Review of genotoxicity studies of glyphosate and glyphosate-based formulations

Critical Reviews in Toxicology

Volumn 43, Issue 4, 2013, Pages 283-315

  Kier, Larry D ^a   Kirkland, David J ^b  

^a Private Consultant   (United States)

^b Kirkland Consulting   (United Kingdom)

Author keywords

Formulation; Genotoxicity; Glyphosate; Mutagenicity; Roundup

Indexed keywords

GLYPHOSATE;

AMES TEST; APOPTOSIS; CELL ASSAY; CYTOKINESIS; CYTOTOXICITY; DNA DAMAGE; ERYTHROCYTE; ESCHERICHIA COLI; GENE MUTATION; GENOTOXICITY; HUMAN; MICRONUCLEUS; MUTAGENICITY; NONHUMAN; REVERTANT; REVIEW; SALMONELLA TYPHIMURIUM; SISTER CHROMATID EXCHANGE; STRUCTURAL CHROMOSOME ABERRATION; STRUCTURE ACTIVITY RELATION;

ANIMALS; DNA DAMAGE; DOSE-RESPONSE RELATIONSHIP, DRUG; ENDPOINT DETERMINATION; ENVIRONMENTAL EXPOSURE; GLYCINE; HERBICIDES; HUMANS; MUTAGENICITY TESTS;

EID: 84877596435     PISSN: 10408444     EISSN: 15476898     Source Type: Journal    
DOI: 10.3109/10408444.2013.770820     Document Type: Review

References (175)

1. Aaron CS, Bolcsfoldi G, Glatt HR, et al. (1994). Mammalian cell gene mutation assays working group report. Mutat Res, 312, 235-9. (Pubitemid 24187386)
2. Acquavella JF, Alexander BH, Mandel JS, et al. (2004). Glyphosate biomonitoring for farmers and their families: results from the Farm Family Exposure Study. Environ Health Persp, 112, 321-6. (Pubitemid 38351394)
3. Akanuma M. (1995a). HR-001: DNA Repair Test (Rec-Assay). Unpublished Regulatory Study. Report Identification Number: IET 94-0141.
4. Akanuma M. (1995b). HR-001 reverse mutation test. Unpublished Regulatory Study. Report Identification Number: IET 94-0142.
5. Akcha F, Spagnol C, Rouxel J. (2012). Genotoxicity of diuron and glyphosate in oyster spermatozoa and embryos. Aquat Toxicol, 106-107, 104-13.
6. Alvarez-Moya C, Silva MR, Arambula AMV, et al. (2011). Evaluation of genetic damage induced by glyphosate isopropylamine salt using Tradescantia bioassays. Genet Mol Biol, 34, 127-30.
7. Amer SM, Aly FAE, Farghaly AA, Ibrahim AAE. (2006). In vitro and in vivo evaluation of the genotoxicity of the herbicide glyphosate in mice. Bull Nat Res Centre (Egypt), 31, 427-46.
8. Amin F, Bowen ID, Szegedi Z, et al. (2000). Apoptotic and nonapoptotic modes of programmed cell death in MCF-7 human breast carcinoma cells. Cell Biol Int, 24, 253-60.
9. Anadon A, Martinez-Larranaga MR, Martinez MA, et al. (2009). Toxicokinetics of glyphosate and its metabolite aminomethyl phosphonic acid in rats. Toxicol Lett, 190, 91-5.
10. Anderson D, Yu TW, Phillips BJ, Schmezer P. (1994). The effect of various antioxidants and other modifying agents on oxygen-radicalgenerated DNA damage in human lymphocytes in the COMET assay. Mutat Res, 307, 261-71. (Pubitemid 24155057)
11. BBA (Federal Biological Center for Agriculture and Forestry-Germany). (1998-2000). Monograph on the active substance glyphosate and its IPA-, Na-and NH4-salts. Annex to the European Commission report for the active substance glyphosate.
12. Benigni R. (1989). Analysis of the National Toxicology Program data on in vitro genetic toxicity tests using multivariate statistical methods. Mutagenesis, 4, 412-19. (Pubitemid 20005775)
13. Boos G, Stopper H. (2000). Genotoxicity of several clinically used topoisomerase II inhibitors. Toxicol Lett, 116, 7-16. (Pubitemid 30440762)
14. Bosch B, Manas F, Gorla N, Aiassa D. (2011). Micronucleus test in post metamorphic Odontophrynus cordobae and Rhinella arenarum (Amphibia: Anura) for environmental monitoring. J Tox Env Health Sci, 3, 155-63.
15. Bradley MO, Hsu IC, Harris CC. (1979). Relationship between sister chromatid exchange and mutagenicity, toxicity and DNA damage. Nature, 282, 318-20. (Pubitemid 10198533)
16. Brendler-Schwaab S, Hartmann A, Pfuhler S, Speit G. (2005). The in vivo comet assay: use and status in genotoxicity testing. Mutagenesis, 20, 245-54. (Pubitemid 41399464)
17. Brewster DW, Warren J, Hopkins 2nd WE. (1991). Metabolism of glyphosate in Sprague-Dawley rats: tissue distribution, identification, and quantitation of glyphosate-derived materials following a single oral dose. Fundam Appl Toxicol, 17, 43-51.
