M., and Gollapudi, B. 1999a. Ames Assays and Unscheduled DNA Synthesis Assays on 2,4-Dichlorophenoxyacetic Acid and its Derivatives. Mutation Research 444: 207-216. MRID No. 45761208
  8. Charles, J.M., Cunny, H.C., Wilson, R.D., Bus, J.S., Ivett, J.L., Murli, H., and Gollapudi, B. 1999b. In Vivo Micronucleus Assays on 2,4-Dichlorophenoxyacetic Acid and its Derivatives. Mutation Research 444: 227-234. MRID No. 45761209 Charles, J.M., Hanley, T.R. Jr., Wilson, R.D., van Ravenzwaay, B., Bus, J.S. 2001. Developmental toxicity studies in rats and rabbits in 2,4-dichlorophenoxyacetic acid and its forms. Tox.Sci. 60. 121-131.
  9. Duffard, R., Bortolozzi, A., Ferri, A., Garcia, G., Evangelista de Duffard, A.M. 1995. Developmental neurotoxicity of the herbicide 2,4-dichlorophenoxyacetic acid. Neurotoxicoogy 16(4):764
  10. Duffard, R., Garcia, G., Rosso, S., Bortolozzi, A., Madariaga, M., di Paolo, O., Evangelista de Duffard, A.M. 1996. Central nervous system myelin deficit in rats exposed to 2,4-dichlorophenoxyacetic acid throughout lactation. Neurotoxicol Teratol. 18(6):691-696
  11. Evangelista de Duffard, A.M., Bortolozzi, A., Duffard, R., 1995. Altered behavioral responses in 2,4-dichlorophenoxyacetic acid treated and amphetamine challenged rats. Neurotoxicology 16(3)470-488.
  12. Feldmann, R.G., Maibach, H.I.. 1974. Percutaneous penetration of some pesticides and herbicides in man. Toxicology and Applied Pharmacology 28, 126-132.
  13. Ferri, A., Duffard, R., Evangelista de Duffard, A.M.. 2007. Selective oxidative stress in brain area of neonate rats exposed to 2,4-dichlorophenoxyacetic acid through mother’s milk. Drug Chem Toxicology 30:17-30.
  14. Figgs, L.W., Holland, N.T., Rothmann, N., Zahm, S.H., et al. 2000. Increased lymphocyte replicative index following 2,4-dichlorophenoxyacetic acid herbicide exposure. Cancer Causes Control. 11(4):373-380.
  15. Garabrant, D.H., Philbert, M.A. 2002. Review of 2,4-dichlorophenoxyacetic acid (2,4-D) Epidemiology and Toxicology. Univ. of Michigan School of Public Health.. Critical Reviews in Toxicology 32(4):233-257.
  16. Gollapudi, B.B., Charles, J.M., Linscombe, V.A., Day, S.J., and Bus, J.S. 1999. Evaluation of the genotoxicity of 2,4-dichlorophenoxyacetic acid and its derivatives in mammalian cell cultures. Mutat. Res. 444:217-225. MRID No. 45761210
  17. Garcia, G.B., Tagliaferro, P., Ferri, A., De Duffard, A.M.E., Duffard, R., Brusco, A. 2004. Study of tyrosine hydroxylase immunoreactive neurons in neonate rats lactationally exposed to 2,4-dichlorophenoxyacetic acid. Neuro Toxicology 25:951-957.
  18. Garcia, G.B., Konjuh, C., Duffard, R.O., Evangelista de Duffard, A.M.E. 2006. Dopamine β-hydroxylase immunohistochemical study in the locus coeruleus of neonate rats exposed to 2,4-dichlorophenoxyacetic acid through mother’s milk. Drug Chem Toxicol. 29(4):435-442.
  19. Garry, V.F., Schreinemachers, D., Harkins, M.E., Griffith, J. 1996. Pesticide Appliers, Biocides, and Birth Defects in Rural Minnesota Volume. Environmental Health Perspectives 104(4):394-399.
  20. Garry, V.F., Hawkins, M.E., Erickson, L.L., Long-Simpson, L.K., Holland, S.E., Burroughs, B.L. 2002. Birth defects, season of conception, and sex of children born to pesticide applicators living in the Red River Valley of Minnesota, USA. Env.Hlth.Perspect. 110 (Suppl.31): 441-449
  21. Giasson, B.I., Lee, V.M. 2000. A new link between pesticides and Parkinson’s disease. Nature Neuroscience 3:1227–1228.
  22. Grover, Cessna, A.J., Muir, N.I., Riedel, S., Franklin, C., Yoshida, K. 1986. Factors affecting the exposure of ground-rig applicators to 2,4-dimethylamine salt. Arch. Environ. Contam. Toxicol. 15: 677-686.
