UNITED STATES ENVIRONMENT AL PROTECTION AGENCY 
WASHINGTON, D.C. 20460 
OFFICE OF CHEMICAL SAFETY 
AND POLLUTION PREVENTION 
MEMORANDUM 
DATE: October 1, 2015 
SUBJECT: GLYPHOSATE: Report of the Cancer Assessment Review Committee 
FROM: 
TO: PC Code: 417300 
Decision No.: NI A 
Petition No.: NIA 
Risk Assessment Type: NA 
TXR No.: 0057299 
MRID No.: NIA 
Jess Rowland, ~~ ~ O?o~d nO­
Deputy Division Director DP Barcode: NI A 
Registration No.: NI A 
Regulatory Action: NI A 
Case No.: NI A 
CAS No.: 1071-83-6 
40 CFR: NIA 
Chair, Cancer Assessment Reviewlmmittee 
And JI 
Karlyn Middleton , Co-Chair 'r~ 
Cancer Assessment Review Committee 
Health Effects Division (7509P) 
Charles Smith, Chief, 
Risk Assessment Branch I 
Health Effects Division (7509P) 
And 
KhueNguyen 
Chemical Review Manager 
Risk Management and Implementation Branch 1 
Pesticide Re-evaluation Division 
On September 16, 2015, the Cancer Assessment Review Committee (CARC) of the Health 
Effects Division, of the Office of Pesticide Programs evaluated the carcinogenic potential of 
Glyphosate in accordance with the EPA 's Final Guidelines for Carcinogen Risk Assessment 
(March, 2005). Attached please find the final Cancer Assessment Document.  
Page 2 of 87 
   
 
CANCER ASSESSMENT DOCUMENT  
 
 
 
 
 
EVALUATION OF THE CARCINOGENIC POTENTIAL OF 
Glyphosate  
 
    
FINAL REPORT 
October 1, 2015 
            
CANCER ASSESSMENT REVIEW COMMITTEE 
HEALTH EFFECTS DIVISION 
OFFICE OF PESTICIDE PROGRAMS 
U.S Environmental Protection Agency 
 G L Y P H O S A T E            F I N A L  
 
Page 3 of 87 
  Table of Contents 
EXECUTIVE SUMMARY ............................................................................................................ 7 
I. INTRODUCTION ................................................................................................................ 1 1 
II. BACKGROUND INFORMATION ..................................................................................... 11  
III. EPIDEMIOLOGY ............................................................................................................. 13  
A. Cohort Study ..................................................................................................................  13 
B. Case-Control Studies ...................................................................................................... 13  
C. Results ....................................................................................................................... ..... 14 
1. Solid Tumor Cancer Studies ....................................................................................... 14  
2. Non-Solid Tumor Cancer Sites .................................................................................. 25  
D. Discussion .................................................................................................................... .. 38 
IV. EVALUATION OF CARCINOGENI CITY IN ANIMALS ............................................. 39  
A. Carcinogenicity Studies in Rats ..................................................................................... 40  
1. Lankas, G, P. A Lifetime Study of Glyphosate in Rats. December 23, 1981. 
Unpublished report No. 77-2062 prepared by Bio Dynamics, Inc. EPA Accession. No. 
247617 – 247621. MRID No. 00093879 .............................................................................. 40  
2. Stout, L. D. and Rueckerf, P.A. (1990). Chronic Study of Glyphosat e Administered in 
Feed to Albino Rats. Laboratory Project  No. MSL-10495; September, 26, 1990, MRID No. 
41643801; Historical Controls; MRID No. 41728701. ........................................................ 41  
3. Atkinson, C., Strutt, A., Henderson, W., et  al. (1993). 104-Week chronic feeding/ 
oncogenicity study in rats with 52-week interim kill. Inveresk Research International (IRI), 
Tranent, Scotland. Study No. 438623; IRI Report No. 7867. April 7, 1993. MRID No. 
49631701. Unpublished ........................................................................................................ 46 
4. Brammer. (2001). Glyphosate Acid: Two Year  Dietary Toxicity and Oncogenicity 
Study in Rats. Central Toxicology Laboratory, Alderley Park Macclesfield, Cheshire, UK: 
Syngenta. (MRID No. 49704601). ........................................................................................ 46  
5. Feinchemie Schwebda. (1996). Combined Chronic Toxicity and Carcinogenicity 
Study with Glyphosate Technical in  Wistar Rats. Bangalore, Indi a: Rallis India, Ltd. (Cited 
in Greim et al. , 2015). .......................................................................................................... 48  
6. Arysta Life Sciences. (1997a). HR-001:  24-Month Oral Chronic Toxicity and 
Oncogenicity Study in Rats. Kodaira-shi, T okyo, Japan: The Institute of Environmental 
Toxicology  (Cited in Greim et al. , 2015). .......................................................................... 49  
7. Nufarm. (2009a). Glyphosate Technical: Dietary Combined Chronic Toxicity/ 
Carcinogenicity in the Rat. Shardlow, Derbys hire, UK: Harlan Laboratories Ltd. (Cited in 
Greim et al. , 2015). .............................................................................................................. 50  G L Y P H O S A T E            F I N A L  
 
Page 4 of 87 
  B. Carcinogenicity Studies in Mice .................................................................................... 51  
1. Knezevich, A.L and Hogan, G. K. (1983). A chronic feeding study of glyphosate in 
mice. Unpublished report prepared by Bio/ Dynamic Inc., dated July 21, 1983. Report No. 
77-2011. EPA Accession No. 251007 – 251009, and 251014. ............................................. 51  
2. Atkinson, C., Martin, T., Hudson, P., a nd Robb, D. (1993). Glyphosate: 104 week 
dietary carcinogenicity study in mice. Inveresk Research International, Tranent, EH33 2NE, 
Scotland. IRI Project No. 438618. April 7, 1993. MRID 49631702. ................................... 54  
3. Arysta Life Sciences. (1 997b). HR-001: 18-Month Onc ogenicity Study in Mice. 
Kodaira-shi, Tokyo, Japan: The Institute of Environmental Toxicology (Cited in Greim et 
al., 2015). ............................................................................................................................. 55 
4. Nufarm. (2009b). Glyphosate Technical: Di etary Carcinogenicity Study in the 
Mouse. Derbyshire, UK: Harlan La boratories Ltd. (Cited in Greim et al.,  2015). ............... 56  
IV. TOXICOLOGY ................................................................................................................. 57  
A. Metabolism .................................................................................................................... . 57 
B. Mutagenicity .................................................................................................................. . 58 
1. Bacterial reverse mutation assays ............................................................................... 59  
2. In vitro  mammalian cell gene mutation assays ........................................................... 60  
3. In vitro chromosomal aberration assays ..................................................................... 60  
4. In vivo micronucleus and chromosomal aberration assays ......................................... 61  
5. Other genotoxicity assays ........................................................................................... 63  
6. Conclusions ................................................................................................................ 64  
C. Structure-Activity Relationship ...................................................................................... 64  
D. Subchronic and Chronic Toxicity Studies ...................................................................... 64  
1. Subchronic Toxicity ................................................................................................... 64  
2. Chronic Toxicity ......................................................................................................... 65  
V.  COMMITTEE’S ASSESSMENT OF TH E WEIGHT-OF-THE-EVIDENCE ..................... 68  
A. Evidence for Carcinogenicity in Humans ...................................................................... 68  
1. Cancer at Multiple Sites ............................................................................................. 68  
2. Brain Cancer ............................................................................................................... 68  
3. Leukemia .................................................................................................................... 6 8 
4. Multiple My eloma ...................................................................................................... 68  
5. Non-Hodgkin Lymphoma........................................................................................... 69  
B. Evidence for Carcinogenicity in  Experimental Animals ................................................ 70  
1. Evidence for Carcinogenicity in Rats ......................................................................... 70  G L Y P H O S A T E            F I N A L  
 
Page 5 of 87 
  2. Evidence for Carcinogenicity in Mice ........................................................................ 72  
C. Discussion .................................................................................................................... .. 74 
1. Mutagenicity ............................................................................................................... 76  
2. Structure Activity Relationship .................................................................................. 77  
VI. CLASSIFICATION OF CARCIN OGENIC POTENTIAL ............................................... 77  
VII. QUANTIFICATION OF CARCINOGENIC POTENTIAL ............................................. 78  
VIII. BIBLIOGRAPHY .......................................................................................................... 78  
 
 < iLYPHOS.'\ TE FINAi. 
COMi'v11Tll£E MEi\·tBERS IN XITENO.'\Nl'E: 
Jess Rt\\\'lund. l'vl.S .. Chair 
Kmlyn Middleton. \1.S .. Co-Chair ·' . -··· . .------i -. ------------·----
(ir~gory Akerman. Ph.D. 
I .ori Brunsmnn . B.S . 
.lun•llhan Chen. Ph.D. 
:\nwar Dunbar. Ph.D. 
Ray f..:cnt. Ph.D . 
. kssk<1 Kidwell. \·t.S . 
.lohn Liccione. Ph.D. 
l>anncllc 1.olxkll. Ph.D .. Epidemiologist. ORI) 
\ianc.:~ ~kCurroll . M.S. 
Chris Schlosser. M.S. 
Clmrlt:s Woml D. V .M .• l'h.JJ .. Pathologist. ORD 
Page 6 nf87 GLYPHOSATE    FINAL    
Page 7 of 87 
   
EXECUTIVE SUMMARY 
 
Glyphosate is a nonselective herbic ide that is currently register ed for pre- and post-emergence 
application to a variety of fru it, vegetable, and field crops. 
 
In 1985, the agency, in accordance with the Proposed Guidelines for Carcinogen Risk Assessment, 
classified glyphosate as a Group C chemical (Po ssible Human Carcinogen) based on the presence 
of kidney tumors in male mice. There was no evidence for carcinogenicity in male or female rats. Furthermore, there were no mutage nicity concerns (TXR No. 0052067).  
 In 1986, the agency requested the FIFRA Scientif ic Advisory Panel (SAP) to evaluate the 
carcinogenic potential of gl yphosate. On February 24, 1986, the SAP recommended that 
glyphosate should be categorized as a Group D chemical: Not Classifiable as to Human 
Carcinogenicity. The panel determined that the da ta on renal tumors in male mice were equivocal: 
they were only adenomas, and the increase did not  reach statistical significance. The panel also 
advised the agency to issue a data  call-in notice for further studies in rats and/or mice to clarify 
unresolved questions (SAP Report, 02/24/ 1986). This review is available at 
http://www.epa.gov/pesticides/chem_sear ch/cleared_reviews /csr_PC-103601_24-Feb-86_209.pdf  
 
In 1991, the Carcinogenicity Peer  Review Committee (CPRC) of the Health Effects Division 
(HED), of the Office of Pesticid e Programs (OPP), of the U.S. Environmental Protection Agency 
(USEPA) evaluated the carcinogenic potential of glyphosate. In accordan ce with the agency’s 
1986 Draft Guidelines for Carcinogen Risk Assessment,  the CPRC classified glyphosate as a 
Group E Chemical: “Evidence of Non-Carcinogenic ity for Humans” based upon lack of evidence 
for carcinogenicity in mice and rats and the la ck of concern for mutagenicity (TXR# 0008897). 
Earlier this year (March 2015), the International Agency for Re search on Cancer (IARC), Lyon, 
France, assessed the carcinogeni c potential of glyphosate. Th e IARC reviewed the available 
epidemiological studies and carcino genicity studies for glyphosate in experimental animals. The 
IARC concluded that there is limited evidence  in humans for the carcinogenicity of glyphosate 
based on a positive association for non-Hodgkin lym phoma (NHL). The IARC also concluded that 
there is sufficient evidence  in experimental animals based on significant positive trends for kidney 
tumors in one study and for hemangiosarcomas in another study in male mice. IARC determined 
that there is strong evidence for genotoxicity. Overall, IA RC classified glyphosate as “ probably 
carcinogenic to humans (Group 2A)  (IARC, 2015).   
IARC’s conclusion was based on epidemiologic studi es available in the open literature and 
carcinogenicity studies in rats (4 studies) and mice (2 studies ) by dietary administration. Of these 
six studies reviewed by IARC, tw o studies in rats and one stu dy in mice were previously not 
available to OPP. The conclu sion by IARC and the additional st udies not available to OPP, 
prompted the agency to re-evaluate the carcinogenic potential of glyphosate.  
 GLYPHOSATE    FINAL    
Page 8 of 87 
  On September 16, 2015, HED’s Cancer Assessmen t Review Committee (CARC) evaluated all 
available epidemiological studies published in the open literature that examined the association 
between glyphosate exposure and one or more cancer outcomes. This included one cohort study, 
seven nested case-control studies based on th e cohort study population, and 25 case- control 
studies. The CARC also evaluated 11  chronic toxicity/carci nogenicity studies in rats (7) and mice 
(4) following dietary administration for up to two years. Six of the studies (4 rat and 2 mouse) 
were submitted to OPP to support registration/re-re gistration requirements,  including two studies 
in rats and one study in mice which were not previ ously available to OPP (but reviewed by IARC). 
Data for review of the other five  studies (3 rat and 2 mouse) were  obtained from a review article 
and its supplement published in the open literature (Greim et al.,  2015) that also had not been 
previously reviewed by the agency (IARC did not evaluate the five studi es cited in the Greim et al.  
2015 review article). The CARC also evaluated the mutagenicity/genotoxicity studies submitted to 
OPP as well as studies summarized in two review articles (Williams et al., 2000, and Kier and 
Kirkland, 2013) published in  the open literature. 
 The CARC concluded that the ep idemiological studies in humans  showed no association between 
glyphosate exposure and cancer of the following: oral cavity, es ophagus, stomach, colon, rectum, 
colorectum, lung, pancreas, kidney, bladder, prostate, brain (gli omas), soft-tissue sarcoma, 
leukemia, or multiple myelomas.   The CARC concluded that there is conflicting evidence for the associ ation between glyphosate 
exposure and NHL. No association between gl yphosate exposure and NHL was found in 
population-based case-control studies in the United  States, Canada or France. Additionally, the 
large prospective Agricultural Health Study (AHS ) with 54,315 licensed pest icide applicators in 
Iowa and North Carolina did not show a significantly increased ri sk of NHL. A population-based 
case-control study from Sweden suggested an association between glyphosate exposure and NHL; 
however, this finding was based on only 4 glyphosate-exposed cases and 3 controls.  
 When data from two case-control studies in Sweden (one on NHL and the other on hairy cell 
leukemia) were pooled, a univariat e analysis showed an increased risk (odds ratio (OR) = 3.04; 
95% confidence interval (CI) = 1.08–8.52); however, wh en study site, vital status, and exposure to 
other pesticides were taken into account in a multivariate analysis, the risk was attenuated (OR=1.85; 95% CI=0.55–6.20). In another case -control study in Sweden, among the 29 
glyphosate-exposed cases, a multivariate analysis showed an increased risk for NHL (OR=1.51; 
95% CI=0.77–2.94) and B-cell lymphoma (OR=1.87;  95% CI=0.998–3.51). A me ta-analysis of the 
six separate studies showed an  association between glyphosate exposure and NHL with a meta-risk 
ratio of 1.5 (95% CI=1.1–2.0) (Schinasi and Le on, 2014). The CARC noted that most of the 
studies in the database were underpowered, suffere d from small sample size of cancer cases with 
glyphosate exposure, and had risk/odds ratios with large confidence interval s. Additionally, some 
of the studies had biases associ ated with recall and missing data. 
 
In an attempt to address the noted power/sample  size issues across studies, IARC used adjusted 
weighting estimates of the two Swedish studies (Hardell et al. 2002 and Eriksson et al. 2008) and GLYPHOSATE    FINAL    
Page 9 of 87 
  reported an lower odds ratio in a second me ta-analysis of the same data (OR=1.3; 
95% CI=1.03–1.65). Given the limitations of the studi es used and uncertainty  in the analytical 
methods, the CARC concluded that a different weighting scheme coul d have resulted in a different 
meta risk ratio. Thus, while epidemiologic literat ure to date does not support a direct causal 
association, the CARC recommends th at the literature shou ld continue to be monitored for studies 
related to glyphosate and risk of NHL. 
 