18. Burlinson B, Tice RR, Speit G, et al. (2007). Fourth International Workshop on Genotoxicity Testing: Results of the in vivo comet assay workgroup. Mutat Res, 627, 31-5. (Pubitemid 46091764)
19. Callander RD. (1996). Glyphosate acid: an evaluation of mutagenic potential using S. Typhimurium and E. Coli. Unpublished Regulatory Study. Report Identification Number: CTL/P/4874.
20. Callander RD. (1999). Potassium salt of glyphosate: bacterial mutation assay in S. Typhimurium and E. Coli. Unpublished Regulatory Study. Report Identification Number: CTL/P/6184.
21. Camolesi MR. (2009). [Glyphosate 480 g/l liquid formulation] Bacterial Reverse Mutation Test (Ames Test). Unpublished Regulatory Study. Report Identification Number: RL8563/2008 6.0AM-B.
22. Camolesi MR. (2010). MON 77280 Bacterial Reverse Mutation Test (Ames Test). Unpublished Regulatory Study. Report Identification Number: XX-2010-501.
23. Catoyra JM. (2009). [Reverse Mutation Assay of Roundup Full II M in Salmonella typhimurium]. Unpublished Regulatory Study. Report Identification Number: Study Number XX-2011-0622.
24. Cavalcante DG, Martinez CB, Sofia SH. (2008). Genotoxic effects of Roundup on the fish Prochilodus lineatus. Mutat Res, 655, 41-6.
25. Cavas T, Konen S. (2007). Detection of cytogenetic and DNA damage in peripheral erythrocytes of goldfish (Carassius auratus) exposed to a glyphosate formulation using the micronucleus test and the comet assay. Mutagenesis, 22, 263-8. (Pubitemid 47216616)
26. Chruscielska K, Graffstein B, Szarapinska-Kwaszewska J, et al. (2000). Glyphosate evaluation of chronic activity and possible farreaching effects. Part 2. Studies on mutagenic activity. Pestcydy, 2000, 21-5.
27. Cifone MA, Myhr B, Eiche A, Bolcsfoldi G. (1987). Effect of pH shifts on the mutant frequency at the thymidine kinase locus in mouse lymphoma L5178Y TK\+/-cells. Mutat Res, 189, 39-46.
28. Cimino MC. (2006). Comparative overview of current international strategies and guidelines for genetic toxicology testing for regulatory purposes. Environ Mol Mutagen, 47, 362-90. (Pubitemid 43900290)
29. Clay P. (1996). Glyphosate acid: L5178Y TK\+/-mouse lymphoma gene mutation assay. Unpublished Regulatory Study. Report Identification Number: CTL/P/4991.
30. Conners DE, Black MC. (2004). Evaluation of lethality and genotoxicity in the freshwater mussel Utterbackia imbecillis (Bivalvia: Unionidae) exposed singly and in combination to chemicals used in lawn care. Arch Environ Contam Toxicol, 46, 362-71. (Pubitemid 38326390)
31. Costa KC. (2008). Evaluation of the mutagenic potential of GLYPHOSATE TECHNICAL by micronucleus assay in mice. Unpublished Regulatory Study. Report Identification Number: 3996.402.395.07.
32. Coutinho do Nascimento A, Grisolia C. (2000). Comparative analysis between micronuclei tests in mice and in peripheral erythrocytes of Oreochromis niloticus in evaluation of mutagenic potential of the agrotoxins deltamethrin, dicofol, glyphosate, and imazapyr. Pesticides: R Ecotoxicol E Meio Ambiente, Curitiba, 10, 41-8.
33. de Castilhos Ghisi N, Cestari, MM. (2012). Genotoxic effects of the herbicide Roundup in the fish Corydoras paleatus (Jenyns 1842) after short-term, environmentally low concentration exposure. Environ Monit Assess. doi: 10.1007/s10661-012-2783-x.
34. Decuyper-Debergh D, Piette J, Laurent C, van de Vorst A. (1989). Cytotoxic and genotoxic effects of extracellular generated singlet oxygen in human lymphocytes in vitro. Mutat Res, 225, 11-14. (Pubitemid 19034133)
35. Delaney CA, Pavlovic D, Hoorens A, et al. (1997). Cytokines induce deoxyribonucleic acid strand breaks and apoptosis in human pancreatic islet cells. Endocrinology, 138, 2610-14. (Pubitemid 27215269)
36. Dimitrov BD, Gadeva PG, Benova DK, Bineva MV. (2006). Comparative genotoxicity of the herbicides Roundup, Stomp and Reglone in plant and mammalian test systems. Mutagenesis, 21, 375-82. (Pubitemid 44691126)
37. Djelic N, Spremo-Potparevic B, Bajic V, Djelic D. (2006). Sister chromatid exchange and micronuclei in human peripheral blood lymphocytes treated with thyroxine in vitro. Mutat Res, 604, 1-7.