  23. Harris, S.A., Solomon, K.R. 1992. Percutaneous penetration of 2,4-dichlorophenoxyacetic acid and 2,4-d dimethylamine salt in human volunteers. J. Toxicol. Environ. Health. 36:233-240.
  24. Hines, C. J., Deddens, J.A., Tucker, S.P., Hornung, R.W. 2001. Distributions and Determinants of Pre-Emergent Herbicide Exposures among Custom Applicators. Annals of Occupational Hygiene 45, no. 3: 227-239.
  25. Holland, N.T., Duramad, P., Rothmann, N., Figgs, L.W., et al. 2002. Micronucleus frequency and proliferation in human lumphocytes after exposure to herbicide 2,4-dichlorophenoxyacetic acid in vitro and in vivo. Mutation Research 521:165-178.
  26. Howard, Phillip H. (ed.). 1991. Handbook of Environmental Fate and Exposure Data for Organic Chemicals. pp 145-156. Lewis Publishers, Chelsea, MI.
  27. Hurst, M.R., Sheahan, D.A. 2003. The potential for oestrogenic effects of pesticides in headwater streams in the UK. The Science of the Total Environment 301:87-96.
  28. Hwang, U-G. 2002. Effect of 2,4-dichlorophenoxyacetic acid on vitellogenin synthesis and E2-ER binding affinity or hepatocytes in rainbow trout (Oncorhynchus mykiss). Han’guk Yangsik Hakhoechi 15(1):31-37. (English abstract)
  29. Jung, J., Ishida, K., Nishihara, T. 2004. Anti-estrogenic activity of fifty chemicals evaluated by in vitro assays. Life Sciences 74:3065-3074.
  30. Jungbauer, A., Beck, V. 2002. Yeast reporter system for rapid determination of estrogenic activity. J. Chromatography B 777:167-178. Kim, H.J. Kim, W.D, et al. 2002 Mechanism of phenoxy compounds as an endocrine disruptor. J. Toxicology Public Health 18:331-339.
  31. Kojima, H., Katsura, E., Takeuchi, S., Niiyama, K., Kobayashi, K. 2004. Screening for estrogen and androgen receptor activities in 200 pesticides by in vitro reporter gene assays using Chinese hamster ovary cells. Environ. Health Perspectives 112(5):524-531.
  32. Konjuh, C., Garcia, G., Lopez, L., Evangelista de Duffard, A.M., Brusco, A., Duffard, R. 2008. Neonatal hypomyelination by the herbicide 2,4-dichlorophenoxyacetic acid. Chemical and ultrastructural studies in rats. Toxicol Sci. 104(2):332-340.
  33. Kramer, V. Blewitt, C., Gersich, M. 2008. Comments on ‘‘Evaluation of Estrogenic Activities of Aquatic Herbicides and Surfactants Using a Rainbow Trout Vitellogenin Assay. Tox.Sci. 104: 228-230.
  34. Lavy, T.L., L.A. Norris, J.D. Mattice and D.B. Marx. 1987. Exposure of forest ground workers to 2,4-D, picloram and dichlorprop. Environmental Toxicology and Chemistry, Vol. 6, pp.209-244.
  35. Lerda, D., Rizzi, R. 1991. Study of reproductive function in persons occupationally exposed to 2,4-D. Mutation Research 262:47-50
  36. Lin, N., Garry, V.F. 2000. In vitro studies of cellular and molecular developmental toxicity of adjuvants, herbicides, and fungicides commonly used in Red River Valley, Minnesota. J. Toxicol. Environ. Health Part A 60:423-439.
  37. Madrigal-Bujaidar, E., Hernandez-Ceruelos, A., Charmorro, G. 2001. Induction of sister chromatid exchanges by 2,4-dichlorophenoxyacetic acid in somatic and germ cells of mice exposed in vivo. Food Chem Toxicol 39(9):942-946.
  38. Marty, M.S., S.A. Saghir, A.J. Clark, C.L. Zablotny, J.S. Bus, A.W. Perala, B.L. Yano and B.H Neal. 2009. A dietary dose range-finding and toxicokinetic (tk) study of 2,4-dichlorophenoxyacetic acid (2,4-D) in adult crl:cd(sd) rats and their offspring: II. Toxicity. SOT poster.
  39. Moody, R.P., Franklin, C.A., Ritter, L., Maibach, H.I., 1990. Dermal absorption of the phenoxy herbicides 2,4-D, 2,4-D amine, 2,4-D isooctyl, and 2,4,5-T in rabbits, rats, rhesus monkeys, and humans: a cross-species comparison. J. Toxicol. Environ. Health 29, 237–245, Erratum in: J. Toxicol. Environ. Health (1991). 32 107-108.