Overall, the CARC concluded that there was no evidence of carcinogenicity in the eleven 
carcinogenicity studies conducted in  Sprague Dawley or Wistar ra ts and CD-1 mice. There were 
no treatment-related increases in th e occurrence of any tumor type in either sex of either species. 
 By contrast, the IARC concluded that there is sufficient evidence  in experimental animals based on 
a positive trend in the incidence of a relatively ra re tumor type, renal tubu lar carcinoma and renal 
tubule adenoma or carcinoma (combined) in CD-1 males in one feeding study. A second study 
reported a positive trend for hemangiosarcomas in male CD-1 mice. The CARC did not consider 
these tumors to be treatment-related since th e observed tumors did not exhibit a clear dose-
response relationship, were not s upported non-neoplastic changes, we re not statistically significant 
on pairwise analysis with concurre nt control groups, and/or were w ithin the range of the historical 
control data. If the kidney tumors and the hema ngiosarcomas are really treatment-related, it is 
unlikely that the same tumors would not have been detected at higher incide nces in the studies in 
the other studies of CD-1 mice when tested at similar or higher doses (1000–4000 mg/kg/day). 
Moreover, in 4 of the 11 studies (3 rat and 1 mo use) evaluated by CARC, there was no biologically 
or statistically significant increases  in the occurrence of any tumor t ype in either species. The other 
observed differences in incidence did not show a dose response relationship, and were within the 
range of the background/historic al control range. The four st udies which were negative for 
carcinogenicity were reported in  the review article by Greim et al. (2015) but were not included in 
the IARC evaluation. This omission of the negative findings from reliable studies may have had a 
significant bearing on the conclu sion drawn for evidence of ca rcinogenicity in animals.  
 The CARC evaluated a total of 54 mutagenicity/genotoxicity st udies which included studies 
submitted to the agency, as well as studies re ported in the two revi ew articles (Williams et al., 
2000, and Kier and Kirkland, 2013). A nu mber of studies reported in the review article by Kier and 
Kirkland (2013) were not considered by IARC. Th e CARC, based on a weight-of-evidence of the 
in vitro and in vivo studies, concluded that there is no con cern for genotoxicity or mutagenicity. 
Glyphosate was no mutagenic in bacter ial reversion (Ames) assays or in vitro mammalian gene 
mutation assays.  There is no convincing evidence  that glyphosate induces  micronuclei formation 
or chromosomal aberrations in vitro or in vivo .  
 By contrast, IARC’s conclusion th at glyphosate is genotoxic based on positive results that included 
studies that tested glyphosate-for mulated products as well as studies  where the test material was 
not well-characterized ( i.e., no purity information was provided) . The IARC analysis also focused 
on DNA damage as an endpoint ( e.g., comet assay). DNA damage is often reversible and can 
result from events that are secondary to toxi city (cytotoxicity), as  opposed to permanent DNA GLYPHOSATE    FINAL    
Page 10 of 87 
  changes which are detected in tests fo r mutations and chromosomal damage ( e.g. chromosomal 
aberrations or micronuclei induction). The stud ies that IARC cited as  positive findings for 
chromosomal damage had deficiencies in the de sign and/or conduct of the studies confounding the 
interpretation of the results. In addition these positive findings were not reproduced in other 
guideline or guideline-like studies  evaluating the same endpoints. Fu rthermore, IARC’s evaluation 
did not include a number of negative results from st udies that were reported in the review article 
by Kier and Kirkland (2013). The inclusion of the positive findings fr om studies with known 
limitations, the lack of reproducible positive fi ndings and the omission of  the negative findings 
from reliable studies may have had a signifi cant bearing on IARC’s c onclusion on the genotoxic 
potential of glyphosate.  
 In accordance with the 2005 Guidelines for Carci nogen Risk Assessment, based on the weight-of- 
evidence, glyphosate is classified  as “Not Likely to be Ca rcinogenic to Humans”. This 
classification is based on the following weight-of-evidence considerations:  
 The epidemiological evidence at this time does not support a causal relationship between 
glyphosate exposure and solid tumors.  Ther e is also no evidence to support a causal 
relationship between glyphosate exposure a nd the following non-solid  tumors: leukemia, 
multiple myeloma, or Hodgkin lymphoma. The ep idemiological evidence at this time is 
inconclusive for a causal or  clear associative relations hip between glyphosate and NHL. 
Multiple case-control studies and one pros pective cohort study found no association; 
whereas, results from a small number of cas e-control studies (mostly in Sweden) did 
suggest an association. Limitations for most of these studies include small sample size, 
limited power, risk/odd ratios with large confid ence intervals, and recall bias as well as 
missing data. The literature will continue to be  monitored for studies related to glyphosate 
and risk of NHL.  
 In experimental animals, there is no eviden ce for carcinogenicity. Diet ary administration of 
glyphosate at doses ranging from 3.0 to 1500 mg /kg/day for up to two years produced no 
evidence of carcinogenic response to treatment in seven separate studies with male or 
female Sprague-Dawley or Wistar rats. Simila rly, dietary administ ration of glyphosate at 
doses ranging from 85 to 4945 mg/kg/day for up to two years produced no evidence of 
carcinogenic response to treatment in four separa te studies with male or female CD-1 mice. 
The CARC did not consider any of the obser ved tumors in 11 carcinogenicity studies in 
rats and mice to be treatment-related since th e observed tumors did not exhibit a clear dose-
response relationship, were not s upported pre-neoplastic changes ( e.g., foci, hypertrophy, 
and hyperplasia), were not statistically signifi cant on pairwise statistical analysis with 
concurrent control groups, and/or  were within the range of th e historical control data.   
 
 Based on a weight of evidence approach  from a wide range of assays both in vitro  and in 
vivo including endpoints for gene mutation, chromosomal damage, DNA damage and 
repair, there is no in vivo  genotoxic or mutagenic concern for glyphosate. 
 GLYPHOSATE    FINAL    
Page 11 of 87 
   
I. INTRODUCTION 
 
On September 16, 2015 the Cancer Assessment Review Committee (CARC) of the Health Effects Division of the Office of Pestic ide Programs met to re-evaluate the carcinogenic potential of 
glyphosate.  
II. BACKGROUND INFORMATION 
 
Glyphosate ( N-(phosphonomethyl) glycine) is  a nonselective herbicide that  is currently registered 
for pre- and post-emergence application to a variety of fruit, vegetable, and field crops. Tolerances 
are currently established for residues of glyphosate in/on various plant commodities at 
0.2–400 ppm (40 CFR §180.364 (a)) (1). Registered uses ra nge from tree nuts, citrus, and grapes to 
corn, soybeans, cotton, and rice. Gl yphosate is also regist ered for use on transg enic crop varieties 
such as canola, corn, cotton, soybeans, sugar beet s, and wheat. Aquatic and terrestrial registered 
uses of glyphosate include non-selective contro l of nuisance aquatic weeds, ornamentals, 
greenhouses, residential areas, ornamental lawns and turf, fallow land, pastures, and 
nonagricultural rights-of-way. 
 The chemical structure and nomenclature for glyphosate is presented in Table 1. 
  
Table 1. Chemical Nomenclature of Glyphosate 
Compound 
 
Common name Glyphosate 
Company experimental name DPX-B2856 
IUPAC/CAS name N-(phosphonomethyl)glycine 
CAS registry number 1071-83-6 
 
Glyphosate is formulated in liquid and solid fo rms, and it is applied using ground and aerial 
equipment. Application rates of glyphosate to food crops ra nge from <1 pound (lb) of acid 
equivalent (ae) per acre (A) for a variety of crops to approximatel y 15 lb ae/A for spray and spot 
treatments of crops including tree nuts, apples, citrus, and peaches. Residential lawn and turf 
application rates range from <1 lb ae/A to appr oximately 10.5 lb ae/A. The application timing of 
glyphosate is varied. Glyphosate can be  applied early and late in the season, at pre-plant, planting, 
pre-emergence, pre-bloom, bud stag e, pre-transplant, pre-harvest, post-plant, post-transplant, post-
bloom, and post-harvest. It can  also be applied during dorma nt stages and to fallow land, 
established plantings, stubble, and when need ed. In September 1993, the agency issued the 
glyphosate Reregistration Eligib ility Decision (RED) document (D362745), available from 
http://www.epa.gov/pesticides/reregis tration/REDs/old_reds/glyphosate.pdf . 
 PO
OH
OHNH
OHOGLYPHOSATE    FINAL    
Page 12 of 87 
  In 1985, the agency, in accordance with the Proposed Guidelines for Carcinogen Risk Assessment, 
classified glyphosate as a Group C chemical (Po ssible Human Carcinogen) based on the presence 
of kidney tumors in male mice. There was no evidence for carcinogenicity in male or female rats. Furthermore, there were no mutage nicity concerns (TXR No. 0052067).  
 In 1986, the agency requested the FIFRA Scientif ic Advisory Panel (SAP) to evaluate the 
carcinogenic potential of gl yphosate. On February 24, 1986, the SAP recommended that 
glyphosate should be categorized as a Group D chemical: Not Classifiable as to Human 
Carcinogenicity. The panel determined that the da ta on renal tumors in male mice were equivocal: 
they were only adenomas, and the increase did not  reach statistical significance. The panel also 
advised the agency to issue a data  call-in notice for further studies in rats and/or mice to clarify 
unresolved questions (SAP Report, 02/24/ 1986). This review is available at 
http://www.epa.gov/pesticides/chem_sear ch/cleared_reviews /csr_PC-103601_24-Feb-86_209.pdf  
 
In 1991, the Carcinogenicity Peer  Review Committee (CPRC) of the Health Effects Division, 
Office of Pesticide Programs, in  accordance with the agency’s 1986 Draft Guidelines for 
Carcinogen Risk Assessment,  classified glyphosate as a Grou p E Chemical: Evidence of Non-
Carcinogenicity for Humans. This classificat ion was based upon lack of evidence for 
carcinogenicity in mice and rats and the lack of concern for mutagenicity (TXR No. 0008897). 
 In 2002, the European Union (EU) concluded that  there was no evidence of carcinogenicity for 
glyphosate in long-term studies with mice and rats (EU, 2002). 
 In 2004, the Joint FAO/WHO Meeting on Pesticide Residues (JMPR) concluded that there was no 
evidence of carcinogenicity for glyph osate in long term studies in  mice and rats and there was no 
evidence for genotoxic potential (JMPR, 2004).  In 2015, the International Agency for Research on Cancer (IARC) classified glyphosate as a Group 
2A chemical (Probable Human Carcinogen) based on limited evidence  of carcinogenicity in 
humans and sufficient evidence in experimental animals. The limited evidence in humans was based on a positive association between non-H odgkin lymphoma (NHL) and glyphosate exposure 
from published epidemiology studies. The sufficient evidence  in experimental animals was based 
on a positive trend in the inci dence of renal tubular carcinom a and renal tubule adenoma/ 
carcinoma combined in male CD-1 mice in one st udy and on a positive tre nd in the incidence of 
hemangiosarcomas in male CD-1 mice in anot her study. There is strong evidence that glyphosate 
causes genotoxicity (IARC, 2015).  In 2015, two chronic toxicity/car cinogenicity studies in ra ts (MRID Nos. 49631701; 4970460) and 
one carcinogenicity study in mice (MRID No. 49631702) that were revi ewed by IARC, but not 
previously available to OPP, were submitted and reviewed. This assessment by the CARC includes 
all of the studies (epidemiology and animals) re viewed by IARC as well as a subset of animal 
studies reported in a review article by Greim et al.  (2015) but not reviewed by IARC. 
 GLYPHOSATE    FINAL    
Page 13 of 87 
   
III. EPIDEMIOLOGY  
This section includes a review of  epidemiologic cohort and case-c ontrol studies of glyphosate to 
evaluate whether exposure to glypho sate is associated causally with  the risk of developing cancer 
in humans.    The Agricultural Health Study (AHS) is  a large prospective study conducted in Iowa and North 
Carolina. Participants (private and commercial applicators) were asked to complete a 21-page 
questionnaire that included da ta on personally mixing and/or applying pesticides (including 
glyphosate), and frequency (days of use per year) and duration (years of use) of pesticide use. Data 
on the use of personal protective equipment, ot her farming practices, dietary and lifestyle 
information, demographic data, and medical informa tion were also collected  via the questionnaire 
(Alavanja et al.,  1996). The role of pesticide use and lymp h hematopoietic cancers, and in 
particular NHL, has been studied in several i nvestigations. For most of the cancer endpoints 
studied in relation to pesticide use, only one epidemiology study is available (De Roos et al., 
2005); however, for NHL and other non-solid tumo rs, several investigat ions are published. 
  
A. Cohort Study 
 
There are multiple published studies which use da ta from the same cohort, the AHS (Alavanja et 
al., 2003; Flower et al., 2004; De Roos et al., 2005; Engel et al., 2005; Lee et al., 2007; Landgren 
et al., 2009; Andreotti et al., 2009; and Dennis et al., 2010). It should be noted that t here is some 
overlap between the cases and person-time reported findings in the AHS.  
  
B. Case-Control Studies 
 
Three case-control studies conducted by the Nationa l Cancer Institute in Iowa and Minnesota 
during the 1980s were reported by Brown et al.  (1990), Cantor et al. (1992) and Brown et al. 
(1993).   De Roos et al. (2003) and Lee et al. (2004a) reported the results of  case-control studies conducted 
in Iowa, Minnesota, Nebraska an d/or Kansas in the U.S.A.  
 The Canadian population based case-contro l studies were reported by McDuffie et al., 2001; 
Hohenadel et al., 2011; Karunanayke et al., 2012; and Kachuri et al., 2013.  
 Results of the Swedish case-control  studies were reported by Nordstrom et al. , 1998; Hardell and 
Erikson, 1999 and Hardell et al., 2002; and Eriksson et al., 2008. 
 A single case-control study conducte d in France was reported by Orsi et al. (2009). 
  GLYPHOSATE    FINAL    
Page 14 of 87 
   
Coco et al., (2013) reported the results of a pooled analyses of case-control studies conducted in 
six European countries between 1998 and 2004.  Case-control studies on the cancer of the brai n (mainly gliomas) were reported by Ruder et al. 
2004; Carreon et al., 2005; Lee et al. , 2005; and Yiin et al., 2012. 
 Case-control studies on other cancer sites were reported by Alavanja et al., 2004 (lung); Bank et 
al., 2011 and Koutros et al., 2013 (prostate); Pahwa et al., 2012 (soft tissue sarcoma) and Lee  et 
al., 2004b (stomach and esophagus).  
 Schinasi and Leon (2014) conducted a meta-analysis of the si x studies that evaluated NHL and 
glyphosate exposure (McDuffie et al., 2001; Hardell et al., 2002; DeRoos et al., 2003; 2005;  
Eriksson et al., 2008; and Orsi et al., 2009). Sorahan (2015) conducted a re-analysis of the multiple 
myeloma in the U.S. AHS.  
C. Results 
 
A summary of the studies evalua ting the association between gl yphosate exposure and cancer are 
discussed below.  
 Results of the studies reporting data on solid  tumors (non-lymphohematopoietic) at various 
anatomical sites are presented in Table 2.   
 Results of the studies reporting data on glyphosate exposure and non-solid tumors 
(lymphohematopoietic) are pr esented in Table 3. 
 
1. Solid Tumor Cancer Studies 
 
Within the AHS study cohort, a number of authors evaluated several anatom ical cancer sites in 
relation to pesticide use. A discu ssion of studies outside of the AHS  cohort that ad dressed pesticide 
use in relation to non-solid tumors including mu ltiple myeloma and NHL is presented below in 
Section C.2. (Non-Solid Tumor Sites).  
(i) Cancer at Multiple Sites 
 
De Roos et al., (2005)  evaluated associations between glyphos ate exposure and cancer incidence in 
the AHS cohort study of 57,311 licensed pesticide applicators in Iowa and North Carolina. The authors used Poisson regression to estimate e xposure-response relationships between glyphosate 
and incidence of all cancers combined and 12 relatively common cancer subtypes. Exposure to 
glyphosate was not associated with all cancers combined [R ate Ratio (RR) =1.0 with 
95% Confidence Interval (CI) of 0.90–1.2)] or a ny cancer at a specific anatomical site.  
 
  GLYPHOSATE    FINAL    
Page 15 of 87 
   
Several AHS nested case-control analyses as well as the cohort analysis from De Roos et al., 2005, 
also provide information concerning the carcinog enic potential of glyphosate. As presented in 
Table 2, there is no statistical ev idence of an association with  glyphosate presented across these 
studies. Specifically, AHS researchers reported no statistical evidence of an association between 
glyphosate use and cancers of the oral cavity (De Roos et al., 2005), colon (De Roos et al., 2005; 
Lee et al., 2007), rectum (De Roos et al., 2005; Lee et al., 2007), lung (De Roos et al., 2005), 
kidney (De Roos et al., 2005), bladder (De Roos et al., 2005), pancreas (De Roos et al., 2005; 
Andreotti et al., 2009), breast (Engel et al., 2005), prostate (Alavanja et al., 2003; Koutros et al., 
2013) or melanoma (De Roos et al., 2005; Dennis et al. , 2010). The risk ratios  (OR) or rate ratios 
(RR) and 95% confidence interval (CI) fo r these studies are pr ovided in Table 2. 
 In a population-based study (Band et al. , 2011) outside of the AHS, Cana dian research ers reported 
non-significantly elevated odds of prostate cancer in relation to glyphosate use (OR=1.36; 
95% CI=0.83–2.25). This study included prosta te cancer cases from 1983-1990, prior to the 
prostate-specific antigen (PSA) era. Consequently, the study in cluded more advanced tumors 
before diagnosis. Additionall y, these data are in conflict w ith the results of Alavanja et al. (2003), 
which reflects the PSA-era cases ( i.e., cases which are typically identif ied at an earlier stage in the 
progression of the disease). Koutros et al. (2013) did not identify an association with advanced 
prostate cancer (OR=0.93; 95% CI=0.73–1.18) in a prostate cancer follow-up study within the 
AHS.  A Canadian case-control study (Pahwa et al., 2011) examined exposure to pesticides and soft 
tissue sarcoma and found no relation with th e use of glyphosate (OR=0.90; 95% CI= 0.58–1.40). 
 Flower et al. (2004) examined the relation between parent al pesticide use and all pediatric cancers 
reported to state registries among children of AHS  participants and did not observe a significant 
association with maternal use exposure to gl yphosate (OR=0.61; 95% CI= 0.32–1.16) or paternal 
(prenatal) exposure to glyphosat e: (OR=0.84; 95% CI= 0.35– 2.54). 
 