38. Durward R. (2006). Glyphosate technical: micronucleus test in the mouse. Unpublished Regulatory Study. Report Identification Number: 2060/014.
39. Duthie SJ, Johnson W, Dobson VL. (1997). The effect of dietary flavonoids on DNA damage (strand breaks and oxidised pyrimidines) and growth in human cells. Mutat Res, 390, 141-51. (Pubitemid 27230219)
40. Eastmond DA, Hartwig A, Anderson D, et al. (2009). Mutagenicity testing for chemical risk assessment: update of the WHO/IPCS Harmonized Scheme. Mutagenesis, 24, 341-9.
41. Eckl PM, Ortner A, Esterbauer H. (1993). Genotoxic properties of 4-hydroxyalkenals and analogous aldehydes. Mutat Res, 290, 183-92. (Pubitemid 23355129)
42. EFSA. (2011). Scientific opinion on genotoxicity testing strategies applicable to food and feed safety assessment. EFSA Scientific Committee. EFSA J, 9, 2379.
43. Erexson GL. (2003a). In vivo mouse micronucleus assay with MON 78239. Unpublished Regulatory Study. Report Identification Number: CV-2002-187.
44. Erexson GL. (2003b). In vivo mouse micronucleus assay with Mon 78634. Unpublished Regulatory Study. Report Identification Number: CV-2002-189.
45. Erexson GL. (2006). In vivo mouse bone marrow micronucleus assay. Unpublished Regulatory Study. Report Identification Number: CV-2005-120.
46. Flugge C. (2009a). Mutagenicity study of glyphosate TC in the Salmonella Typhimurium reverse mutation assay (in vitro). Unpublished Regulatory Study. Report Identification Number: 23916.
47. Flugge C. (2009b). Micronucleus test of glyphosate TC in bone marrow cells of the CD rat by oral administration. Unpublished Regulatory Study. Report Identification Number: 23917.
48. Flugge C. (2010a). Mutagenicity study of trop M (glyphosate 480) in the Salmonella Typhimurium reverse mutation assay (in vitro). Unpublished Regulatory Study. Report Identification Number: 24753.
49. Flugge C. (2010b). Mutagenicity study of glyphosate TC in the Salmonella Typhimurium reverse mutation assay (in vitro). Unpublished Regulatory Study. Report Identification Number: 24880.
50. Flugge C. (2010c). Micronucleus test of trop M (glyphosate 480) in bone marrow cells of the NMRI mouse by oral administration. Unpublished Regulatory Study. Report Identification Number: 24754.
51. Flugge C. (2010d). Mutagenicity study of [glyphosate 757 g/kg granular formulation] in the Salmonella Typhimurium reverse mutation assay (in vitro). Unpublished Regulatory Study. Report Identification Number: 25631.
52. Flugge C. (2010e). Micronucleus test of [glyphosate 757 g/kg granular formulation] in bone marrow cells of the CD rat by oral administration. Unpublished Regulatory Study. Report Identification Number: 25632.
53. Folmar L, Sanders H, Julin A. (1979). Toxicity of the herbicide glyphosate and several of its formulations to fish and aquatic invertebrates. Arch Environ Contam Toxicol, 8, 269-78. (Pubitemid 9144259)
54. Fox V. (1998). Glyphosate acid: in vitro cytogenetic assay in human lymphocytes. Unpublished Regulatory Study. Report Identification Number: CTL/P/6050.
55. Fox V, Mackay JM. (1996). Glyphosate acid: mouse bone marrow micronucleus test. Unpublished Regulatory Study. Report Identification Number: SM0796.
56. Gava MA. (2000). Evaluation of the mutagenic potential of the test substance GLIFOSTO IPA TECNICO NUFARM by micronucleus assay in mice. Unpublished Regulatory Study. Report Identification Number: RF-G12.022/00.
57. Gieseler F, Bauer E, Nuessler V, et al. (1999). Molecular effects of topoisomerase II inhibitors in AML cell lines: correlation of apoptosis with topoisomerase II activity but not with DNA damage. Leukemia, 13, 1859-63. (Pubitemid 29535272)
58. Giesy JP, Dobson S, Solomon KR. (2000). Ecotoxicological risk assessment for Roundup-Herbicide. Rev Environ Contam Toxicol, 167, 35-120.
59. Glei M, Klenow S, Sauer J, et al. (2006). Hemoglobin and hemin induce DNA damage in human colon tumor cells HT29 clone 19A and in primary human colonocytes. Mutat Res, 594, 162-71. (Pubitemid 43170996)
60. Gohre K, Casida JE, Ruzo LO. (1987). N-Oxidation and cleavage of the amino acid derived herbicide glyphosate and anilino acid of the insecticide fluvalinate. J Agric Food Chem, 35, 386-92.
61. Grisolia CK. (2002). A comparison between mouse and fish micronucleus test using cyclophosphamide, mitomycin C and various pesticides. Mutat Res, 518, 145-50. (Pubitemid 46135376)
62. Guilherme S, Gaivao I, Santos MA, Pacheco M. (2010). European eel (Anguilla anguilla) genotoxic and pro-oxidant responses following short-term exposure to Roundup-a glyphosate-based herbicide. Mutagenesis, 25, 523-30.