  40. Moody,R.P., Nadeau, B., 1992. Effect of the mosquito repellent DEET and long-wave ultraviolet radiation on permeation of the herbicide 2,4-D and the insecticide DDT in natural rubber gloves. Am Industrial Hygiene Assoc Journal 53:436-441.
  41. Moody, R.P., Wester, R.C., Melendres, J.L., Maibach, H.I., 1992. Dermal absorption of the phenoxy herbicide 2,4-D dimethylamine in humans: effect of DEET and anatomic site. J. Toxicol. Environ. Health 36, 241–250.
  42. Morgan, M.K., L.S. Sheldon, K.W. Thomas, P.O. Egegly, C.W. Croghan, P.A. Jones, J.C. Chuang, and N.K. Wilson. 2008. Adult and children’s exposure to 2,4-D from multiple sources and pathways. J. Exposure of Science and Environmental Epidemiology 18, 486-494.
  43. Nishihara, T., J. Nishikawa, T. Kanayama, F. Dakeyama, K. Saito, M. Imagawa, S. Takatori, Y. Kitagawa, S. Hori, H. Utsumi. 2000. Estrogenic activities of 517 chemicals by yeast two-hybrid assay. J. Health Science 46(4):282-298.
  44. Nishioka, M.G., H.M. Burkholder, M.C. Brinkman, and S.M. Gordon. 1996. Measuring transport of lawn-applied herbicide acids from turf to home: correlation of dislodgeable 2,4-D turf residues with carpet dust and carpet surface residues. Environ. Sci. Technol. 30, 3313-3320.
  45. NRDC 2008. Natural Resources Defense Council’s petition to revoke all tolerances and cancel all registrations for the pesticide 2,4-D. (submission to EPA Nov. 6, 2008)
  46. Oakes, D.J., Webster, W.S., Brown-Woodman, P.D.C., Ritchie, H.E.. 2002. A study of the potential for a herbicide formulation containing 2,4-D and picloram to cause male-mediated developmental toxicity in rats. Tox.Sci. 68: 200-206.
  47. Pelletier O., Ritter, L., Caron, J., Somers, D. 1989. Disposition of 2,4-dichlorphenoxyacetic acid dimethylamine salt by Fischer 344 rats dosed orally and dermally. J Toxicol Environ Health 28:221-234.
  48. Petit, F., Le Goff, P., Cravedi, J-P, Valotaire, Y., Pakdel, F. 1997. Two complementary bioassays for screening the estrogenic potency of xenobiotics; recombinant yeast for trout estrogen receptor and trout hepatocyte cultures. J. Molecular Endocrinology 19:321-335.
  49. Rawlings, N.C., Cook, S.J., Waldbillig, D. 1998. Effects of the pesticides carbofuran, chlorpyrifos, dimethoate, lindane, triallate, trifluralin, 2,4-D and pentachlorophenol on the methbolic endocrine and reproductive endocrine system in ewes. J. Toxicol Environ Hlth 54:21-36.
  50. Rodwell, D. E., Brown, W.R. 1986. A Dietary Two-Generation Reproduction Study in Fischer 344 Rats with 2,4-Dichlorophenoxyacetic Acid. Project No. WIL-81137. Unpublished study, WIL Research Laboratories, Inc., Ashland, OH. MRID # 00163996.
  51. Ross, R.H., Driver, J.H., Harris, S.A., Maibach, H.I. 2005. Dermal absorption of 2,4-D: a review of species differences. Regulatory Toxicology and Pharmacology 41: 82-91.
  52. Rosso, S.B., Garcia, G.B., Madariaga, M.J., Evangelista de Duffard, A.M., Duffard, R.O. 2000. 2,4-Dichlorophenoxyacetic acid in developing rats alters behaviour, myelination and regions brain gangliosides pattern. Neurotoxicology 21(1-2):155-163.
  53. Saghir, S.A., Mendrala, A.L., Bartels, M.J., Day, S.J., Hansen, S.C., Sushynski, J.M., and Bus, J.S. 2006. Strategies to assess systemic exposure of chemicals in subchronic/chronic diet and drinking water studies. Toxicol Appl Pharmacol 211, 245-260.
  54. Saghir, S.A., Marty, M.S., Clark, A.J., Zablotny, C.L., Bus, J.S., Peral, A.W., Yano, B.L., Neal, B.H. 2009. A dietary dose range-finding and toxicokinetic (tk) study of 2,4-dichlorophenoxyacetic acid (2,4-D) in adult crl:cd(sd) rats and their offspring: I. Toxicokinetics. SOT poster.
  55. Soto, A.M., Sonnenschein, C., Chung K.L., Fernandez M.F., Olea N., Serrano F.O. 1995. The E-SCREEN assay as a tool to identify estrogens: An update on estrogenic environmental pollutants. Environ. Health Perspectives Supplements 103(S7):113-122
  56. Spiteri, I.D., Guillette, L.J. Jr, Crain, D.A. 1999. The functional and structural observations of the neonatal reproductive system of alligators exposed in ovo to atrazine, 2,4-D, or estradiol. Toxicol. Ind. Hlth. 15: 181-186.