(ii) Brain (Glioma) Cancer 
 
Lee et al. (2005) investigated the asso ciation between brain cancer with farming and agricultural 
pesticide use. The authors conducted telephone in terviews of men and women diagnosed with 
gliomas (n=251) between 1988 and 1993 in Nebraska and in controls (n=498)  identified from the 
same regions. Matching for age and vital status, study authors reported a non-significant elevated 
odds of glioma (OR=1.5; 95% CI=0.7–3.1) in relati on to glyphosate use; how ever, the results were 
significantly different between those who self-reported pestic ide use (OR=0.4; 95% CI=0.1–1.6), 
and for those for whom a proxy respondent was used (OR=3.1; 95% CI=1.2–8.2), indicating recall 
bias was likely a charac teristic of this study. 
   GLYPHOSATE    FINAL    
Page 16 of 87 
   
Three population-based case-control st udies evaluated the risk of brai n cancer, specifically, glioma 
risk, among men and women participating in  the Upper Midwest Health Study (Carreon et al., 
2005; Ruder et al., 2004; Yiin et al., 2012). Ruder et al. (2004) reported no association between 
brain cancer and glyphosate use, but di d not present any specific results ( i.e. quantitative data). 
Among glioma cases identified 1995–1997 by Carreon et al. (2005), the authors found little 
evidence of a role for glyphosate in  the etiology of this tumor. He rbicide use, including glyphosate 
was not associated with glioma in wome n by proxy respondents (OR=0.75; 95% CI=0.4–1.3) or 
excluding proxy respondents (OR=0.6; 95% CI=0.3–1.2). In the study by Carreon et al. (2005), 
there was no difference in risk estimate by vital status (use of self-repo rt or proxy respondent), 
suggesting recall bias was more limited  in this study in contrast to Lee et al. (2005). Using a 
quantitative measure of pesticide ex posure (in contrast to an ever-use  metric), the authors similarly 
observed no statistical evidence of  an association with  glyphosate; risk estimates were roughly 
equal to the null value (hom e and garden use: OR=0.98; 95% CI=0.67–1.43; non-farm jobs: 
OR=0.83; 95% CI=0.39–1.73) (Yiin et al., 2012). 
 
(iii) Stomach and Esophageal Cancers 
 
In a population-based case control study in eastern Nebraska, Lee et al. (2004) investigated 
pesticide use and stomach and esophageal ad enocarcinomas. Cancer cases (stomach=170 and 
esophagus=137) were identified thro ugh the state cancer registry, a nd confirmed by a pathologist. 
The exposure assessment was based on self-report ed pesticide use, with follow-up telephone 
interview to verify the reported informati on. There was no association between glyphosate 
exposure and either stomach cancer (OR=0.8; 95%  CI=0.4–1.5) or esophageal cancer (OR=0.7; 
95% CI=0.3–1.4).   GLYPHOSATE    FINAL    
Page 17 of 87 
  Table 2. Summary of Findings: Solid Tumor Cancer Studies 
 
Study  
Study Design  
Exposure Assessment Risk Estimate: Risk Ratio 
(RR) / Odds Ratio (OR)  (95% Confidence Interval CI)  
Conclusions  
Potential Confounders Considered 
Cancer at Multiple Sites 
De Roos et al. (2005) 
 AHS: Iowa and North Carolina, U.S.A. Cohort 
 1993-2001  54,315 licensed 
pesticide applicators Self-report 
questionnaire; validated, reliability tested; adjusted for other pesticides 
 All cancers  
RR =1.0 (0.9-1.2)     
 No association 
between glyphosate exposure and all cancer including NHL Age at enrollment 
(continuous), education, cigarette smoking, alcohol consumption, family history of cancer 
in first degree relatives, 
and state of residence (dichotomous: Iowa/NC) 
Site-Specific Cancers: Lung; Oral cavity; Colon; Rectum; Kidney; Bladder; Prostate and Melanoma 
De Roos et al. (2005) 
 
AHS: Iowa and North 
Carolina, U.S.A. Cohort 
 
1993-2001 
 54,315 licensed pesticide applicators Self-report 
questionnaire; 
validated, reliability 
tested; adjusted for other pesticides  Lung 
RR= 0.9 (0.6-1.3) 
Oral Cavity 
RR=1.0 (0.5-1.8) 
Colon 
RR=1.4 (0.8-2.2) Rectum 
RR=1.3 (0.7-2.3) Pancreas 
RR=0.7 (0.3-2.0) Kidney 
RR=1.6 (0.7-3.8) Bladder 
RR=1.5 (0.7-3.2) Prostate 
RR=1.1 (0.9-1.3) Melanoma 
RR=1.6 (0.8-3.0) No significant 
association 
between glyphosate 
exposure and cancer of the lung, oral cavity, colon, rectum, pancreas, 
kidney, bladder, 
prostate or melanomas Age at enrollment 
(continuous), education, 
cigarette smoking, 
alcohol consumption, family history of cancer in first degree relatives, and state of residence 
(dichotomous: Iowa/NC) 
  GLYPHOSATE    FINAL    
Page 18 of 87 
  Table 2. Summary of Findings: Solid Tumor Cancer Studies 
 
Study  
Study Design  
Exposure Assessment Risk Estimate: Risk Ratio 
(RR) / Odds Ratio (OR)  (95% Confidence Interval CI)  
Conclusions  
Potential Confounders Considered 
Site-Specific Cancers: Breast Cancer 
 Engel et al. (2005) 
 AHS: Iowa and North Carolina, U.S.A. Nested Case-Control 
 1993-1997  30,454 wives of 
licensed pesticide 
applicators with no history of breast cancer at enrollment Self-report 
questionnaire  
 
  
 Direct exposure  
(wives who applied)  OR=0.9 (0.7-1.1)  (Exposed: 82 cases, 10,016 controls) 
 
Indirect exposure (wives whose husbands applied)  OR=1.3 (0.8-1.9) (Exposed: 109 cases, 
9,304 controls) 
 No association 
between glyphosate exposure and breast cancer Age, race and state of 
residence (Iowa and North Carolina). Limited to licensed applicators. Potential exposure to 
multiple pesticides 
Site-Specific Cancers: Pancreatic Cancer  
Andreotti et al.  (2009) 
 
AHS: Iowa and North 
Carolina, U.S.A. Nested Case-Control 
 
1993-1997; follow-
up to 2004   93 cases 82,503 controls  Self-report 
questionnaire; 
validated, reliability 
tested Ever-use 
OR=1.1 (0.6, 1.7)  
(Exposed: 55 cases) No association 
between glyphosate 
exposure and 
pancreatic cancer  Age, smoke, diabetes, 
applicator type. Limited 
to licensed applicators. 
Potential exposure to multiple pesticides  GLYPHOSATE    FINAL    
Page 19 of 87 
  Table 2. Summary of Findings: Solid Tumor Cancer Studies 
 
Study  
Study Design  
Exposure Assessment Risk Estimate: Risk Ratio 
(RR) / Odds Ratio (OR)  (95% Confidence Interval CI)  
Conclusions  
Potential Confounders Considered 
Site-Specific Cancers: Prostate Cancer  
Alavanja et al.  (2003) 
 
AHS: Iowa and North 
Carolina, U.S.A.  Nested Case-Control 
 
1993-1997; cancer 
thru 1999   55,332 male applicators 
 Self-report 
questionnaire; 
validated, reliability 
tested  No quantitative risk estimate 
reported No quantitative 
estimate due to lack 
of significant 
exposure-response association with prostate cancer.  Age, family history. 
Limited to licensed 
applicators. Potential 
exposure to multiple pesticides 
Band et al. (2011) 
 
British Columbia, Canada Case-Control 
 
1983- 1990  1,516 prostate cancer patients 
4,994 age-matched 
controls  Job exposure matrix 
for agriculture; 
detailed occupational history; exposure aggregated over all jobs reported. 60 
exposed cases OR=1.36 (0.83-2.25) 
(Exposed: 25 cases 
60 controls) No association 
between glyphosate 
exposure and prostate cancer Alcohol consumption, 
cigarette years, education 
level, pipe smoking years and respondent 
Koutros et al.  (2013) 
 AHS: Iowa and North Carolina, U.S.A.  Nested Case-Control 
 1993-2003   1,962 incident cases,
including 919 
aggressive prostate cancers among 54,412 applicators  Self-report 
questionnaire, validated  OR=0.93 (0.73-1.18) No association 
between glyphosate exposure and prostate cancer Age, state, race, family 
history of prostate cancer, smoking, fruit servings, and leisure-time physical activity in the winter 
 GLYPHOSATE    FINAL    
Page 20 of 87 
  Table 2. Summary of Findings: Solid Tumor Cancer Studies 
 
Study  
Study Design  
Exposure Assessment Risk Estimate: Risk Ratio 
(RR) / Odds Ratio (OR)  (95% Confidence Interval CI)  
Conclusions  
Potential Confounders Considered 
Site-Specific Cancers: Colorectal Cancer  
Lee et al. (2007) 
 AHS: Iowa and North Carolina, U.S.A. 
 Nested Case-Control 
 1993-97; follow-up to 2002  
56,813 licensed 
pesticide applicators  Self-report 
questionnaire Colon  
OR=1.0 (0.7-1.5) 
(Exposed: 151 cases  49 controls)  
Rectum  
OR=1.6 (0.9-2.9) 
(Exposed: 74 cases 18, controls)  Colorectal 
OR=1.2 (0.9-1.6) (Exposed: 225 cases 67 controls) No significant 
association between glyphosate exposure and colon, rectum or 
colorectal cancer 
 Age, smoking, state, total 
days use pesticides. Limited to licensed applicators. Potential exposure to multiple 
pesticides 
 
Site-Specific Cancers: Cutaneous Melanoma  
Dennis et al.  (2010) 
 
AHS: Iowa and North 
Carolina, U.S.A. 
 Nested Case-Control 
1993-1997 
 
150 cases,  24,554 non-cases  AHS self-report 
questionnaire 
 No quantitative risk estimate 
reported No quantitative 
estimate due to lack 
of an association 
with cutaneous melanoma Age, sex, tendency to 
burn, red hair, sun 
exposure time, BMI at 20 
years  GLYPHOSATE    FINAL    
Page 21 of 87 
  Table 2. Summary of Findings: Solid Tumor Cancer Studies 
 
Study  
Study Design  
Exposure Assessment Risk Estimate: Risk Ratio 
(RR) / Odds Ratio (OR)  (95% Confidence Interval CI)  
Conclusions  
Potential Confounders Considered 
Site-Specific Cancers: Soft Tissue Sarcoma  
Pahwa et al. (2011) 
 Canada   
Case-Control 1991-1994 
 
342 cases,  1506 age/resident matched controls  
 Self-reported use, 
structured interview/ questionnaire; 
cumulative exposure 
(+/-10 days/yr) OR=0.90 (0.58-1.40) No association 
between glyphosate exposure and soft 
tissue sarcoma 
 Significant medical 
history variables and with strata for the variables of 
age group and province 
of residence  
Total Childhood Cancer  
Flower et al. (2004) 
 AHS: Iowa and North Carolina, U.S.A. 
 Nested Case-
Control; hybrid prospective/ retrospective   
1993-1998  
 21, 375 children of licensed pesticide applicators 
 
In Iowa (n=17,357) North Carolina (n=4018) Self-report 
questionnaire; duration and frequency of pesticide use; Female Family 
questionnaire (child 
name)  Maternal use 
OR=0.61 (0.32-1.16) 
32 cases    
 
Paternal use (prenatal)  
OR=0.84 (0.35-2.34);   No association was 
detected between frequency of parental pesticide application of 
glyphosate and 
childhood cancer risk. Potential exposure to 
other pesticides. Child age in multiple logistic  
[standardized incidence ratio (SIR)]  was 
unadjusted GLYPHOSATE    FINAL    
Page 22 of 87 
  Table 2. Summary of Findings: Solid Tumor Cancer Studies 
 
Study  
Study Design  
Exposure Assessment Risk Estimate: Risk Ratio 
(RR) / Odds Ratio (OR)  (95% Confidence Interval CI)  
Conclusions  
Potential Confounders Considered 
Brain Cancer (Glioma)  
Lee et al. (2005a) 
 Nebraska  Population based 
Case-Control study  
1988-1993;  
 251 glioma cases 498 controls Self-reported 
questionnaire information, telephone 
follow-up for unclear 
responses; men and women assessed separately Self-Report 
OR=0.4 (0.1- 1.6) 
(Exposed: 4 cases 
17 controls)  
 Overall  
OR=1.5 (0.7-3.1)  (Exposed: 17 cases 
32 controls) 
 Proxy report  
OR=3.1 (1.2- 8.2) (Exposed:13 cases 15 controls) 
 
  Non-significant 
excess risk for the overall group, but 
inconsistent for 
self-report and proxy indicating recall bias Age, proxy, respond type 
 
Ruder et al. (2004) 
 Upper Midwest Health Study (Iowa, 
Michigan, Minnesota 
and Wisconsin, U.S.A.)  Population-based 
Case-Control   1995-1997 
 
457 glioma cases  648 population controls 
 Self-report 
questionnaire, with telephone based follow-up  No quantitative risk estimate 
reported for glyphosate.  No association with 
glyphosate exposure and brain cancer 
 Farm residence, age, use 
of other pesticides  GLYPHOSATE    FINAL    
Page 23 of 87 
  Table 2. Summary of Findings: Solid Tumor Cancer Studies 
 
Study  
Study Design  
Exposure Assessment Risk Estimate: Risk Ratio 
(RR) / Odds Ratio (OR)  (95% Confidence Interval CI)  
Conclusions  
Potential Confounders Considered 
Carreon et al. (2005) 
 Upper Midwest Health Study (Iowa, Michigan, Minnesota 
and Wisconsin)  Population-based 
Case-Control   1995-1997   
341 glioma cases, 
528 controls Self-report 
questionnaire   Proxy respondents 
OR=0.75 (0.4-1.3) 
(Exposed: 18 cases 41 Controls)  
Excluding proxy 
OR=0.6 (0.3-1.2) 
(Exposed:10 cases)  No association with 
glyphosate exposure and brain cancer Age, education and use of 
other pesticide 
Yin et al. (2012)  Upper Midwest Health 
Study (Iowa, 
Michigan, Minnesota and Wisconsin)  Population-based 
Case-Control  
 
1995-1997  
 798 glioma cases 1,175 controls
  Self-report 
questionnaire Home/garden use 
 
OR=0.98; 95% CI=0.67 - 1.43;  
 
Non-farm jobs: OR=0.83; 95% 
CI=0.39-1.73)    
 
   No significant 
positive association with glyphosate 
exposure and brain 
cancer Age, sex, education and 
use of other pesticide  GLYPHOSATE    FINAL    
Page 24 of 87 
  Table 2. Summary of Findings: Solid Tumor Cancer Studies 
 
Study  
Study Design  
Exposure Assessment Risk Estimate: Risk Ratio 
(RR) / Odds Ratio (OR)  (95% Confidence Interval CI)  
Conclusions  
Potential Confounders Considered 
Esophagus and Stomach Cancer  
Lee et al. (2004b) 
 Nebraska, U.S.A. 
 
     Population based 
Case-Control  
 
1988-1993  137 esophageal cases; 
 
170 stomach cases;  502 controls Self-report pesticide 
use, telephone structured interview Esophagus 
OR=0.7 (0.3-1.4) 
(Exposed:12 cases 
46 controls) 
 Stomach  
OR=0.8 (0.4-1.5)  (Exposed: 12 cases 
46 controls) 
 No association with 
glyphosate exposure and 
esophagus or 
stomach cancer  Age, sex 
 
             GLYPHOSATE    FINAL    
Page 25 of 87 
  2. Non-Solid Tumor Cancer Sites  
A number of studies evaluating the possible link between pestic ide use and lymphohematopoietic 
cancers such as leukemia, multiple myeloma and NHL are presented in Table 3. 
 
(i) Leukemia 
 
In a population-based case-control st udy in Iowa and Minnesota, Brown et al. (1990) investigated 
leukemia risk and pesticide use; authors did not observe an association with the ever-use of 
glyphosate in this study (OR=0.9; 95% CI=0.5–1 .6). The study population (578 cases; 340 living 
and 238 deceased and 1245 controls) was identified  from cancers reported to state registry or 
authorities in 1981–1984, and the pes ticide exposure assessment wa s performed through in-person 
interviews which the author s state likely reduced the exposure misclassification ( i.e. incorrect 
exposure information). Although the large sample si ze is a strength of this study, the limitations 
include not controlling for exposur e to other pesticides, limited power for studying the effects of 
glyphosate use, and the potential for recall bias.  In a Swedish population-based case-control study, 121 cases in men and 484 controls matched for 
age and sex were identified in 1987–1992 throug h the Swedish cancer re gistry. The authors 
reported a non-statis tically significant el evated risk of hairy cell le ukemia in relation to glyphosate 
use (OR=3.1; 95% CI=0.8–12.0), controlling for ag e, sex, and residential location. However, 
because these results are based on only 4 glyphosat e-exposed cases and 5 exposed controls as 
noted by the authors, this risk should be interp reted with caution. Also, th ere was limited power to 
detect an effect and there was no adjustment for other exposures. At this time, there is limited 
available literature concerning glyph osate use and leukemia (Nordstrom et al., 1998). 
 