63. Guilherme S, Gaivao I, Santos MA, Pacheco M. (2012). DNA damage in fish (Anguilla anguilla) exposed to a glyphosate-based herbicide-elucidation of organ-specificity and the role of oxidative stress. Mutat Res, 743, 1-9.
64. Hartmann A, Pfuhler S, Dennog C, et al. (1998). Exercise-induced DNA effects in human leukocytes are not accompanied by increased formation of 8-hydroxy-2'-deoxyguanosine or induction of micronuclei. Free Radic Biol Med, 24, 245-51. (Pubitemid 28008802)
65. Hartmann A, Schumacher M, Plappert-Helbig U, et al. (2004). Use of the alkaline in vivo Comet assay for mechanistic genotoxicity investigations. Mutagenesis, 19, 51-9. (Pubitemid 38088395)
66. Helal A, Moussa H. (2005). Chromosomal aberrations induced by glyphosate isopropylamine herbicide and trials for diminuting its toxicity using some chemical inactivators and antioxidant. Vet Med J Giza, 53, 169-87.
67. Henderson L, Wolfreys A, Fedyk J, et al. (1998). The ability of the Comet assay to discriminate between genotoxins and cytotoxins. Mutagenesis, 13, 89-94. (Pubitemid 28052511)
68. Heydens WF, Healy CE, Hotz KJ, et al. (2008). Genotoxic potential of glyphosate formulations: mode-of-action investigations. J Agric Food Chem, 56, 1517-23. (Pubitemid 351364091)
69. Holeckova B. (2006). Evaluation of the in vitro effect of glyphosatebased herbicide on boving lymphocytes using chromosome painting. Bull Vet Inst Pulawy, 50, 533-6. (Pubitemid 46385021)
70. Honarvar N. (2005). Micronucleus assay in bone marrow cells of the mouse with glyphosate technical. Unpublished Regulatory Study. Report Identification Number: 872000.
71. Honarvar N. (2008). Glyphosate technical-micronucleus assay in bone marrow cells of the mouse. Unpublished Regulatory Study. Report Identification Number: 1158500.
72. ICH S2(R1). (2011). Guidance on genotoxicitytesting and data interpretation for pharmaceuticals intended for human use. International Conferenece on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. Available from: http://www.ich.org/fileadmin/ Public-Web-Site/ICH-Products/Guidelines/Safety/S2-R1/Step4/S2R1-Step4.pdf [last accessed 27 Aug 2012].
73. Jensen JC. (1991a). Mutagenicity test: Ames Salmonella assay with glyphosate, batch 206-JaK-25-1. Unpublished Regulatory Study. Report Identification Number: 12323.
74. Jensen JC. (1991b). Mutagenicity test: in vitro mammalian cell gene mutation test with glyphosate, batch 206-JaK-25-1. Unpublished Regulatory Study. Report Identification Number: 12325.
75. Jensen JC. (1991c). Mutagenicity test: micronucleus test with glyphosate, batch 206-JaK-25-1. Unpublished Regulatory Study. Report Identification Number: 12324.
76. Jones E. (1999). Potassium salt of glyphosate: mouse bone marrow micronucleus test. Unpublished Regulatory Study. Report Identification Number: CTL/P/6242.
77. Kaya B, Creus A, Yanikoglu A, et al. (2000). Use of the Drosophila wing spot test in the genotoxicity testing of different herbicides. Environ Mol Mutagen, 36, 40-6.
78. Kier LD, Brusick DJ, Auletta AE, et al. (1986). The Salmonella typhimurium/mammalian microsomal assay. A report of the U.S. Environmental Protection Agency Gene-Tox Program. Mutation Res, 168, 69-240.
79. Kiffe M, Christen P, Arni P. (2003). Characterization of cytotoxic and genotoxic effects of different compounds in CHO K5 cells with the comet assay (single-cell gel electrophoresis assay). Mutat Res, 537, 151-68. (Pubitemid 36638637)
80. Kirkland DJ, Aardema M, Banduhn N, et al. (2007). In vitro approaches to develop weight of evidence (WoE) and mode of action (MoA) discussions with positive in vitro genotoxicity results. Mutagenesis, 22, 161-75. (Pubitemid 47355712)
81. Kirkland D, Speit G. (2008). Evaluation of the ability of a battery of three in vitro genotoxicity tests to discriminate rodent carcinogens and non-carcinogens III. Appropriate follow-up testing in vivo. Mutat Res, 654, 114-32.
82. Kirsch-Volders M, Sofuni T, Aardema M, et al. (2003). Report from the in vitro micronucleus assay working group. Mutation Res, 540, 153-63. (Pubitemid 37209943)
83. Kocsis JJ, Harkaway S, Santoyo MC, Snyder R. (1968). Dimethyl sulfoxide: interactions with aromatic hydrocarbons. Science, 160, 427-8.
84. Koller VJ, Furhacker M, Nersesyan A, et al. (2012). Cytotoxic and DNAdamaging properties of glyphosate and Roundup in human-derived buccal epithelial cells. Arch Toxicol, 86, 805-13.