  57. Sturtz, N., Evangelista de Duffard, A.M., Duffard, R. et al. 2000. Detection of 2,4-dichlorophenoxyacetic acid (2,4-D) residues in neonates breast-fed by 2,4-D exposed dams. Neurotoxiciology 2000 Feb-Apr;21(1-2):147-154.
  58. Sturtz, N., Bongiovanni, B., et al. 2006. Detection of 2,4-dichlorophenoxyacetic acid in rat milk of dams exposed during lactation and milk analysis of their major components. Food and Chem Toxicol 44:8-16.
  59. USEPA. 2007. Generic and Product Specific Data Call-in Notice. March 2007
  60. USEPA. 2005. Reregistration Eligibility Decision for 2,4-D. EPA 738-R-05-002 (RED). June 2005.
  61. USEPA Memorandum. 2002. Office of Prevention, Pesticides, and Toxic Substances, 2,4-D. Extension of Time-Limited Tolerance on Soybean Seed, Request from Registration Division (RD) for an Updated Human Health Risk Assessment. p12-13 (January 31, 2002)
  62. USEPA Memorandum. 2004a. 2,4-D: Response to Public Comments [PC Code 030001, DP Barcode D307717]. December 16, 2004
  63. USEPA Memorandum. 2004b. 2,4-D. HED’s Human Health Risk Assessment for the Reregistration Eligibility Decision (RED). PC Code 030001; DP Barcode D287199. March 01, 2004.
  64. USEPA Memorandum. 2005. 2,4-D: Response to Phase 5 Public Comments [PC Code 030001, DP Barcode D315562. June 7, 2005. US Federal Register. 2005. Vol. 70, No. 153 /Wednesday, August 10, 2005 /Rules and Regulations 46706 – 46740. Order Denying Objections to Issuance of Tolerances.
  65. US Federal Register. 2006. Vol. 71, No. 148 /Wednesday, August 2, 2006 /Rules and Regulations 43906 - 43924. Order Denying Petition To Revoke Tolerances.
  66.  US Federal Register. 2007a. Vol. 72, No. 108 /Wednesday, June 6, 2007 /Rules and Regulations 31221 - 31237. Proposed Tolerance Actions.
  67. US Federal Register. 2007b. Vol. 72, No. 176 /Wednesday, September 12, 2007 /Rules and Regulations 52013 – 52019. 2,4-D Tolerance Actions.
  68. US Federal Register. 2007c. Vol. 72, No. 207 /Friday, October 26, 2007 /Rules and Regulations 60934 - 60988. 2,4-D Tolerance Actions.
  69. US Federal Register. 2007d. Vol. 72, No. 233 / Wednesday, December 5, 2007 / Proposed Rules and regulations 68622 - 68698. Order Denying NRDC’s Petition to Revoke All DDVP Tolerances.
  70. van Ravenzwaay, B., Hardwick, T. D., Needham, D., Pethen, S., and Lappin, G. J., 2003. Comparative metabolism of 2,4-dichlorophenoxyacetic acid (2,4-D) in rat and dog. Xenobiotica 33, 805-821.
  71. Vonier, P. M., C.D. Andrew, J.A. Mclachlan, L.J. Guillette, Jr.; S.F. Arnold. 1996. Interaction of environmental chemicals with the estrogen and progesterone receptors from the oviduct of the American alligator. Environmental Health Perspectives, 104(12):1318-1322.
  72. Wester, R.C., J. Melendres, L. Sedik, H. Maibach, and J.E. Riviere. 1998. Percutaneous absorption of Salicylic Acid, Theophylline, 2,4-D Dimethylamine, Diethyl Hexyl Phthalic Acid, and p-Aminobenzoic Acid in the isolated perfused procine skin flap compared to man in vivo. Toxicology and Applied Pharmacology 151, 159-165.
  73.  Xie, L., Thrippleton, K., Irwin, M. A., Siemering, G. S., Mekebri, A., Crane, D., Berry, K., and Schlenk, D. (2005). Evaluation of estrogenic activities of aquatic herbicides and surfactants using a rainbow trout vitellogenin assay. Toxicol. Sci. 87, 391–398.
  74. Yeary, R.A., 1986. Urinary excretion of 2,4-D in commercial lawn specialists. Appl. Ind. Hyg. 3, 119-121.
  75. Zeljezic, D., Garaj-Vrhovac, V. 2004. Chromosomal aberrations, micronuclei and nuclear buds induced in human lymphocytes by 2,4-dichlorophenoxyacetic acid pesticide formulation. Toxicology 200:39-47.

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