(ii) Multiple Myeloma 
 
In a follow-up analyses using the same study population from Iowa and Minnesota Brown et al.  
(1993) investigated whether pesticide use is also  related to multiple myeloma. Among men in Iowa 
(173 cases, 605 controls), the aut hors observed a statistically non-si gnificant elevated association 
with glyphosate use (OR=1.7; 95% CI=0.8–3.6). Howeve r, the authors caution that while the study 
may lend support to the role of pesticides in ge neral, the study limitatio ns preclude use of the 
evidence as a definitive finding for any one compound. 
 De Roos et al. (2005) reported a suggestive associ ation between multiple myeloma and 
glyphosate-exposed pesticide applicators based on a small number (32) of cases. For applicators 
with the full data set (54,315) and without ad justment for other variables the OR was 1.1; 
95% CI=0.5–2.4. In the fully adjusted model, ther e was a non-statis tically significantly elevated 
risk (OR=2.6; 95% CI=0.7–9.4), however, the number of  participants included in this analysis was 
lower (n=40,716) due to missing data for the covari ates. The authors postula ted that the increased 
myeloma risk could be due to bias resulting from a selection of subjects in adjusted analyses that 
differed from subjects include d in unadjusted analyses. 
 GLYPHOSATE    FINAL    
Page 26 of 87 
   
Sorahan (2015), using Poisson regression, re-a nalyzed the AHS data reported by De Roos et al. 
(2005) to examine the reason for the disparate find ings in relation to the use of a full data set 
versus the restricted data set. Risk ratios were  calculated for exposed and non-exposed subjects. 
When adjusted for age and sex, the OR was 1.1 2 with the 95% CI of 0.5–2.49 for ever-use of 
glyphosate. Additional adjustment fo r lifestyle factors and use of ot her pesticides did not have any 
effect (OR=1.24; 95% CI=0.52–2.94).  In a population-based case-control study among men in six Canadian provinces between 1991 and 
1994, researchers reported non-statistically signifi cantly elevated odds of multiple myeloma in 
relation to glyphosate use (OR=1.22; 95% CI=0.77–1.93), based upon 32 glyphosate exposed 
multiple myeloma case and 133 controls (Pahwa et al., 2012). 
Kachuri et al. (2013), using the same Canadian study population as above, further explored 
multiple myeloma in relation to days per year glyphosate used in 342 cases of multiple myeloma and 1357 controls. For ever use, the OR=1.19 and 95% CI=0.76–1.87. For light users 
(≤2 days/year) there was no a ssociation (OR=0.72; 95% CI=0.39–1.32; 15 exposed cases); 
whereas, for heavy users (>2 days/ year), th ere was a non-significant increased odds ratio 
(OR=2.04; 95% CI=0.98–4.23; 12 exposed cases). The limitation in this study was the same as the 
previous study ( i.e., the number of cases and controls exposed to glyphosate were very low). 
Landgren et al. (2009), within the AHS study population, in vestigated the association between 
pesticide use and prevalence of monoclonal gammopathy of undetermined significance (or 
MGUS). The MGUS is considered a pre-clinical marker of multiple myeloma progression. The authors did not observe a link with glyphosate use in the AHS cohort (OR=0.50; 
95% CI=0.20–1.0). 
(iii) Lymphoma 
 
The National Cancer Institute (NC I) performed a series of populati on-based case-control studies in 
the Midwestern U.S. in the early to mid- 1980s. These studies incl ude several hundred non-
Hodgkin lymphoma (NHL) cases and controls, the identifie d cases were through disease registries 
which in many cases, were histopathologically conf irmed. The investigators ascertained pesticide 
exposure through use of a structured  interview with follow-up con cerning pesticide use over time.  
 Cantor et al.  (1992), in a case-control study of NHL in terviewed a total of 622 white men and 1245 
population based-controls in Iowa and Minnesota . Only 26 cases and 49 controls ever handled 
glyphosate yielding an OR of 1.1 with the 95% CI of 0.7–1.9. The study, however, did not adjust 
for exposure to other pesticides.   De Roos et al.  (2003) used pooled analysis (n=3,417) of three case-control studies of NHL 
conducted in white men in Nebraska, Kansas an d in Iowa and Minnesota. Based on 36 exposed 
cases and 61 exposed controls, the risk estimates for the asso ciation between glyphosate exposure 
and NHL was significant (OR=2.1; 95% CI=1.1–4.0) in  the logistic regression analyses. However, GLYPHOSATE    FINAL    
Page 27 of 87 
  utilizing hierarchical regression techniques to adjust for exposure  to other pesticide exposures, 
there was an increase risk, but the increase was not sta tistically significant (OR=1.6; 
95% CI=0.90–2.8). Overall, the data showed a suggestive association. 
 Based on the above findings, Lee et al., (2004) examined the relationship between asthma and 
pesticide exposure, and NHL. Pooling data from  several midwestern st ates (IA, MN, and NE) 
increased the study sample size, and additional pe sticide use information was incorporated to 
adjust the risk estimate (duration and frequency of use, telephone follow-up interview). The study 
included 872 men with NHL and 2381 frequency-matc hed controls. The authors reported that the 
OR associated with glyphosate was not statis tically significantly diffe rent among those with 
asthma (OR=1.2; 95% CI=0.4–3.3; 6 exposed cases) and among those without asthma (OR=1.4; 
95% CI=0.98–2.1; 53 exposed cases), adjust ing for age, state and vital status. 
 
The three studies discussed above (Cantor et al., 1992; De Roos et al., 2003 and Lee et al., 2004) 
reflect the same population in the AHS and used different levels of information (duration and 
frequency of exposure) and differe nt analytic techniques [hierarc hical regression and stratified 
analysis (by atopy)]. While studie s with increasing levels of re finement to methodology report a 
stronger risk estimates in relati on to glyphosate, additional studies are needed to exclude the role 
of chance and other limitations that may e xplain positive (non-statistically significant) 
associations.  A population-based case–control stu dy (Hardell and Erickson, 1999) investigated the exposure to 
pesticides as a risk factor for NHL in Sw eden during 1987–1990. Exposure data were ascertained 
by comprehensive questionnaires and supplemented by telephone interviews . Of the 404 cases and 
741 controls, only 4 glyphosate-expo sed cases and 3 controls were included in the study. In a 
univariate analysis, the risk estimate wa s elevated, but precision was low (OR=2.3; 
95% CI=0.40–13.0).  Hardell et al. (2002) analyzed pooled data from two case-control studies from Sweden that 
examined NHL (Hardell and Erickson, 1999) and another on hairy cell leukemia, a subtype of 
NHL (Nordstrom et al., 1998). In the univariate analysis gl yphosate exposure was found to be 
significantly increased (OR=3.04; 95% CI=1.08–8.52) but, when study s ite, and vital status were 
considered in a multivariate analyses, there wa s a non-statistically elev ated risk among glyphosate 
users (OR=1.85; 95% CI=0.55–6.20). However, the wide  range of the CI suggest that the study is 
under powered and, therefore the findings do not a llow definitive conclusion on the association of 
NHL and glyphosate exposure.  In another case-control study in Sweden (1999–2003), Eriksson et al. (2008) examined the effects 
of exposure to different agents and NHL among 910 NHL cases and 1016 non-NHL controls. 
Glyphosate exposure which was reported in 29 ca ses and 18 controls produced an OR of 2.02 
(95% CI=1.10–3.71) in a univari ate analysis and an OR of  1.51 (95% CI=0.77–2.94) in a 
multivariate analysis conducted to clarify the relative importance of exposure to different 
pesticides. When exposure was for more than 10 days/year, the OR was 2.36 (95% CI=1.16–4.40) GLYPHOSATE    FINAL    
Page 28 of 87 
  and for exposure less than 10 days/year, the OR was 1.69 (95% CI=0.7–4.07). The risk estimate 
was elevated also for B-cell lymphoma and glyphosate exposure (OR=1.87; 95% CI=0.998–3.51). 
 McDuffie et al.  (2001) in a multicenter-population base d study among men of six Canadian 
provinces estimated the association between glyphosate and NHL. The study included 517 cases 
and 1506 controls identified betwen1991and 1994 th rough provincial cancer registries. In this 
study, authors histopathologically confirmed 84% of cases, implemented a two-tiered exposure 
questionnaire; and assessed the validity of the que stionnaire through quality control studies both of 
which increased the accuracy of th e test results. There was a non-sta tistically significant increased 
risk of NHL from glyphosate exposure. The OR was 1.26 and the 95% CI was 0.87–1.80 for 51 exposed cases, adjusted for age and provin ce and the OR was 1.20 with a 95% CI of 0.83–1.74 
when adjusted for age, province and high-risk exposure (adjusted for st atistically significant 
medical variables such as history of measles, mumps, cancer, allergy desensitization shots, and a 
positive family history of cancer in a first-degree relative).  In a follow-up study which controlled for exposure to other pesticides, the risk to NHL from 
glyphosate exposure was attenuate d. Glyphosate exposure which was reported in 19 cases and 78 
controls produced an OR of 0.92 with 95% CI of 0.54–1.55 (Hohenadel et al. , 2011). Within this 
series of studies, the authors al so evaluated Hodgkin lymphoma (HL) , and observed little statistical 
evidence of an association, using similar st udy design and methods. Among the 38 cases exposed 
to glyphosate the OR was 0.99 with a 95% CI of 0.62–1.56 (Karunanayake et al.,  2012). 
 In a hospital-based case control study conduc ted between 2000 and 2004 in France, authors 
identified 491 NHL cases and 456 age-and sex-ma tched controls, and performed telephone-based 
questionnaire to assess pesticide and other c onfounding variables. There was no association 
between NHL and glyphosate use; for the 12 expo sed cases, the OR was 1.0 and the 95% CI was 
0.5–2.2). For Hodgkin lymphoma, for the 6 exposed cases, the OR was 1.7 and the 95% CI was 
0.6–5.0 (Orsi et al., 2009). 
 The EPILYMPH case-control study was conducted across six countries in Europe (Czech 
Republic, France, Germany, Ireland, Italy, and Spain) to explore the role of occupational exposure 
to specific chemicals and risk  of lymphoma overall, B-cell lymphoma and other subtypes. 
Although the study recruited 2348 cases and 2462 cont rols, only a very small number of cases 
were exposed to glyphosate (n=4 ) and controls (n=2). A non-si gnificant increase in OR was 
observed for B-cell lymphoma (OR=3.1; 95% CI=0.6–17.1) , but the estimate is unstable due to the 
small number of exposed cas es and controls (Cocco et al.,  2013) 
 Schinasi and Leon (2014) conducte d a meta-analysis exploring o ccupational glyphosate exposure 
and NHL using data from six of the above mentioned studies (McDuffie et al., 2001; Hardell et al., 
2002; DeRoos et al., 2003 and 2005; Eriksson et al., 2008; and Orsi et al., 2009). Since the authors 
identified a variety of sources of heterogeneity between publica tions, they calculated meta-risk 
ratio (RR) estimates and 95% CIs using ra ndom effect models, allowing between study 
heterogeneity to contribute to  the variance. They reported I2 values, which represented the GLYPHOSATE    FINAL    
Page 29 of 87 
  percentage of the total variance explained by st udy heterogeneity and measure inconsistency in 
results. Larger I2 values indicate greater inconsistency. Fo r glyphosate, the meta-risk ratio was 1.5 
with a 95% CI of 1.0–2.0 and the I2 value was 32.7% indicating greate r inconsistency in these data 
sets. This study combined multiple smaller studies th at on their own were very limited in statistical 
power to detect differences.  The 2015 IARC evaluation noted that fully adjusted risk estimates in two of the Swedish studies 
(Hardell et al., 2002 and Eriksson et al., 2008) were not used in the analysis conducted by Schinasi 
and Leon (2014). Consequently, IARC conducted a reex amination of the results of these studies. 
For an association between glyphosate exposure a nd NHL, the IARC estimated a meta-risk ratio of 
1.3 (95% CI=1.03–1.65), I
2 =0%; p=0.589 for heterogeneity) (IARC 2015). 
  GLYPHOSATE    FINAL    
Page 30 of 87 
  Table 3. Summary of Findings: Non Solid Tumor Cancer Studies 
 
Study  
Study Design  
Exposure Assessment Risk Estimate: Risk Ratio 
(RR/ Odds Ratio (OR)  
(95% CI)  
Conclusions  
Potential Confounders 
Considered 
Leukemia 
Brown et al. (1990 ) 
 
Iowa and Minnesota, U.S.A. Population-based 
Case-Control 
 1981-1984  578 cases 
1245 controls 
 In person interview; 
surrogates used.  OR=0.9 (0.5-1.6) 
(Exposed:15 cases 
49 controls) No association 
between 
glyphosate exposure and leukemia Vital status (alive, dead), 
residency (IA or MN), 
tobacco use, parent, sibling, or child with a lymphopoietic cancer, high risk occupation and exposure to substances 
(benzene, hair dyes etc) related 
to risk of leukemia 
Nordstrom et al. 
(1998)  Sweden Population-based 
Case-Control  1987-1992  121 cases 
484 controls 
 Self-reported pesticide 
questionnaire and follow-up telephone interview   
 
 OR=3.1 (0.8-12) 
(Exposed: 4 cases 5 controls) A non-statistically 
significant elevated risk of hairy cell leukemia Age, sex, country of residence 
(selected using matching, dissolved matching analyses) No adjustment for exposure from other pesticides 
Multiple Myeloma 
Brown et al. (1993 ) 
 
Iowa, U.S.A. Population based 
Case-Control 
 
1981-1984  173cases 650 controls Interview based 
questionnaire with 
follow-up OR=1.7 (0.8-3.6) 
(Exposed: 11 cases 
40 controls) Limited power to 
assess association 
of glyphosate 
exposure and multiple myeloma Age and vital status 
 
 
   GLYPHOSATE    FINAL    
Page 31 of 87 
  Table 3. Summary of Findings: Non Solid Tumor Cancer Studies 
 
Study  
Study Design  
Exposure Assessment Risk Estimate: Risk Ratio 
(RR/ Odds Ratio (OR)  
(95% CI)  
Conclusions  
Potential Confounders 
Considered 
De Roos et al. (2005) 
 Iowa and North Carolina, U.S.A. Prospective 
Cohort  1993-2001  54,315 licensed 
pesticide applicators Self-administered 
questionnaire Full data set 
RR =1.1 (0.5-2.4) 
(Exposed: 32 cases)  Adjusted for age etc 
RR=2.6 (0.7-9.4) No risk for full 
data set. Excess risk only with no missing information of 22 cases in the 
restricted data set 
(Sorahan, 2015) Missing data on covariates 
when multiple adjustments were made, limiting interpretation  
Orsi et al. (2009) 
 
France Hospital based Case-
Control 
 
2000-2004  491 cases 456 controls Self-report 
questionnaire, with 
follow-up telephone 
based questionnaire, expert review; two stage exposure collection process OR=2.4 (0.8-7.3) 
(Exposed: 5 cases 
18 controls) No significant 
association with 
glyphosate 
exposure and multiple myeloma Age, center, socioeconomic 
category 
Pahwa et al. (2012)  
 Canada Population based 
Case-Control  1991-1994 
 
342 cases 1506 controls Self-reported pesticide 
use, structured interview with questionnaire; 
cumulative exposure 
(+/-10 days/yr)  OR=1.22 (0.77-1.93) 
(Exposed: 32 cases 133 controls) No significant 
association with glyphosate exposure and 
multiple myeloma Significant medical history 
variables (history of measles, history of mumps, history of allergies, history of arthritis, 
history of shingles, and a 
positive family history of cancer in a first-degree relative), and with strata for the variables of age group and 
province of residence GLYPHOSATE    FINAL    
Page 32 of 87 
  Table 3. Summary of Findings: Non Solid Tumor Cancer Studies 
 
Study  
Study Design  
Exposure Assessment Risk Estimate: Risk Ratio 
(RR/ Odds Ratio (OR)  
(95% CI)  
Conclusions  
Potential Confounders 
Considered 
Kachuri et al. (2013) 
 Canadian Provinces Population based 
Case-Control  1991-1994  342 cases 
1357 controls 
  Self-administered 
questionnaire For ever use 
OR=1.19 (0.76-1.87) 
Exposed: 32 cases 121controls  Light (<2 d/yr) use 
OR=0.72 ( 0.39 -1.32) Exposed: 15 cases 88 controls   Heavy (>2 d/yr) use 
OR=2.04 (0.98-4.23) Exposed: 12 cases 29 controls No association 
with glyphosate exposure and multiple myeloma for ever or light users 
Increase for heavy 
users is non-significant   
 
 Relatively low response rate 
Monoclonal Gammopathy of Undetermined Significance (MGUS) 
Landgren et al. (2009) 
 
AHS: Iowa and North Carolina, U.S.A. Nested Case-Control 
 
1993-1997  678 participants Self-administered 
questionnaire OR=0.5 (0.2-1.0) No association 
with glyphosate 
exposure and MGUS, a premalignant disorder that often precedes multiple 
myeloma  Age and education GLYPHOSATE    FINAL    
Page 33 of 87 
  Table 3. Summary of Findings: Non Solid Tumor Cancer Studies 
 
Study  
Study Design  
Exposure Assessment Risk Estimate: Risk Ratio 
(RR/ Odds Ratio (OR)  
(95% CI)  
Conclusions  
Potential Confounders 
Considered 
Non-Hodgkin Lymphoma (NHL) 
Cantor et al.  (1992) 
 