85. Levine SL, Han Z, Liu J, et al. (2007). Disrupting mitochondrial function with surfactants inhibits MA-10 Leydig cell steroidogenesis. Cell Biol Toxicol, 23, 385-400.
86. Lope N. (2008). Reverse mutation assay of Roundup Ultramax (MON 79672) in Salmonella typhimurium. Unpublished Regulatory Study. Report Identification Number: XX-2011-0621.
87. Manas F, Peralta L, Raviolo J, et al. (2009). Genotoxicity of glyphosate assessed by the comet assay and cytogenetic tests. Environ Toxicol Phar, 28, 37-41.
88. Marques MFC. (1999). A micronucleus study in mice for glifosate tecnico nufarm. Unpublished Regulatory Study. Report Identification Number: RF-G12.79/99.
89. Matsumoto K. (1995). HR-001: in vitro cytogenetics test. Unpublished Regulatory Study. Report Identification Number: IET 94-0143.
90. Mecchi MS. (2003a). Salmonella-Escherichia Coli/mammalian-microsome reverse mutation assay with a confirmatory assay. Unpublished Regulatory Study. Report Identification Number: CV-2002-186.
91. Mecchi MS. (2003b). Salmonella-Escherichia Coli/mammalian-microsome reverse mutation assay with a confirmatory assay. Unpublished Regulatory Study. Report Identification Number: CV-2002-188.
92. Mecchi MS. (2008a). Bacterial reverse mutation assay with a confirmatory assay. Unpublished Regulatory Study. Report Identification Number: CV-08-030.
93. Mecchi MS. (2008b). Bacterial reverse mutation assay with a confirmatory assay. Unpublished Regulatory Study. Report Identification Number: CV-08-242.
94. Mecchi MS. (2008c). Salmonella-Escherichia Coli/mammalian-microsome reverse mutation asay with a confirmatory assay with MON 76171. Unpublished Regulatory Study. Report Identification Number: CV-2007-102.
95. Mecchi MS. (2009a). Salmonella-Escherichia coli/mammalian-microsome reverse mutation assay with a confirmatory assay. Unpublished Regulatory Study. Report Identification Number: CV-2007-082.
96. Mecchi MS. (2009b). Salmonella-Escherichia coli/mammalian-microsome reverse mutation assay with a confirmatory assay with MON 76138. Unpublished Regulatory Study. Report Identification Number: CV-2007-094.
97. Michels G, Watjen W, Niering P, et al. (2005). Pro-apoptotic effects of the flavonoid luteolin in rat H4IIE cells. Toxicology, 206, 337-48. (Pubitemid 39601019)
98. Miyaji CK. (2008). Evaluation of the mutagenic potential of the test substance glyphosate technical by reverse mutation assay in Salmonella Typhimurium (Ames test). Unpublished Regulatory Study. Report Identification Number: 3996.401.392.07.
99. Mladinic M, Berend S, Vrdoljak AL, et al. (2009a). Evaluation of genome damage and its relation to oxidative stress induced by glyphosate in human lymphocytes in vitro. Environ Mol Mutagen, 50, 800-7.
100. Mladinic M, Perkovic P, Zeljezic D. (2009b). Characterization of chromatin instabilities induced by glyphosate, terbuthylazine and carbofuran using cytome FISH assay. Toxicol Lett, 189, 130-7.
101. Monroy CM, Cortes AC, Sicard DM, de Restrepo HG. (2005). Cytotoxicity and genotoxicity of human cells exposed in vitro to glyphosate. Biomedica, 25, 335-45.
102. Morita T, Watanabe Y, Takeda K, Okumura K. (1989). Effects of pH in the in vitro chromosomal aberration test. Mutat Res, 225, 55-60. (Pubitemid 19034140)
103. Morita T, Honma M, Morikawa K. (2012). Effect of reducing the top concentration used in the in vitro chromosomal aberration test in CHL cells on the evaluation of industricl chemical genotoxicity. Mutat Res, 741, 52-6.
104. Negro Silva LF. (2009). A17035A-mammalian erythrocyte micronucleus test. Unpublished Regulatory Study. Report Identification Number: RL7459/2008-14.0MN- B.
105. Negro Silva LF. (2011). Glyphosate SL (A13013Z)-mammalian erythrocyte micronucleus test. Unpublished Regulatory Study. Report Identification Number: RL69575MN-B.
106. Nousis, L, Doulias PT, Aligiannis N, et al (2005). DNA protecting and genotoxic effects of olive oil related components in cells exposed to hydrogen peroxide. Free Rad Res, 39, 987-95.
107. OECD 471. (1983). Genetic toxicology: Salmonella typhimurium reverse mutation assay. OECD Guidelines for Testing of Chemicals. Available from: http://www.oecd.org/env/chemicalsafetyandbiosafety/testingofchemicals/45125466. pdf [last accessed 27 Aug 2012].
108. OECD 471. (1997). Bacterial reverse mutation test. OECD guideline for testing of chemicals. Available from: http://www.oecd.org/chemicalsafety/ assessmentofchemicals/1948418.pdf [last accessed 27 Aug 2012].
109. OECD 472. (1983). Genetic toxicology: Escherichia coli reverse mutation assay. Guideline for testing of chemicals. Available from: http://www.oecd.org/ env/chemicalsafetyandbiosafety/testingofchemicals/45125467.pdf [last accessed 27 Aug 2012].
110. OECD 473. (1983). Genetic toxicology: in vitro mammalian cytogenetic test. OECD guideline for the testing of chemicals. Available from: http://www.oecd.org/env/ehs/testing/45125550.pdf [last accessed 27 Aug 2012].
111. OECD 473. (1997). In vitro mammalian chromosome aberration test. OECD guideline for the testing of chemicals. Available from: http://www.oecd- ilibrary.org/environment/test-no-473-in-vitro-mammalianchromosome-aberration- test-9789264071261-en [last accessed 27 Aug 2012].
112. OECD 474. (1983). Genetic toxicology: micronucleus test. OECD guideline for testing of chemicals. Available from: http://www. oecd.org/env/ehs/testing/ 45125573.pdf [last accessed 27 Aug 2012].
113. OECD 474. (1997). Mammalian erythrocyte micronucleus test. OECD guideline for the testing of chemicals. Available from: http://www.oecd.org/ chemicalsafety/assessmentofchemicals/1948442.pdf [last accessed 27 Aug 2012].
114. OECD 475. (1984). Genetic toxicology: in vivo mammalian bone marrow cytogenetic test-chromosomal analysis. OECD guideline for testing of chemicals. Available from: http://www.oecd.org/env/ehs/testing/45125582.pdf [last accessed 27 Aug 2012].
115. OECD 475. (1997). Mammalian bone marrow chromosome aberration test. OECD guideline for the testing of chemicals. Available from: http://www.oecd.org/ chemicalsafety/assessmentofchemicals/1948450.pdf [last accessed 27 Aug 2012].
116. OECD 476. (1984). Genetic toxicology: in vitro mammalian cell gene mutation tests. OECD guideline for testing of chemicals. Available from: http://www.oecd.org/chemicalsafety/testing/45125600.pdf [last accessed 27 Aug 2012].
117. OECD 476. (1997). In vitro mammalian cell gene mutation test. OECD guideline for the testing of chemicals. Available from: http://www.oecd.org/ chemicalsafety/assessmentofchemicals/1948426.pdf [last accessed 27 Aug 2012].
118. OECD 478. (1984). Genetic toxicology: rodent dominant lethal test. oecd guideline for testing of chemicals. Available from: http://www.oecd.org/env/ chemicalsafetyandbiosafety/testingofchemicals/45125644.pdf [last accessed 27 Aug 2012].
119. OECD 487. (2010). In vitro mammalian cell micronucleus test. OECD guideline for the testing of chemicals. Available from: http://www.oecd- ilibrary.org/environment/test-no-487-in-vitro-mammaliancell-micronucleus-test- 9789264091016-en [last accessed 27 Aug 2012].
120. OECD GLP. (1982). Good laboratory practice in the testing of chemicals. OECD monograph No. 45. OECD, Paris. ISBN 92-64-12367-9.
121. OECD GLP. (1997). OECD principles on good laboratory practice (as revised in 1997). OECD Series on Principles of Good Laboratory Practice and Compliance Monitoring Number 1. Available deom: http://www.oecd.org/chemicalsafety/testing/ oecdseriesonprinciples ofgoodlaboratorypracticeglpandcompliancemonitoring.htm [last accessed 11 Jan 2013].
122. Parry JM, Parry E, Phrakonkham P, Corvi R. (2010). Analysis of published data for top concentration considerations in mammalian cell genotoxicity testing. Mutagenesis, 25, 531-8.
123. Perkins PJ, Boermans HJ, Stephenson GR. (2000). Toxicity of glyphosate and triclopyr using the frog embryo teratogenesis assay-Xenopus. Environ Toxicol Chem, 19, 940-5. (Pubitemid 30173774)
124. Piesova E. (2004). The influence of different treatment length on the induction of micronuclei in bovine lymphocytes after exposure to glyphosate. Folia Vet Lat, 48, 130-4.
125. Piesova E. (2005). The effect of glyphosate on the frequency of micronuclei in bovine lymphocytes in vitro. Acta Veterinaria, 55, 101-9. (Pubitemid 40905394)
126. Poletta GL, Larriera A, Kleinsorge E, Mudry MD. (2009). Genotoxicity of the herbicide formulation Roundup (glyphosate) in broad-snouted caiman (Caiman latirostris) evidenced by the Comet assay and the micronucleus test. Mutat Res, 672, 95-102.
127. Poletta GL, Kleinsorge E, Paonessa A, et al. (2011). Genetic, enzymatic and developmental alterations observed in Caiman latirostris exposed in ovo to pesticide formulations and mixtures in an experiment simulating environmental exposure. Ecotox Environ Safe, 74, 852-9.