Iowa and Minnesota, U.S.A. Population based 
Case-Control 
 1980-1983  622 cases 
1245 controls Structured interview, 
questionnaire 
response; farm activities and specific pesticide use   OR=1.1 (0.7-1.9) 
Exposed: 26 cases 
49 controls No association 
with glyphosate 
exposure and NHLVital status, age, state, 
smoking, family history, high 
risk occupation, high risk exposure. Not controlled for exposure to other pesticides.  
De Roos et al.  (2003) 
 Iowa, Nebraska, Minnesota, Kansas, 
U.S.A. Case-Control 
 1983-1986\Nebraska  
1979-1981\Kansas 
1979-1986  870 white male cases 
2569 white male 
controls Interview-based 
questionnaire, demographic Logistic regression 
OR=2.1 (1.1-4.0) 
Exposed: 36 cases 61 controls 
 
Hierarchical regression  
OR=1.6; (0.9-2.8)  Significant 
increased OR in logistic model but in the hierarchical 
model, the OR 
attenuated and no significant association with glyphosate 
exposure and NHLAge, study site, use of all other 
pesticides (group); hierarchal regression informed priors based on chemical-specific 
information  
Lee et al. (2004a) 
 Iowa, Nebraska, Minnesota, U.S.A Population based 
Case-Control  1980-1986  
872 white male 
cases    In person, structured 
interview (pesticide use, duration, frequency, first and last year used); 5-yr 
follow-up interview, 
10-min telephone on pesticide use Non-asthmatic 
OR=1.4 (0.98-2.1) 
(Exposed: 53 cases 91 controls) 
 
Asthmatic 
OR=1.2 (0.4-3.3) 
(Exposed: 6 cases 
12 controls) No significant 
association with glyphosate exposure and NHL either for 
asthmatics or non-
asthmatics Adjusted for age, vital status, 
state  GLYPHOSATE    FINAL    
Page 34 of 87 
  Table 3. Summary of Findings: Non Solid Tumor Cancer Studies 
 
Study  
Study Design  
Exposure Assessment Risk Estimate: Risk Ratio 
(RR/ Odds Ratio (OR)  
(95% CI)  
Conclusions  
Potential Confounders 
Considered 
De Roos et al.  (2005) 
 AHS: Iowa and North Carolina, U.S.A. Nested Case-Control 
 1993-2001  54,315 licensed pesticide applicators Self-administered 
questionnaire OR=1.1 (0.7-1.9 
(Exposed: 92 cases)  No significant 
association with glyphosate exposure and NHLAge, smoking, other 
pesticides, alcohol consumption, family history of cancer, education 
Hardell and Erickson (1999) 
 
Sweden Population based 
Case-Control 
 
1987-1990  404 male cases 741 male controls Questionnaire and 
follow-up interview Univariate 
OR=2.3 (0.4-13.0)  
(Exposed: 4 cases 
3 controls)  Multivariate 
OR=5.8 (0.6-54) Some evidence of 
a link with 
glyphosate, 
matching variables; cannot conclude regarding causal 
role for any 
specific pesticide Age, region, vital status 
(matching). Few subjects 
exposed. Variables used in 
multivariate were no specified. Study has limited power to detect an effect 
Hardell et al. (2002) 
 Sweden Population based 
Case-Control  Combined Hardell 1999 with another case-control study 
examining hairy cell 
leukemia (one of 61 types of NHL)   1987-1990 
515 cases 
1141 controls Questionnaire and 
follow-up interview Univariate 
OR=3.04 (1.08-8.52) 
(Exposed: 8 cases 8 controls)  Multivariate 
OR=1.85 (0.55-6.20) Risk attenuates 
when adjusted for other variables in the multivariate analysis Age, country, study site, vital 
status, other pesticide exposure in the multivariate analysis  GLYPHOSATE    FINAL    
Page 35 of 87 
  Table 3. Summary of Findings: Non Solid Tumor Cancer Studies 
 
Study  
Study Design  
Exposure Assessment Risk Estimate: Risk Ratio 
(RR/ Odds Ratio (OR)  
(95% CI)  
Conclusions  
Potential Confounders 
Considered 
Eriksson et al. (2008) 
 Sweden    
 
    
 
 Population based 
Case-Control  1999-2002  910 cases 
1016 controls 
  Questionnaire and 
follow-up interview Univariate 
OR=2.02 (1.10-3.71) 
(Exposed: 29 cases 18 controls)  Multivariate 
OR=1.55 (0.77-2.94)   With <10 days/ year 
OR=1.69 (0.7-4.07) (Exposed: 12 cases 
9 controls) 
With > 10 days/year 
OR=2.36 (1.04-5.37) (Exposed: 17 cases 9 controls) 
 
B-cell lymphoma 
OR=1.87 (0.998-3.51) Suggestive 
association for NHL with glyphosate exposure  
 
 Age, sex, year of diagnosis. 
Multivariate analysis adjusted for exposure to other pesticides 
McDuffie et al.  (2001) 
 Canada Population based 
Case-Control  1991-1994  
517 cases 
1506 controls Two-tiered self-report 
questionnaire; cumulative exposure (> 10 days/yr) 
Univariate 
OR=1.26 (0.87-1.8) (Exposed: 51 cases 133 controls)  
Multivariate 
OR=1.20 (0.83-1.74) No significant 
association with glyphosate exposure and NHLAdjusted for statistically 
significantly medical variables (history of measles, mumps, cancer, allergy shots, and a positive family history of 
cancer) males only GLYPHOSATE    FINAL    
Page 36 of 87 
  Table 3. Summary of Findings: Non Solid Tumor Cancer Studies 
 
Study  
Study Design  
Exposure Assessment Risk Estimate: Risk Ratio 
(RR/ Odds Ratio (OR)  
(95% CI)  
Conclusions  
Potential Confounders 
Considered 
Hohenadel et al.  
(2011)  Canada Case-Control 
 1991-1994 513 cases 1506 controls Two-tiered self-report 
questionnaire; cumulative exposure (> 10 days/yr) 
OR=0.92 (0.54-1.55) (Exposed: 19 cases 78 controls) No significant 
association with glyphosate exposure and NHLAge, province and proxy 
respondent, males only 
Orsi et al. (2009) 
 
France Hospital based 
Case-Control 
 
2000-2004  491 cases 456 controls Self-report 
questionnaire, with 
follow-up telephone 
based questionnaire, expert review; two stage exposure collection process OR=1.0 (0.5-2.2) 
(Exposed: 12 cases 
24 controls) 
  No association 
with glyphosate 
exposure and NHLAge, center, socioeconomic 
category 
Cocco et al.  (2013) 
 Czech Republic, France, Germany, Italy, Ireland and Spain EPICLYMPH  
 Case-Control  1998–2003 2348 cases  
2462 controls  Occupational 
exposure; trained interviewers conducted in person interviews with cases and controls  OR=3.1 (0.6-17.1) 
(Exposed: 4 cases 2 controls) No significant 
association with glyphosate exposure and B-cell Age, center, socioeconomic 
category   
Hodgkin Lymphoma  
Orsi et al. (2009) 
 
France  Hospital based 
Case-Control 
 
2000-2004  491 cases 456 controls Self-report 
questionnaire, with 
follow-up telephone 
based questionnaire, expert review; two stage exposure collection process OR=1.7 (0.6-5.0) 
(Exposed: 6 cases 
15 controls) No significant 
association with 
glyphosate 
exposure and HL Age, center, socioeconomic 
category GLYPHOSATE    FINAL    
Page 37 of 87 
  Table 3. Summary of Findings: Non Solid Tumor Cancer Studies 
 
Study  
Study Design  
Exposure Assessment Risk Estimate: Risk Ratio 
(RR/ Odds Ratio (OR)  
(95% CI)  
Conclusions  
Potential Confounders 
Considered 
Karunanayake et al.,  
(2012).   Canada Case-Control 
 1991-1994  361 cases 1,506 controls 
 Questionnaire and 
follow-up interview Univariate 
OR=1.14(0.74-1.76) 
(Exposed :38  133 controls)  Multivariate 
OR=0.99 (0.62-1.56) No association 
with glyphosate exposure and HL History of measles, acne, hay 
fever, shingles and positive family history of cancer in a first-degree relative 
 
                   GLYPHOSATE    FINAL    
Page 38 of 87 
  D. Discussion 
 
In epidemiologic studies, the quality of the exposure assessmen t is a major concern since the 
validity of the evaluations depends in large part on the ability to correctly quantify and classify an 
individual’s exposure. During their life-time, farm ers are typically exposed to multiple pesticides 
and several of them are used together posing a challenge for identifying specific risk factors. 
Moreover, there is no direct info rmation on pesticide exposure or absorbed dose because analyses 
are based on self-reported pesticide use. The studies included in this epidemiology assessment 
relied primarily on questionnaires and interviews to describe part icipants’ past and/or current 
exposure to glyphosate. Since the questionnaires are commonly used  to account for exposure and 
capture self-reporting, it can be subject to misc lassification and recall bias. For example, case-
control studies are at risk  of recall bias in the reporting of pe sticide use in the past because cases 
may have spent more time thinking about past ex posures than controls. This could lead to 
differential misclassification and bi as relative risk from null. The possible effect of confounding 
factors, which are related to bot h the exposure of interest and the risk of disease, may make it 
difficult to interpret the results. Therefore, th e ability of epidemiologic studies to provide 
convincing evidence of causation un der such circumstances may be limited. Causation is suspected 
if several studies are consistent in their findings and; if the association between the agent and the 
risk of disease is strong ( i.e., high risk ratio). Support from animal data will help to make the case 
for causation, particularly by esta blishing biological plau sibility and the existence of a potential 
mechanism. Another important consideration in assessing epidemiologic studies is that 
commercially formulated products (not the active ingredient) are used by farmers. For example, 
glyphosate is sold as Roundup®, which is a comb ination of the active ingredient and other 
chemicals that often include a surfactant (polyeth yleneamine) used to enhance the spreading of 
spray droplets when they cont act the foliage. Thus, it is po ssible that different glyphosate-
containing formulations were used  across the different studies. 
 Most of the studies discussed he re were hypothesis-generating in na ture, consisted of small sample 
sizes with limited power to detect associations  and evaluated use of glyphosate in addition to 
several other pesticides and often evaluated risk of multiple different types of cancer. Therefore, 
the role of chance given the many different stat istical tests performed and the lack of a pre-
specified hypothesis, limit epidemiologic inferen ce. This hypothesis-generating evidence observed 
in the studies requires further prospective follow- up studies to determine whether a true association 
with glyphosate is indeed null. The case-contr ol studies are retrospe ctive studies and are 
susceptible to recall bias for e xposure reporting which could account  for discrepancies in the study 
findings. Variation in the quality of exposure assessment, study design and methods, as well as 
available information concerning potential c onfounding variables could also explain these 
inconsistencies in the data. In contrast, a prospective cohort study evaluates a number of diseases 
simultaneously and facilitates pe rformance of periodic assessments of agricultural and other 
exposures. Periodic assessment of recent exposur es enhances recall and reduces non-differential 
misclassification. The ability to determine exposure prior to the onset of a disease eliminates the 
case-recall bias, which was an issue identif ied as a weakness in case-control studies. 
 GLYPHOSATE    FINAL    
Page 39 of 87 
   
IV. EVALUATION OF CARCINOGENICITY IN ANIMALS  
A total of 11 chronic toxi city/carcinogenicity studies (7 rat a nd 4 mouse) were included in this 
weight of evidence review. Of these, six stud ies were submitted for review to EPA under the 
registration/reregistration programs includi ng two studies in ra ts (MRID No. 496311701 and 
49704601) and one in mouse (MRID No. 49631702) not pr eviously reviewed. Data for review of 
the other five studies were obtained fr om a published review article by Greim et al., 2015 and were 
available online at http://informahealthcare.com/doi/abs/10.3109/10408444.2014.1003423. The 
IARC acknowledged the Greim et al.,  (2015) review article, but did not evaluate the studies cited 
in the review because the information provided in  the review and its supplement was insufficient. 
For this assessment, each study reported in the Greim et al.,  (2015) review article was evaluated in 
accordance with the agency’s 2012 Guidance for Cons idering and Using Open Literature Toxicity 
Studies to Support Human Health Risk Assessment ( http://www.epa.gov/pesticides/science/lit-
studies.pdf). In accordance with this guidance, the followi ng four studies were not included in this 
weight of evidence assessment since there is low confidence were determined to be unreliable for 
carcinogenicity evaluation.    
 A two year feeding study in Sprague-Dawley ra ts (Excel, 1997) was not included due to the 
lack of test article characterizati on (no purity of test material).  
 
 The two-year drinking water study in Wi star rats reported by Chruscielska et al., (2000) 
was not included since the tested material was a formulated product (13.6% ammonium 
salt) and there were a number of deficienci es (lack of purity, water consumption and body 
weight data) in the conduct and reporting of the study.  
 
 An initiation-promotion study (George et al. , 2010) in male Swiss mice that tested a 
commercial formulation of glyphosate (41%) with study deficiencies ( e.g. small number 
(20) of animals, tested only males, a nd lack of histopathological examination).  
 
 A carcinogenicity study in Swiss mice (Feinc hemie Schwebda, 2001) was not included due 
to the presence of vira l infection within the colony, which confounded the interpretation of 
the study findings. Malignant lymphomas we re reported in this study in all groups. 
However, lymphomas are one of the most co mmon types of spontane ous neoplastic lesions 
in aging mice (Brayton et al., 2012). Murine leukemia viru ses (MuLVs) are a common 
cause of lymphoma in many different strains of mice (Ward 2006). Tadesse-Heath et al. 
(2000) reported 50% lymphoma (mostly B-cell or igin) incidence in a colony of Swiss mice. 
Although the incidences in this  study were within or n ear the normal variation of 
background occurrence, it is no t clear whether or not the viral component may have 
contributed to incidence value reported or the lower survival seen at the high dose in the 
study. Raw data are not availabl e to perform appropriate st atistical analyses of the 
lymphomas correcting for the intercurrent mortality. 	GLYPHOSATE    FINAL    
Page 40 of 87 
  	
A. Carcinogenicity Studies in Rats 
 
1. Lankas, G, P. A Lifetime Study of  Glyphosate in Rats. December 23, 1981. 
Unpublished report No. 77-2062 prepared by Bio Dynamics, Inc. EPA Accession. No. 247617 – 247621. MRID No. 00093879. 
  
a. Experimental Design 
 
Groups of Sprague-Dawley rats (50/sex/dose)  were fed diets cont aining glyphosate (98.7%, 
pure) at concentrations of 0, 30, 100 or 300 ppm  for 26 months. These concentrations were 
adjusted during the course of the study so th at actual doses of 0, 3, 10, and 31 mg/kg/day in 
males and 0, 3, 11, and 34 mg/kg/day in females were maintained.  
b. Survival Analysis 
 
 There were no treatment-related eff ects on survival at  any dose level. 
 
c. Discussion of Tumor Data 
 
There was an increase in the incidences of interstitial cell tumors in the testes of male rats at the low (3/5; 6%), mid (1 /50; 2%) and the high dose (6/50; 12%; P=0.013 pairwise 
comparison) when compared to controls (0/5 0; 0%). In 1991, HED’s Cancer Peer Review 
Committee (CPRC) did not consid er the increases to be treatment-related based on the 
following weight of evidence considerations: 1)  lack of dose-response; 2) absence of pre-
neoplastic lesions ( i.e., interstitial cell hyperplasia); 3) the incide nces were within the 
normal biological variation seen for this tumor type  in this strain of rats; 4) the incidences 
in the concurrent controls (0%) was not  representative of the normal background 
incidences noted in the historical contro l animals (mean, 4.5%; range, 3.4% to 6.7%) and 
5) no interstitial cell tumors were seen when te sted at much higher doses in the same strain 
of rats in an another study (discussed belo w). The CARC agreed with the CPRC conclusion 
and rationale and noted additi onal rat studies which also sh owed no effect on interstitial 
cell tumors.  Although there was no evidence of a treatment- related increase in the incidences of 
pancreatic islet cell tumors in male rats, the data are presented in Table 4 since this tumor 
also seen in the second study discussed below. 
  GLYPHOSATE    FINAL    
Page 41 of 87 
   
Table 4. Pancreatic Islet Cell Tumors in  Male Sprague-Dawley Rats (MRID 00093879)  
Tumor Type 0 ppm 30 ppm 100 ppm 300 ppm 
Adenomas (%) 0/50 (0) 5/49 (10) 2/50 (4) 2/50 (4) 
Carcinomas (%) 0/50 (0) 0/49 (0) 0/50 (0) 1/50 (2) 
Combined (%) 0/50 (0) 5/49 (10) 2/50 (4) 3/50 (6) 
 
d. Non-Neoplastic Lesions 
No treatment-related non-neopl astic lesions were seen.  
 
e. Adequacy of the Dosing for A ssessment of Carcinogenicity 
The CPRC concluded that the highest dose tested was not adequate to assess the 
carcinogenic potential of glyphosate. Consequently, a second study was conducted 
(discussed below).     
 