128. Prasad S, Srivastava S, Singh M, Shukla Y. (2009). Clastogenic effects of glyphosate in bone marrow cells of swiss albino mice. J Toxicol [Online]: Article ID: 308985. Available from: http://www.hindawi. com/journals/jt/2009/ 308985/[last accessed 27 Aug 2012].
129. Quintana PJ, de Peyster A, Klatzke S, Park HJ. (2000). Gossypol-induced DNA breaks in rat lymphocytes are secondary to cytotoxicity. Toxicol Lett, 117, 85-94.
130. Raipulis JTM, Balode M. (2009). Toxicity and genotoxicity testing of Roundup. Proc Latvian Acad Sci SectB, 63, 29-32.
131. Ranzani MRTC. (2000). Evaluation of the mutagenic potential of the test substance Glifosato IPA Tecnico Nufarm. Unpublished Regulatory Study. Report Identification Number: Study No. RF-G11.040/00.
132. Richeux F, Cascante M, Ennamany R, et al. (1999). Cytotoxicity and genotoxicity of capsaicin in human neuroblastoma cells SHSY-5Y. Arch Toxicol, 73, 403-9. (Pubitemid 29496289)
133. Ribeiro do Val R. (2007). Bacterial reverse mutation test (Ames test) for [glyphosate technical]. Unpublished Regulatory Study. Report Identification Number: RL3393/2007-2.0AM-B.
134. Rossberger S. (1994). DNA repair test with primary rat hepatocytes. Unpublished Regulatory Study. Report Identification Number: 931564.
135. Salamone MF, Mavournin KH. (1994). Bone marrow micronucleus assay: a review of the mouse stocks used and their published mean spontaneous micronucleus frequencies. Environ Mol Mutagen, 23, 239-73. (Pubitemid 24227883)
136. Sasaki YF, Saga A, Akasaka M, et al. (1998). Detection of in vivo genotoxicity of haloalkanes and haloalkenes carcinogenic to rodents by the alkaline single cell gel electrophoresis (comet) assay in multiple mouse organs. Mutat Res, 419, 13-20. (Pubitemid 28512967)
137. Saunders RA, Davies RR. (2005). Notes on rabbit internal medicine. Oxford: Blackwell Publishing.
138. Savage JR. (1976). Classification and relationships of induced chromosomal structual changes. J Med Genet, 13, 103-22.
139. Schreib G. (2010). Reverse mutation assay using bacteria (Salmonella Typhimurium and Escherichia Coli) with glyphosate technical. Unpublished Regulatory Study. Report Identification Number: 102025.
140. Scott D, Galloway SM, Marshall RR, et al. (1991). Genotoxicity under extreme culture conditions. International Commission for Protection Against Environmental Mutagens and Carcinogens. A report from ICPEMC Task Group 9. Mutat Res, 257, 147-205.
141. Sekihashi K, Yamamoto A, Matsumura Y, et al. (2002). Comparative investigation of multiple organs of mice and rats in the comet assay. Mutat Res, 517, 53-75. (Pubitemid 34600993)
142. Sivikova K, Dianovsky J. (2006). Cytogenetic effect of technical glyphosate on cultivated bovine peripheral lymphocytes. Int J Hyg Environ Health, 209, 15-20. (Pubitemid 41811254)
143. Smith CC, Adkins DJ, Martin EA, O'Donovan MR (2008). Recommendations for design of the rat comet assay. Mutagenesis, 23, 233-40.
144. Sokolowski A. (2007a). Salmonella Typhimurium and Escherichia Coli reverse mutation assay with glyphosate technical. Unpublished Regulatory Study. Report Identification Number: 1061401.
145. Sokolowski A. (2007b). Salmonella Typhimurium and Escherichia coli reverse mutation assay with glyphosate technical. Unpublished Regulatory Study. Report Identification Number: 1061402.
146. Sokolowski A. (2007c). Salmonella Typhimurium and Escherichia Coli reverse mutation assay glyphosate technical. Unpublished Regulatory Study. Report Identification Number: 1061403.
147. Sokolowski A. (2009a). Salmonella Typhimurium and Escherichia Coli reverse mutation assay with glyphosate technical. Unpublished Regulatory Study. Report Identification Number: 1236400.
148. Sokolowski A. (2009b). Glyphosate technical Salmonella Typhimurium and Escherichia Coli reverse mutation assay. Unpublished Regulatory Study. Report Identification Number: 1264500.
149. Speit G. (1986). The relationship between the induction of SCEs and mutations in Chinese hamster cells. I. Experiments with hydrogen peroxide and caffeine. Mutat Res, 174, 21-6. (Pubitemid 16118933)
150. Storer RD, McKelvey TW, Kraynak AR, et al. (1996). Revalidation of the in vitro alkaline elution/rat hepatocyte assay for DNA damage: improved criteria for assessment of cytotoxicity and genotoxicity and results for 81 compounds. Mutat Res, 368, 59-101. (Pubitemid 26226329)
151. Suresh TP (1992). Dominant lethal test in Wistar rats. Unpublished Regulatory Study. Report Identification Number TOXI:888-DLT.