 
2. Stout, L. D. and Rueckerf, P.A. (1990). Chro nic Study of Glyphosate Administered in 
Feed to Albino Rats. Laboratory Proj ect No. MSL-10495; September, 26, 1990, MRID 
No. 41643801; Historical Controls; MRID No. 41728701.  
a. Experimental Design 
 
Groups of Sprague-Dawley rats (60/sex/dose)  were fed diets cont aining glyphosate (96.5%, 
pure) at dietary concentrations of 0, 2000, 8000 or 20,000 ppm 24 months. These levels 
were equivalent to 0, 89, 362 or 940 mg/kg/ day, respectively, for the males and 0, 113, 457 
or 1183 mg/kg/day, respectively, for the females.  An interim sacrifice was conducted on 10 
rats/sex/dose at 12 months.  
b. Discussion of Tumor Data 
 
The most frequently seen tumors were panc reatic cell adenomas, hepatocellular adenomas 
and thyroid C-cell adenomas in males. Data for these tumors and the respective historical control data are presente d in Tables 5 thru 11. 
 Pancreatic cell adenomas are presented in Ta ble 5 and the histori cal control data are 
presented in Table 6. Hepatocellular adenomas seen in males are presented in Table 7 and 
the historical control data are presented in  Table 8. The thyroid C-cell adenomas and/or 
carcinomas observed in males and females are presented in Tables 9 and 10, respectively, 
and the historical control data  are presented in Table 11. 
    GLYPHOSATE    FINAL    
Page 42 of 87 
   
(i) Pancreas 
 
There was no statistically significant trend te st by dose for pancreatic islet cell tumors. 
Increased incidences of adenomas only were observed at the low- a nd high-dose groups but 
not at the mid-dose group.  
Table 5. Pancreatic Islet Cell Tumors  in Male Sprague-Dawley Rats  
Cochran-Armitage Trend & Fisher’s Exact Test (MRID No. 41643801)   
Tumor Type 0 ppm 2000 ppm 8000 ppm 20000 ppm 
Adenomas 
(%) 
P = 1/43a 
(2) 
0.170 8/45 
(18) 
0.018* 5/49 
(10) 
0.135 7/48b 
(15) 
0.042* 
Carcinomas 
(%) 
P= 1/43c 
(2) 
0.159 0/45 
(0) 
0.409 0/49 
(0) 
0.467 0/48 
(0) 
0.472 
Combined 
(%) 
P= 2/43 
(2) 
0.241 8/45 
(18) 
0.052 5/49 
(10) 
0.275 7/48 
(15) 
0.108 
a. Number of tumor-bearing animals/Number of animals exam ined, excluding those that died or were sacrificed 
prior to study week 55. 
b. First adenoma observed at week 81 in the 20,000 ppm group 
c. First carcinoma observed at week 105 in the controls (0 ppm) 
 * Significant in a pair-wise comparison (P<0.05) 
 
Historical control data on the incidence of panc reatic islet cell adenomas in male Sprague-Dawley 
rats in 2-year studies (1983–1989) conducted at the testing facility (M onsanto Environmental 
Health Laboratory; MRID No. 4172 8701) are presented in Table 6. 
 
Table 6. Historical Control Data — Pancreati c Islet Cell Adenomas in Male Sprague- 
Dawley Rats (MRID No. 41728701) 
Study No. 1 2 3 4 5 6 7 
Study Year 07/83 02/85 10/85 6/85 9/88 1/89 3/89 
Tumor Incidence 2/68 5/ 59 4/69 1/57 5/60 3/60 3/59 
% 2.9% 8.5% 5.8% 1.8% 8.3% 5.0% 5.1% 
 
       GLYPHOSATE    FINAL    
Page 43 of 87 
   
The CPRC concluded that the pancreatic islet cell  adenomas are not treatment-related based on the 
following weight of evidence consid erations: 1) although the inciden ces at the low (18%) and high 
(15%) dose groups exceeded the hist orical control range (1.8–8.5%), there was lack of statistical 
significance in Cochran-Armitage tr end test; 2) the tumor incidence in the concurrent control was 
at the low end of the historical control range; 3) considerable inter-group va riability in the numbers 
of males with tumors ( i.e., no dose-response); 4) there were no preneoplastic changes; 5) there was 
no progression from adenomas to carcinomas; and 6)  the apparent statistical significance of the 
pairwise comparisons of the trea ted groups with the concurrent control may be due to the low 
incidences in the controls and not to an actual carcinogenic response. Furthermore, the incidences 
of pancreatic cell tumors for the two studies di d not show dose-response a nd the incidences were 
within the historical control range (0 to 17%) reported in  the open literature (Arnold et al.,  1985; 
Borelli et al. , 1990; Borzelleca et al. , 1986, 1989, 1990; Burnett et al. , 1988; Trochimowicz et al. , 
1988). The CARC agreed with the CPRC conclusi on and rationale and not ed subsequent rat 
studies which also showed no effect on islet cell tumors. 
 
(ii) Liver 
 
There was a dose trend for adenomas only. There we re no statistically significant increases in the 
occurrence of benign or malignant  hepatocellular tumor types (Tab le 7). The observed variations 
in incidence were within the rang e of the historical control data. 
 
Table 7. Glyphosate: Hepatocellular Tumo rs in Male Sprague-Dawley Rats Cochran-
Armitage Trend & Fisher’s Exact Test (MRID No. 41643801)   
Tumor Type 0 ppm 2000 ppm 8000 ppm 20000 ppm 
Adenomas 
(%) 
P = 2/44a 
(5) 
0.016* 2/45 
(4) 
0.683 3/49 
(6) 
0.551 7/48b 
(15) 
0.101 
Carcinomas 
(%) 
P = 3/44 
(7) 
0.324 2/45 
(4) 
0.489 1/49 
(2) 
0.269 2/48c 
(4) 
0.458 
Adenoma/Carcinoma 
(%) 
P = 5/44 
(11) 
0.073 4/45 
(9) 
0.486 4/49 
(8) 
0.431 9/48 
(19) 
0.245 
a. Number of tumor-bearing animals/Number of animals exam ined, excluding those that died or were sacrificed 
prior to study week 55. 
b. First adenoma observed at week 88 in the 20000 ppm group 
c. First carcinoma observed at week 85 in the 20000 ppm group 
  
Historical control data on the incidence of hepatocellular adenomas and carcinomas in male 
Sprague-Dawley rats in 2-year studies (1983–1989) conducted at th e testing facility (Monsanto 
Environmental Health Laboratory; MRID No. 41728701) are presented in Table 8. GLYPHOSATE    FINAL    
Page 44 of 87 
  Table 8. Historical Control Data  : Hepatocellular Adenomas in  
Male Sprague-Dawley Ra ts (MRID No. 41728701) 
Study No. 1 2 3 4 5 6 7 
Study Year 07/83 02/85 10/85 6/85 9/88 1/89 3/89 
Adenomas 5/60 
(8.3%) 11/68 
16.2%) 1/70 
(1.4%) 3/59 
(5.1%) 11/60 
(18.3%) 5/60 
8.3%) 4/60 
(6.7%)
Carcinomas 4/60 
(6.7%) 0/68 
(0%) 1/70 
(1.4%) 2/59 
(3.4%) 3/60 
(5%) 1/60 
(1.7%) 0/60 
(0%) 
 
The CPRC concluded that the slightly increased incidence of adenomas in male rats are not 
treatment-related since: 1) the increase was not st atistically significant in pairwise comparison with 
the controls; 2) the incidences were within the historical control range;  3) except for a single 
animal at the mid-dose late in the study (89 w eeks), no hyperplasia, preneoplastic foci or other 
non-neoplastic lesions were seen; and 4) there was no evidence of progression from adenomas to 
carcinomas. The CARC agreed with the CPRC conclusion and rationale. 
(iii) Thyroid 
The increased incidences in C-cell adenomas obser ved at the mid and high-dose groups of rats of 
both sexes did not show a statis tically significant difference in pairwise comparisons with the 
controls (Table 9 and 10, respectively). Ther e was a dose trend observed for adenomas and 
adenomas/carcinomas in females (P=0.03). Historic al control data are pr esented in Table 11. 
Table 9. Glyphosate: Thyroid C-Cell Tumors in Male Sprague-Dawley Rats 
Cochran-Armitage Trend & Fisher’s Exact Test  
 (MRID No. 41643801) 
Tumor Type 0 ppm 2000 ppm 8000 ppm 20000 ppm 
Adenomas 
(%) 
P = 2/54a, b 
(4) 
0.069 4/55 
(7) 
0.348 8/58 
(14) 
0.060 7/58 
(12) 
0.099 
Carcinomas 
(%) 
p = 0/54 
(0) 
0.452 2/55c 
(4) 
0.252 0/58 
(0) 
1.000 1/58 
(4) 
0.518 
Adenoma/Carcinoma 
(%) 
p = 2/54 
(11) 
0.077 6/55 
(11) 
0.141 8/58 
(14) 
0.060 8/58 
(14) 
0.060 
a. Number of tumor-bearing animals/Number of animals exam ined, excluding those that died or were sacrificed 
prior to study week 55. 
b. First adenoma observed at week 54 in the controls  
c. First carcinoma observed at w eek 93 in the 20,000 ppm 
 GLYPHOSATE    FINAL    
Page 45 of 87 
  Table 10. Glyphosate: Thyroid C-Cell Tumo rs in Female Sprague Dawley Rats 
Cochran-Armitage Trend & Fisher’s Exact Test 
(MRID No. 41643801) 
Tumor Type 0 ppm 2000 ppm 8000 ppm 20000 ppm 
Adenomas 
(%) 
P= 2/57a 
(4) 
0.031* 2/60 
(7) 
0.671 6/59b 
(10) 
0.147 6/55 
(11) 
0.124 
Carcinomas 
(%) 
P= 0/57 
(0) 
0.445 0/60 
(0) 
1.000 1/59c 
(2) 
0.509 0/55 
(0) 
1.000 
Adenoma/Carcinoma 
(%) 
p= 2/57 
(4) 
0.033* 2/60 
(3) 
0.671 7/59 
(12) 
0.090 6/55 
(11) 
0.124 
a. Number of tumor-bearing animals/Number of animals exam ined, excluding those that died or were sacrificed 
prior to study week 55. 
b. First adenoma observed at week 72 in the controls 
c. First carcinoma observed at week  93 in the 8000 ppm group. 
 
Table 11. Historical Control Data – Th yroid C-cell Tumors in Sprague-Dawley 
Rats (MRID No. 41728701) 
Tumor Type Males Females 
Adenomas 1.8 – 10.6% 3.3 – 10.0% 
Carcinomas 0.0 – 5.2% 0.0 – 2.9% 
 
The CPRC concluded that the thyroid tumors in either sex are not treatment-related since: 
1) the increased incidences exhibited no st atistically significant trend or pairwise 
comparisons with the controls in males; 2) in females, there was a trend but no pairwise 
significance; 3) there was no progression from adenomas to carcinomas; and 4) there was no 
dose-related increase in severity of grade or incidence of hyperplasia in males or females. 
The CARC agreed with the CPRC conclusion and rationale and noted other rat studies which 
showed no effect on thyroid C-cell tumors. 
 
c. Non-Neoplastic Lesions 
 There were no treatment-related pr ecursor lesions at any dose level. 
 
d. Adequacy of the Dosing for A ssessment of Carcinogenicity 
Dosing was considered to be adequate to assess carcinogenicity since the highest dose 
tested was near or beyond the limit dose (1000 mg/kg/day). 
 
 
  GLYPHOSATE    FINAL    
Page 46 of 87 
  3. Atkinson, C., Strutt, A., Henderson, W., et  al. (1993). 104-Week chronic feeding/ 
oncogenicity study in rats with 52-week in terim kill. Inveresk Research International 
(IRI), Tranent, Scotland. Study No. 438623; IRI Report No. 7867. April 7, 1993. MRID No. 49631701. Unpublished. 
  
a. Experimental Design 
 
In a combined chronic toxicity/carcinoge nicity study, glyphosate (98.9% pure) was 
administered to 50 male and female Sprague-D awley rats/sex/dose in the diet at 0, 10, 100, 
300, and 1000 mg/kg/day for 104 weeks. An interim sacrifice was conducted on 15 rats/sex/dose after 52 weeks of treatment.  
b. Survival Analysis 
 
No adverse effects on survival were seen  in either sex across the doses tested 
 
c. Discussion of Tumor Data 
 
There were no treatment-related increases in the occurrence of any tumo r type in this study. 
 
d. Non-Neoplastic Lesions 
  
There were no treatment-related non-n eoplastic lesions in this study.  
 
e. Adequacy of the Dosing for A ssessment of Carcinogenicity 
Dosing was considered to be adequate to assess carcinogenicity since the highest dose 
tested was the limit dose (1000 mg/kg/day) and at  this dose increased sa livary gland weight 
accompanied by cellular alterations in the mandi bular and/or parotid glands occurred in 
both males and females. 
 
 
4. Brammer. (2001). Glyphosate Acid: Two Year  Dietary Toxicity and Oncogenicity 
Study in Rats. Central Toxicology Laborator y, Alderley Park Macclesfield, Cheshire, 
UK: Syngenta. (MRID No. 49704601). 
 
a. Experimental Design 
 
In a combined chronic toxicity study, glyphos ate acid (97.6% pure) was administered to 
groups of Wistar rats in the diet. Groups of 52 male and 52 female rats received diets 
containing 0, 2,000, 6,000, and 20,000 ppm glyphosate for 24 months. The achieved doses 
were 0, 121, 361 or 1214 mg/kg/day in ma les and 0, 145, 437 or 1498 mg/kg/day in 
females, respectively. Three satellite groups of 12 rats/sex/group were also included for GLYPHOSATE    FINAL    
Page 47 of 87 
  interim sacrifice at 12 months of treatment. Parameters evaluated included clinical signs, 
body weight, food consumption, hematology, clinical  chemistry, and urinalysis, as well as 
organ weights, necropsy and histopathological examination.  
 
b. Survival Analysis 
 
No adverse effects on survival were seen  in either sex across the doses tested 
 
c. Discussion of Tumor Data 
As shown in Table 12, there was an increase in the incidence of hepatocellular adenomas in 
male rats at the high dose when compared to controls. This increase was not considered to 
be treatment-related due to 1) absence of dos e-response relationship; 2) lack of progression 
to malignancy; 3) no evidence of pre-neoplastic lesions; 4) the incidences were within the 
range (0–11.5%) of historical controls for th is strain (Wistar) of rats in 26 studies 
conducted during the relevant time period (1984 –2003) at the testing la boratory; and 5) the 
0% incidence in concurrent controls is lo wer than the average background incidence for 
liver adenomas in male Wistar rats. 
Table 12. Liver Adenomas in Male Wistar Rats 
Fisher’s Exact Test and Exact Trend Test Results  
 0 2000 6000 20000 
Adenomas 
(%) 
P =  0/52a 
(0) 
0.00804** 2/52 
(4) 
0.24757 0/52 
(0) 
1.00000 5/52 
(10) 
0.02826* 
a =Number of tumor-bearing animal s/Number of animals examined. 
In addition, statistically highe r survival (P=0.02) was observed in males at 20,000 ppm at 
the end of 104 weeks relative to controls, and an overall trend for improved survival was 
observed in treated males (P=0.03).  The inter-current (early) deaths were 37/52, 36/52, 
35/52, and 26/52 for the control, low, mid and high dose groups, respectively. The terminal 
deaths were 16/52, 17/52, 18/52, and 26/52 for the control, lo w, mid and high dose groups, 
respectively. This survival bias in the hi gh dose group could easily explain a modestly 
higher incidence of an age-related background tu mor like liver adenoma (and fits with lack 
of associated lesions). In the 1990 study in Sprague-Dawley rats (MRID No. 41643801) 
there was also a weak but si gnificant trend test for liver adenomas in males (P=0.02, no 
pairwise); however, in that study adenomas in  all treatment groups we re still w ithin the 
historical control and the CP RC concluded that this effect  was not treatment-related, as 
discussed above. The lack of increased liver  tumor incidence in the other rat studies 
provide additional evidence for lack of an  actual carcinogenic res ponse in the liver. 
  GLYPHOSATE    FINAL    
Page 48 of 87 
   
d. Non-Neoplastic Lesions 
 
There were no treatment-related non-neoplastic le sions in any organs of  either sex at any 
dose level tested.   
 
e. Adequacy of Dosing for Assessment of Carcinogenicity 
 
The highest dose tested in both sexes (1214 mg/kg/day in males and 1498 mg/kg/day in 
females) exceeded the limit dose (1000 mg/kg/ day). Treatment-relate d findings at these 
doses were observed in the li ver and kidney, notably renal papillary necrosis, prostatitis, 
periodontal inflammation, urinary acidosis, hematu ria and slight increas es in the incidence 
of proliferative cholangitis and hepatitis.  
 
 
5. Feinchemie Schwebda. (1996). Combined Chro nic Toxicity and Carcinogenicity Study 
with Glyphosate Technical in Wistar Rats. Ba ngalore, India: Rallis India, Ltd. (Cited 
in Greim et al. , 2015) . 
 
a.  Experimental Design 
 
In a combined chronic/carcinogenicit y study, glyphosate (96.0-96.8% pure) was 
administered to groups of Wistar rats in the diet. Groups of 50 rats/sex/group received diets 
containing 0, 100, 1000, and 10000 ppm glyphosate for 24 months. The average achieved 
doses were 0, 7.4, 73.9, and 740.6 mg/kg/day. Paramete rs evaluated included clinical signs, 
body weights, food consumption, hematology, c linical chemistry, and urinalysis, organ 
weights, gross necropsy, and histopathological examination. 
 
b. Survival Analysis 
 
No adverse effects on survival were observe d in either sex across the doses tested. 
 
c. Discussion of Tumor Data 
 
There were no statistically signi ficant increases in any tumor t ype in this study. Details are 
provide by Greim et al.,  2015 can be found online at 
http://informahealthcare.com/doi/abs/10.3109/10408444.2014.1003423  
 
d. Non-Neoplastic Lesions 
 
 There were no non-neoplastic lesions at any dose level in either sex.   
 GLYPHOSATE    FINAL    
Page 49 of 87 
  e. Adequacy of Dosing for Assessment of Carcinogenicity 
 
The doses tested were determined to be adequa te in both sexes since the highest dose tested 
(741 mg/kg/day) approached th e limit dose (1000 mg/kg/day). 
 
 
6. Arysta Life Sciences. (1997a). HR-001: 24-Month Oral Chronic Toxicity and 
Oncogenicity Study in Rats. Kodaira-shi, Tokyo, Japan: The Institute of Environmental Toxicology
 (Cited in Greim et al. , 2015) . 
 
a. Experimental Design 
In a combined chronic/carcinogenic ity study, glyphosate (94.6–97.6% pure) was 
administered to groups of Sprague-Dawley ra ts in the diet. Groups  of 50 rats/sex/group 
received diets containing 0, 3000, 10000, or  30000 ppm glyphosate for 24 months. The 
achieved doses were 0, 104, 354 or 1127 mg/kg/day in males and 0, 115, 393, or 1247 mg/kg/day in females, respectively. Paramete rs evaluated included clinical signs, body 
weight, food consumption, hematology, clinical chemistry, and urinalysis, organ weights, 
gross necropsy and histopathological examination.  
 
b. Survival Analysis 
 
No adverse effects on survival were observe d in either sex across the doses tested. 
 
c. Discussion of Tumor Data 
There were no statistically signi ficant increases in any tumor t ype in this study. Details are 
provide by Greim et al.,  2015 can be found online at 
http://informahealthcare.com/doi/abs/10.3109/10408444.2014.1003423  
 
d. Non-Neoplastic Lesions 
  
 There were no treatment-related non -neoplastic lesions in this study. 
 
e. Adequacy of Dosing for Assessment of Carcinogenicity 
 
The highest dose 10,000 ppm (1127 mg/kg/day in males and 1247 mg/kg/day in females) 
exceed the limit dose (1000 mg/kg/day) a nd there were increased cecum weights, 
distension of the cecum, loose stool, follicular hyperkeratosis and/or folliculitis/follicular 
abscess of the skin, and decreased body weights. 
 
  GLYPHOSATE    FINAL    
Page 50 of 87 
   
7. Nufarm. (2009a). Glyphosate Technical: Dietary Combined Chronic Toxicity/ 
Carcinogenicity in the Rat. Shardlow, D erbyshire, UK: Harlan Laboratories Ltd. 
(Cited in Greim et al. , 2015) . 
 
a. Experimental Design 
 
In a combined chronic toxicity study, glyphos ate (95.7% pure) was administered to groups 
of Wistar rats in the diet. Groups of 51 ra ts/sex/group received diets containing 0, 1500, 
5000, and 15,000 ppm glyphosate for 24 months. To ensure that a received limit dose of 1000 mg/kg/day was achieved, the highest dose le vel was progressively increased to 24000 
ppm. The achieved doses were 0, 86, 285 or  1077 mg/kg/day in males and 0, 105, 349 or 
1382 mg/kg/day, in females. Parameters eval uated included clini cal signs, body weight, 
food consumption, hematology, clini cal chemistry, and urinalysis, as well as organ weights, 
necropsy and histopathological examination.   
b. Survival Analysis 
 
No adverse effects on survival were seen  in either sex across the doses tested. 
 
c. Discussion of Tumor Data 
 
There were no statistically signi ficant increases in any tumor t ype in this study. Details are 
provide by Greim et al.,  2015 can be found online at 
http://informahealthcare.com/doi/abs/10.3109/10408444.2014.1003423 
 
d. Non-Neoplastic Lesions 
  
There were no treatment-related non-neoplastic le sions in either sex at any dose level.   
 
e. Adequacy of Dosing for Assessment of Carcinogenicity 
 
The highest doses 1077 mg/kg/day in males and 1382 mg/kg/day in females exceed the 
limit dose (1000 mg/kg/day).     
  
   GLYPHOSATE    FINAL    
Page 51 of 87 
  B. Carcinogenicity Studies in Mice 
 
1. Knezevich, A.L and Hogan, G. K. (1983). A chronic feeding study of glyphosate in 
mice. Unpublished report prepared by Bio/ Dynamic Inc., dated July 21, 1983. Report 
No. 77-2011. EPA Accession No. 251007 – 251009, and 251014. 
 
a. Experimental Design 
 
In a carcinogenicity study, groups of 50 male  and female CD-1 mice received glyphosate 
(99.78%, pure) at dietary levels of 0, 1000, 5000, or 30,000 ppm for two years. These doses 
were equivalent to 0, 161, 835, 4945 mg/ kg bw/day for males and 0, 195, 968, and 6069 
mg/kg bw/day for females) for 24 months. Para meters evaluated included clinical signs, 
body weight, food consumption, organ weight s, and histopathological examination. 
 
b. Discussion of Tumor Data 
  
The incidences of renal tubule adenomas were as follows: 0/49 in the controls; 0/49 at the 
low-dose; 1/50 at the mid-dose; and 3/50 at the high dose (TXR No. 0004370). 
 In 1985, the Registrant directed a re-evaluation of the original renal section by a consulting 
pathologist (Dr. Marvin Kuschner). This eval uation identified a small renal tubule adenoma 
in one control male mouse (animal number 1028)  which was not diagnosed as such in the 
original pathology re port (TXR No. 0004855). 
 In 1986, at the request of the agency, additiona l renal sections (3 sections/kidney/mouse 
spaced at 150 micron intervals) were evaluate d in all control and all glyphosate-treated 
male mice in order to determine if additional tumors were present. The additional pathological and statis tical evaluations concluded that the renal tumors in male mice were 
not compound-related (TXR No. 0005590).  At the request of the agency, the Pathology Work Group (PWG) examined all sections of 
the kidneys including the additi onal renal sections. The renal tubular-cell lesions diagnosed 
by the PWG are presented below in Table 13. The PWG noted that because differentiation 
between tubular-cell adenoma and tubular-cell carcinoma is not always clearly apparent 
and because both lesions are derived from the sa me cell type, it appropriate to combine the 
incidences for purposes of ev aluation of statistical analysis. Statistical analyses are 
presented in Table 14. The PWG unanimously  concluded that these lesions are not 
compound-related based on the following consider ations: 1) renal tubular cell tumors are 
spontaneous lesions for which th ere is a paucity of historical control data for this mouse 
stock; 2) there was no statistic al significance in a pairwise comparison of treated groups 
with the controls and there was no evidence of a significant linear trend; 3) multiple renal tumors were not found in any animal; a nd 4) compound-related nephrotoxic lesions, GLYPHOSATE    FINAL    
Page 52 of 87 
  including pre-neoplastic changes, were not pr esent in male mice in this study (TXR No. 
0005590).  
 Table 13. Glyphosate: Kidney Tumo r in Male CD-1 Mice — PWG 
Dose/Tumor Type  Cont rol 1000 ppm 5000 ppm 30,000 ppm 
0 mg/kg/day 161 mg/kg/day 835 mg/kg/day 4945 mg/kg/day 
Tubular-cell adenoma 1/49 0/50 0/50 1/50 
Tubular-cell carcinoma 0 0/50 1/50 2/50 
Combined incidence 1/49 (2 %) 0/50 (0%) 1/50 (2%) 3/50 (6%) 
 
 Statistical analysis of the ma le mouse renal tumors diagnosed  by the PWG are presented below 
in Table 14. 
  
Table 14. Kidney Tumors in Male CD-1 Mice — PWG 
Cochran-Armitage Trend & Fi sher’s Exact Test (MRID 00130406)   
Tumor Type 0 mg/kg/day 161 mg/kg/day 835 mg/kg/day 4945 mg/kg/day 
Adenomas 
(%) 
P = 1/49 
(2) 
0.4422 0/49 
(0) 
1.0000 0/50 
(0) 
1.00000 1/45 
(2) 
0.7576 
Carcinomas 
(%) 
P = 0/49 
(0) 
0.0635 0/49 
(0) 
1.0000 1/50 
(2) 
0.5051 2/50 
(4) 
0.2525 
Combined 
(%) 
P = 1/49 
(2) 
0.0648 0/49 
(0) 
1.0000 1/50 
(2) 
0.7576 3/50 
(6) 
0.3163 
 
Historical control data from the testing laboratory (Bio-dynamics) during the glyphosate-
study period (1976-1982) are pr esented in Table 15.    
 
Table 15. Historical Control Data- Kidney tumors in CD-1 Mice — Bi/dynamics Inc.
Study I.D A B C D E F G 
Study Period 6/78 - 
7/80 12/77- 
4/80 12/77- 
3/80 10/78- 
4/81 11/78- 
4/81 11/77- 
4/80 10/77-4/80 
No. Examined 57 54 61 51 53 59 60 60 60 60 60 60 60 60 
Tubular Adenoma  1 0 0 0 0 0 0 0 2 0 0 0 0 
 
Historical control data from 14 studies conducted between 1977 and 1981 at the testing 
laboratory indicated that the mouse renal tumo rs ranged from 0 to 3.3% and the incidence 
in the current study (3/50; 6 %) exceeded the upper limit of th e historical control range 
(TXR No. 0007252).  
  GLYPHOSATE    FINAL    
Page 53 of 87 
   
The CPRC determined that glyphosate produced  an equivocal carci nogenic response in 
male mice characterized by an increased in cidence of renal tubul ar neoplasms. The 
biological significance of the findings was quest ionable because of: a) lack of significance 
in pairwise comparison with concurrent c ontrols for adenomas, carcinomas and the 
combined tumors; b) there was no concurrent  increase in non-neopl astic renal tubular 
lesions in male mice ( e.g. tubular necrosis/r egeneration, hyperplas ia, hypertrophy, etc.), 
c) the examination of multiple sections of ki dneys from all groups resulted in no additional 
neoplasms; this fact is particularly important  since not only were the original sections 
closely scrutinized by more than one pathol ogist, but additional sections as well, 
d) increased incidence in high dose group was ve ry small compared to control considering 
the very high concentration which produced  highly significant re duction in body weight 
gain in males; e) although the incidences exce eded the historical c ontrol, this finding did 
not override the lack of  statistical significance of compar ison to the concurrent controls. 
Furthermore, the increased incidence of chronic interstitial nephritis in males is not relevant 
to the tubular neoplasms. There was actually a decrease in renal tubul ar epithelial changes 
(basophilia and hyperplasia) in males, and al though there was a dose-related increase in 
these changes in female mice, no tubular neopla sms were observed in females. Overall, the 
Peer Review Committee did not consider the renal tumors to be treatment-related. The 
CARC reaffirmed the CPRC conclusion and rati onale. Also, the lack of increased renal 
tumors in the other mouse studies in the same  strain provides additional evidence for lack 
of an actual carcinogenic response in the kidneys. 
 
c. Non-Neoplastic Lesions 
 
The incidence of centrilobular hepatocyte hypertrophy was slightly but not significantly 
increased in high-dose male mice at terminal sacrifice if all mice were included in the 
analyses. Centrilobular hepatocy te necrosis was significantly (P ≤0.01) increased in high-
dose male mice (10/50; 20%) compared to controls  (2/49; 4%). No significant increases in 
centrilobular hepatocyte hypertr ophy or necrosis were observe d in treated female mice.  
There was a dose-dependent increase in the proxi mal tubular epithelial basophilia in female 
mice; the incidences were: 0/50 (0%) in the controls, 2/50 (4%) at the low dose, 4/50 (8%) 
at the mid dose, and 9/50 (18%) at the high dose (P ≤ 0.01). All other ti ssue alterations 
occurred sporadically and were  found with approximately equal frequency and severity in 
contro1 and treated animals. These were c onsidered unrelated to  glyphosate treatment. 
 
d. Adequacy of the Dosing for A ssessment of Carcinogenicity 
 
The high dose tested in males (4945 mg/ kg/day) and females (6069 mg/kg/day) was 
approximately 4 to 6-fold higher than th e limit dose (1000 mg/kg/day), which produced 
highly significant reduction in body weights in both  sexes. Therefore, the doses tested were 
determined to be adequate to assess the car cinogenic potential of gl yphosate in this study. 
 GLYPHOSATE    FINAL    
Page 54 of 87 
   
2. Atkinson, C., Martin, T., Hudson, P., and Robb, D. (1993). Glyphosate: 104 week 
dietary carcinogenicity study in mice. Inveresk Research International, Tranent, EH33 2NE, Scotland. IRI Project No. 438618. April 7, 1993. MRID 49631702. 
 
a. Experimental Design 
 
In a carcinogenicity study, glyphosate (97.5 – 10 0.2% pure) was administ ered to groups of 
50 CD-1 mice/sex/dose in the diet at doses of 0, 100, 300, or 1000 mg/kg/day for 104 
weeks. No interim sacrifices were performed. Parameters evaluated in cluded clinical signs, 
body weight, food consumption, organ wei ghts, necropsy and histopathological 
examination.  
b. Discussion of Tumor Data 
 
As shown in Table 16, hemangiosarcomas were  found in 4/45 (9%) high-dose male mice 
compared to none in the controls. In the trea ted mice at the high dose, one had the tumors 
present in the liver and spleen, one had the tumor present in the liver only, one had the 
tumors present in the liver, spleen, and pr ostate, and one had the tumor present in the 
spleen only. No hemangiosarcomas were found in the control or low- and mid-dose mice. 
 
Table 16. Hemangiosarcomas in Male CD-1 Mice 
Fisher’s Exact Test and Exact Trend Test Results  
Dose (mg/kg/day) 0 100 300 1000 
Hemangiosarcomas 
(%) 
P =  0/47a 
(0) 
0.00296** 0/46 
(0) 
1.00000 0/50 
(0) 
1.00000 4/45 
(9) 
0.05332 
a= Number of tumor bearing animals/Number of animal s examined, excluding those that died before week 52. 
 Note: ** Significance of trend (P<0.01) denoted at control. 
  
The increase in hemangiosarcomas in male mice was not considered to be treatment-related 
due to 1) tumors seen only at the limit dose; 2) absence of statisti cal significance in the 
pairwise analysis; 3) the inci dences was near or the same as the upper limit (0–8%) for the 
performing laboratory; 4) hemangiosarcomas were not seen in male mice in the other three 
studies when tested at comparable doses ( 946–1467 mg/kg/day) or at considerably higher 
doses (4348–5874 mg/kg/day) in this strain of  mouse; 6) the cons iderable inter-group 
variability in the number of female mice with th is tumor (0, 2 , 0 and 1 in the control, low-, 
mid- and high-dose groups, respectively); 7) Hemangiosarcomas are commonly observed 
in mice as both spontaneous and treatment-rela ted tumors arising from endothelial cells; 
8) hemangiosarcomas appear in both sexe s but are generally more common in males 
(CD-1); 9) As vascular tumors, they can occur at different sites but li ver and spleen tend to 
be the most common sites in male mice.  GLYPHOSATE    FINAL    
Page 55 of 87 
  c. Non-Neoplastic Lesions 
 
 No treatment-related non-ne oplastic lesions were seen. 
 
d. Adequacy of the Dosing for A ssessment of Carcinogenicity 
 
 The highest dose tested was th e limit dose (1000 mg/kg/day). 
 
3. Arysta Life Sciences. (1997b). HR-001: 18-Month Oncogenicity Study in Mice. 
Kodaira-shi, Tokyo, Japan: The Institute of Environmental Toxicology (Cited in 
Greim et al.,  2015). 
 
a. Experimental Design 
 
In a carcinogenicity study, groups of I CR-CD-1 mice (50/sex/group received diets 
containing glyphosate (94.6–97.6% pure) at 0, 1600, 8000 or 40,000 ppm for 18 months.  
The achieved doses were 0, 165, 838 or 4348 mg/kg/day in males and 0, 153, 787 or 4116 
mg/kg/day in females, respectively. Paramete rs evaluated included clinical signs, body 
weight, food consumption, hematology, clinical chemistry, and urinalysis, organ weights, 
gross necropsy and histopathological examination. 
 
b. Survival Analysis 
 
No adverse effects on survival were observe d in either sex across the doses tested. 
 
c. Discussion of Tumor Data 
 
There were no statistically si gnificant increases in any tumo r type in this study. Details 
provided by Greim et al.  (2015) can be found online at 
http://informahealthcare.com/doi/abs/10.3109/10408444.2014.1003423  
 
d. Non-Neoplastic Lesions 
  
 There were no treatment-related non -neoplastic lesions in this study. 
  
e. Adequacy of Dosing for Assessment of Carcinogenicity 
 
The highest dose tested in both sexes exceeded  (4-fold) the limit dose (1000 mg/kg/day). 
 