152. Suresh TP. (1993a). Mutagenicity-Salmonella Typhimurium reverse mutation assay (Ames test). Unpublished Regulatory Study. Report Identification Number: TOXI: 887-MUT.AMES.
153. Suresh TP. (1993b). Mutagenicity-micronucleus test in Swiss albino mice. Unpublished Regulatory Study. Report Identification Number: TOXI: 889-MUT.MN.
154. Suresh TP. (1994). Genetic toxicology-in vivo mammalian bone marrow cytogenetic test-chromosomal analysis. Unpublished Regulatory Study. Report Identification Number: TOXI:890-MUTCH. AB.
155. Tayama S, Nakagawa Y. (1994). Effect of scavengers of active oxygen species on cell damage caused in CHO-K1 cells by phenylhydroquinone, an o-phenylphenol metabolite. Mutat Res, 324, 121-31.
156. Thompson PW. (1996). Technical glyphosate reverse mutation assay (Ames test) using Salmonella Typhimurium and Escherichia Coli. Unpublished Regulatory Study. Report Identification Number: SPL Proj. No. 434/014.
157. Tice RR, Agurell E, Anderson D, et al. (2000). Single cell gel/comet assay: guidelines for in vitro and in vivo genetic toxicology testing. Environ Mol Mutagen, 35, 206-21. (Pubitemid 30196665)
158. Thybaud V, Aardema M, Clements J, et al. (2007). Strategy for genotoxicity testing: hazard identification and risk assessment in relation to in vitro testing. Mutat Res, 627, 41-58. . (Pubitemid 46091766)
159. Tsui MT, Chu LM. (2003). Aquatic toxicity of glyphosate-based formulations: comparison between different organisms and the effects of environmental factors. Chemosphere, 52, 1189-97. (Pubitemid 36781432)
160. Uhde H. (2004). Mutagenicity study of FSG 03090 H-1 in the Salmonella
161. UK COM (2011). Guidance on a strategy for genotoxicity testing of chemical substances. UK Committee on Mutagenicity of Chemicals in Food, Consumer Products and the Environment. Available from: http://www.iacom.org.uk/ guidstate/documents/COMGuidance FINAL2.pdf/[last accessed 17 Sep 2012].
162. U.S. EPA. (1986). Guidelines for mutagenicity risk assessment. Fed. Register 51. 34006-34012. Available from: http://www.epa.gov/raf/publications/ guidelines-mutagenicityl-risk-assessment.htm [last accessed 1 Jan 2013].
163. U.S. FDA (2006). Guidance for industry and review staff: recommended approaches to integration of genetic toxicology study results. Center for Drug Evaluation and Research. U.S. Food and Drug Administration. Available from: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/ Guidances/ucm0 79257.pdf [last accessed 11 Jan 2013].
164. Wallner B. (2010). Reverse mutation assay using bacteria (Salmonella Typhimurium) with glyphosate TC. Unpublished Regulatory Study. Report Identification Number: 101268.
165. Williams GM, Kroes R, Munro IC. (2000). Safety evaluation and risk assessment of the herbicide Roundup and its active ingredient, glyphosate, for humans. Regul Toxicol Pharmacol, 31, 117-65. (Pubitemid 30314343)
166. Wolf T, Niehaus-Rolf C, Banduhn N, et al. (2008). The hen's egg test for micronucleus induction (HET-MN): novel analyses with a series of well-characterized substances support the further evaluation of the test system. Mutat Res, 650, 150-64.
167. Wright NP. (1996). Technical glyphosate: chromosome aberration test in CHL cells in vitro. Unpublished Regulatory Study. Report Identification Number: 434/015.
168. Xu Y. (2006). Salmonella-Escherichia Coli/mammalian-microsome reverse mutation assay with a confirmatory assay with MON 78910. Unpublished Regulatory Study. Report Identification Number: CV-2005-119.
169. Xu Y. (2008a). In vivo mouse bone marrow micronucleus assay. Unpublished Regulatory Study. Report Identification Number: CV-08-031.
170. Xu Y. (2008b). In vivo mouse bone marrow micronucleus assay with MON 76171. Unpublished Regulatory Study. Report Identification Number: CV-2007-103.
171. Xu Y. (2009a). In vivo mouse bone marrow micronucleus assay with MON 79991. Unpublished Regulatory Study. Report Identification Number: CV-2007-083.
172. Xu Y. (2009b). In vivo mouse bone marrow micronucleus assay with MON 76138. Unpublished Regulatory Study. Report Identification Number: CV-2007-095.
173. Xu Y. (2009c). In vivo mouse bone marrow micronucleus assay. Unpublished Regulatory Study. Report Identification Number: CV-08-243.
174. Zeiger E, Haseman JK, Shelby MD, et al. (1990). Evaluation of four in vitro genetic toxicity tests for predicting rodent carcinogenicity: confirmation of earlier results with 41 additional chemicals. Environ Mol Mutagen, 16, 1-14. (Pubitemid 20376833)
175. Zoriki Hosomi R. (2007). Mammalian erythrocyte micronucleus test for [glyphosate technical]. Unpublished Regulatory Study. Report Identification Number: 3393/2007-3.0MN.