 
   GLYPHOSATE    FINAL    
Page 56 of 87 
  4. Nufarm. (2009b). Glyphosate Technical: Diet ary Carcinogenicity Study in the Mouse. 
Derbyshire, UK: Harlan Laboratories Ltd. (Cited in Greim et al.,  2015). 
 
a. Experimental Design 
 
In another feeding study, CD -1 mice (50/sex/dose) rece ived glyphosate (94.6–97.6%, pure) 
at 0, 500, 1500, or 5000 ppm for 18 months. The cal culated test substance intake was 0, 85, 
267 or 946 mg/kg/day. Parameters evaluated included clinical signs, body weight, food 
consumption, organ weights, gross necrops y and histopathological examination.  
 
b. Discussion of Tumor Data 
 
In male mice at the high dose (5000 ppm) th ere were increases in  the incidences of 
adenocarcinomas of the lung and malignant lymphomas as shown in Tables 17. For the 
lung adenocarcinomas, the increases did not reach statistically significant pairwise 
differences, although the trend was significant. For the malignant lymphomas there was a 
trend and pairwise significance.  Details provided by Greim et al.  (2015) can be found 
online at http://informahealthcar e.com/doi/abs/10.3109/10408444.2014.1003423  
 
Table 17. Lung Adenocarcinomas and Malignant Lymphomas in Male CD-1 
Mice (Greim et al.,  2015) 
Fisher’s Exact Test and Exact Trend Test Results  
Dose (ppm) 0 500 1500 5000 
Lung Adenocarcinoma 
(%) 
P =  5/51a 
(10) 
0.02906** 5/51 
(10) 
0.62953 7/51 
(14) 
0.37996 11/51 
(22) 
0.08609 
Malignant Lymphoma 
(%) 
P =  0/51 
(0) 
0.006633** 1/51 
(2) 
0.50000 2/51 
(4) 
0.24752 5/51 
(10) 
0.02820* 
a= Number of tumor bearing anim als/Number of animals examined. 
 Note: ** Significance of trend (P<0.01) denoted at control. 
  
The increase in lung adenocarcinomas was not considered to be trea tment-related due to: 
1) absence of statistical significance in the pairwise analysis; 2) the incidences in all 
treatment groups including the controls were within the historical control range (1.43–26%) 
for the performing laboratory; and 3) lung tumors  were not seen in the other three studies 
when tested at doses ranging from 8 14 to 4945 mg/kg/day for up to two years. 
 
  GLYPHOSATE    FINAL    
Page 57 of 87 
  Historical control data and re sults from the 5 studies can be used to put this finding into 
perspective. The malignant lymphomas were not  considered to be treatment-related since 
the 0% incidence of this lesion in the concur rent control for male mice was lower than the 
historical control mean (4.5%) and range (1.5–2 1.7%) in this strain a nd age of mice (Gikins 
and Clifford, 2005; Son and Gopinath, 2004). Therefore, the apparent statistical 
significance of the pairwise co mparisons of the high dose male groups with the concurrent 
control might have been attribut able to this factor and not to  actual carcinogenic response. 
In addition, malignant lymphomas we re not seen in the other thr ee studies in this strain of 
mice when tested at doses ranging from 814 to 4945 mg/kg/day for up to two years. 
 
c. Non-Neoplastic Lesions 
 
 There were no treatment-related non -neoplastic lesions in this study. 
 
d. Adequacy of the Dosing for A ssessment of Carcinogenicity 
 
 The highest dose (947 mg/kg/day) tested approached the limit dose (1000 mg/kg/day).  
  
IV. TOXICOLOGY 
 
A. Metabolism 
 
Single or repeated doses of radiolabeled 14C-glyphosate were administer ed orally to male and 
female Sprague-Dawley rats. Foll owing a single oral dose of, 14C-glyphosate, 30 to 36% of the 
dose was absorbed and less than 0.27% of the dose was eliminated as CO 2. 97.5% of the 
administered dose was excreted in the urine a nd feces as the parent compound, glyphosate. Amino 
methyl phosphonic acid (AMPA) was the only metabolite found in urine (0.2–0.3% of the 
administered dose) and feces (0.2–0 .4% of the administered dose). Less than 1.0% of the absorbed 
dose remained in tissues and organs, primarily in  bone tissue. Repeated do sing at 10 mg/kg did not 
significantly change the metabolism, di stribution or excretion of glyphosate. 
 In a second study, male and female Sprague-Dawley ra ts received single intr aperitoneal injections 
of radiolabeled 
14C-glyphosate at 1150 mg/kg. Blood samp les were collected 0.25, 0.50, 1, 2, 4, 6 
and 10 hours after injection. Femoral bone marrow sa mples were collected from one third of the 
male and female rats sacrificed at 0.5, 4, or 10 hours after injection. Thirty  minutes after injection 
of glyphosate, the concentration of radioactivity in the bone marrow of male and female rats was 
equivalent to 0.0044% and 0.0072%, respectively, of the administered dose. Assuming first order 
kinetics, the decrease in radioa ctivity in bone marrow occurred w ith a half-life of 7.6 and 4.2 hours 
for males and females, respectively. Similarly, the ha lf-lives of the radioactivity in plasma were 
approximately 1 hour for both sexe s. These findings indicate that  very little glyphosate reaches 
bone marrow, that it is rapidly eliminated from bone marrow, and that it is even more rapidly 
eliminated from plasma.  GLYPHOSATE    FINAL    
Page 58 of 87 
   
B. Mutagenicity  
 
In 1991, the Carcinogenicity Peer  Review Committee concluded th at there was no evidence of 
genotoxicity for glyphosate based on negative findings in submitted guideline studies for the bacterial reverse mutation test (MRID 00078620),  in vitro mammalian cell gene mutation test in 
CHO cells (MRID 00132681), in vivo  mammalian bone marrow chromosomal aberration test 
(MRID 00132683) and a “rec assay” used to detect DNA-damaging agents in Bacillus subtilis  
(MRID 00078619) (TXR 0008898).   Glyphosate has also been evaluated for its genot oxic potential in other regulatory and published 
literature studies. Extensive reviews of the available genotoxicity studies for glyphosate and 
glyphosate products were conducted by Williams et al. (2000) and by Kier and Kirkland (2013). 
IARC also conducted a review of the publically ava ilable genetic toxicity data for glyphosate and 
glyphosate-based formulations (IARC, 2015).  Williams et al., (2000) concluded that “glyphosate is  neither mutagenic nor clastogenic.” 
Similarly, Kier and Kirkland (2013) concluded a “lack of genotoxic potential for both glyphosate 
and glyphosate based formulations  (GBFs) in core gene muta tion and chromosomal effect 
endpoints.” Kier and Kirkland (2013 ) also stated that “the obser vations of DNA-damage effects 
seems likely to be secondary to cytotoxic effect s.” However, IARC (2015) concluded that “there 
is strong evidence that glyphosate causes genotox icity.” It should be noted that the IARC’s 
conclusion was based not only on studies conducted with the active ingredie nt but also on studies 
conducted with the formulation products su ch as Roundup. Roundup is a combination of the 
active ingredient and other chemicals, incl uding a surfactant (pol yoxyethyleneamine) which 
enhances the spreading of spray dr oplets when contact foliage. Of note, the review article by Kier 
and Kirkland (2013) and supplemental informati on provided on the publisher’s website were not 
considered in the IARC evaluation.  In this assessment, the CARC considered a tota l of 54 studies including those submitted to the 
agency under 40 CFR Part 158 as well as the studies presented in the review  articles by Williams 
et al. (2000), Kier and Kirkland (2013), and the IARC monograph (2015). Cons istent with OPP’s 
Guidance for Considering and Using Open Literatu re Toxicity Studies to Support Human Health 
Risk Assessment ( http://www.epa.gov/pesticid es/science/lit-studies.pdf ), literature studies 
discussed in the reviews such as  IARC that did not meet the Klimisch criteria for reliability ( e.g. 
lack of adequate glyphosate purity  information for the test materi al) were not considered by the 
CARC. The CARC determined the mutagenic pot ential of glyphosate in humans by conducting a 
weight-of-evidence evaluation of the results from  the cited bacterial re version (Ames) assays, in 
vitro mammalian gene mutation assays, in vitro and in vivo  chromosomal aberration and 
micronucleus assays as well as other relevant assays evaluating DNA damage. 
 
  GLYPHOSATE    FINAL    
Page 59 of 87 
  1. Bacterial reverse mutation assays 
 
As shown in Table 18, glyphosate was not mutagenic in any of the in vitro  bacterial mutation 
assays using S. typhimurium or E. coli  tester strains with or wit hout microsomal S9 metabolic 
activation. These results are consis tent with the negative findings in  the previously reviewed EPA 
guideline (870.5100) bacterial revers e gene mutation study (MRID 00078620). 
  
 
1. Studies cited in Williams et al. (2000), Kier and Kirkland (2013), or IARC monograph. 
2. S. typhimurium  strains (TA97, TA98, TA100, TA102, TA1535, TA1537, and/or TA1538) or E. coli strains (WP2P and WP2 uvrA) 
3. Glyphosate acid 
4. Monoammonium glyphosate salt 
 Table 18. Results from Bacterial Reverse Gene Mutation Assays1 
Author Cell/Strain2 Purity Highest test 
concentration Results 
–S9 Results 
+S9 
Akanuma,M. 
(1995) TA98, TA100, TA1535, 
TA1537; WP2 uvrA 95.7%3  5000 µg/plate Negative Negative 
Callander, R.D. 
(1996) TA98, TA100, TA1535, 
TA1537; WP2P and 
WP2 uvrA 95.6%3 5000 µg/plate Negative  Negative 
Flügge, C. 
(2010) TA98, TA100, TA102, 
TA1535, TA1537 76.1%4 100 µg/plate Negative Negative 
Flügge, C. 
(2010) TA98, TA100, TA102, 
TA1535, TA1537 96.4% 3160 µg/plate Negative Negative 
Flügge, C. 
(2009) TA98, TA100, TA102, 
TA1535, TA1537 98.8% 3160 µg/plate Negative Negative 
Jensen, J.C.  
(1991) TA98, TA100, TA1535, 
TA1537 98.6% 2500 µg /plate w/o S9; 
5000 µg /plate w/ S9 Negative Negative 
Li and Long 
(1988) TA98, TA100, TA1535, 
TA1537, TA1538;  98% 5000 µg/plate Negative Negative 
NTP 
(1992) TA97, TA100, TA1535  98% 10,000 µg /plate Negative Negative 
Schreib, G. 
(2010) TA98, TA100, TA1535, 
TA1537; WP2 uvrA 96% 5000 µg/plate Negative Negative 
Shirasu et al. 
(1978) TA98, TA100, TA1535, 
TA1537, TA1538 and  
WP2 uvrA  98.4% 5000 µg/plate Negative Negative 
Sokolowski, A. 
(2007c) TA98, TA100, TA1535, 
TA1537; WP2 uvrA 95.0% 5000 µg/plate Negative Negative 
Sokolowski, A. 
(2007a) TA98, TA100, TA1535, 
TA1537; WP2uvrA 95.1% 5000 µg/plate Negative Negative 
Sokolowski, A. 
(2009b) TA98, TA100, TA1535, 
TA1537;WP2P and 
WP2 uvrA 96.3% 5000 µg/plate Negative Negative 
Sokolowski, A. 
(2009a) TA98, TA100, TA1535, 
TA1537; WP2 uvrA 96.66% 5000 µg/plate Negative Negative 
Sokolowski, A. 
(2007b) TA98, TA100, TA1535, 
TA1537; WP2 uvrA 97.7% 5000 µg/plate Negative Negative 
Suresh, T.P. 
(1993) TA98, TA100, TA1535, 
TA1537, TA1538 96.0% 1000 µg/plate Negative Negative 
Thompson, 
P.W. 
(1996) TA98, TA100, TA1535, 
TA1537; WP2 uvrA 95.3% 5000 µg/plate Negative Negative GLYPHOSATE    FINAL    
Page 60 of 87 
  2. In vitro  mammalian cell gene  mutation assays 
 
Glyphosate did not induce forward mu tations in mouse lymphomas cells or Chinese hamster ovary 
(CHO) cells in the presence or absence of  metabolic (S9) activation (Table 19). 
  
Table 19. Results from mammalian gene mutation assays1. 
Author Assay Type Cell type Purity Highest conc. Result 
 -S9 Result 
+S9 
Clay 
(1996) In vitro  mammalian 
gene mutation L5178Y mouse 
lymphoma cells/ 
tk locus 95.6% 1.0 mg/mL Negative Negative 
Jensen, J.C.  
(1991) In vitro  mammalian 
gene mutation L5178Y mouse 
lymphoma cells/ 
tk locus 98.6% 5.0 mg/mL Negative Negative 
Li and Long 
(1988) In vitro  mammalian 
gene mutation CHO cells/ 
HGPRT locus 98% 22.5 mg/mL Negative Negative 
1. Studies cited in Williams’s et al. (2000), Kier and Kirkland (2013), or IARC monograph. 
 
3. In vitro chromosomal aberration assays 
 
Lioi et al. (1998a, 1998b) reported positive findings for chromosomal aberrations in human and 
bovine lymphocytes treated with glyphosate in vitro in the absence of S9 activity. As discussed in 
the Williams review, there is less confidence in the Lioi et al. results based on the use of an 
unusual 72-hour treatment protocol and the obser vation of reduced cell growth in glyphosate-
exposed cells (an indication of a toxic effect) wh ich can affect the evaluation of the study. Lioi et 
al. also reported chromosomal damage in ly mphocytes treated with  other known non-genotoxic 
pesticides in this study at concentration range s similar to where they reported effects for 
glyphosate. By contrast, when the tests were pe rformed according to the OECD guideline, Van de 
Waart (1995) reported no significant increase in chromosomal aberrations in human lymphocytes 
treated with up to 0.56 mg/mL (-S9) and 0.33 mg/m L (+S9) glyphosate, which are concentrations 
3 orders of magnitude higher than those at which Lioi et al. reported aberrations. Glyphosate was 
negative in two other in vitro  chromosomal aberrations studie s using human lymphocytes (Fox, 
1998; Manas et al. 2009) and did not induce chromosomal aberrations in Chinese hamster lung 
cells (Matsumoto, 1995; Wright, 1996). A summary of the findings is presented in Table 20. 
 
  GLYPHOSATE    FINAL    
Page 61 of 87 
  Table 20. Results from in vitro  chromosomal aberration assays1. 
Authors Assay  Cell type Purity Highest test 
concentration Result 
-S9 Result 
+S9 
Van de Waart 
(1995) Chromosomal 
Aberration Human peripheral 
lymphocytes  >98% 0.56 mg/mL 
with S9; 0.33 
mg/mL w/o S9 Negative Negative 
Fox, V. 
(1998) Chromosome 
Aberration  Human peripheral 
lymphocytes 95.6%2  1250 ug/mL Negative Negative 
Lioi et al. 
(1998a) Chromosomal 
Aberration Human peripheral 
lymphocytes >98% 1.4 mg/L Positive Not 
Tested  
Manas et al. (2009) Chromosomal 
Aberration Human peripheral 
lymphocytes 96% 6 mM Negative Not 
Tested
 
Lioi et al. (1998b) Chromosomal 
Aberration Bovine peripheral 
lymphocytes >98% 2.9 mg/L Positive Not 
Tested
 
Matsumoto, K.  
(1995) Chromosomal 
Aberration Chinese Hamster 
Lung (CHL) cells 95.68%2 1000 ug/mL  Negative Negative 
Wright, N.P. 
(1996) Chromosomal 
Aberration Chinese Hamster 
Lung (CHL) cells 95.3% 1250 ug/mL Negative Negative 
1. Studies cited in Williams et al., (2000), Kier and Kirkland (2013), or IARC monograph. 
2. Glyphosate acid 
4. In vivo micronucleus and chromosomal aberration assays 
 
Numerous studies were evaluate d to determine the potential fo r glyphosate to induce micronuclei 
in rodent bone marrow cells. Studies included bo th intraperitoneal (IP)  and oral routes of 
glyphosate administration. In a l iterature study by Bolognesi et al. (1997), the authors reported an 
induction of micronuclei in male mice treated with up to 300 mg/kg (injected as two ½ doses). It is 
noted that this study included only 3 animals/dose, rather than th e 5 animals/dose recommended in 
the agency’s test guideline (870.5395) . In another literature study, Manas et al. (2009) reported an 
induction of micronuclei in BALB/C mice when tested up to 200 mg/kg glyphosate. However, 
there is some concern regarding how the micronucle i were scored in this study. As stated in the 
Kier and Kirkland review, Manas et al.  (2009) reported their findi ngs as an increase in 
micronucleated erythrocytes rather than polychr omatic erythrocytes. Scoring all erythrocytes 
rather than immature polychromatic  erythrocytes can impact the in terpretation of the study as the 
effects cannot be solely attributed to treatment by the test article. Suresh et al. (1993) reported an 
increase in micronuclei in females only in Sw iss albino mice treated with 5 mg/kg glyphosate; 
however, this occurred at a dose that is more th an twice the limit dose for the agency’s guideline 
study. Although the above authors reported posi tive findings, a vast majority of the in vivo  
genotoxicity studies (includi ng the previously reviewed guideline mammalian bone marrow 
chromosomal aberration test) were negative at doses similar to or higher than  the studies discussed 
above, regardless of the dosing regimen or rout e of administration. Furthermore, glyphosate was 
also negative in two rodent dominant lethal test s. A summary of the fi ndings are reported in 
Table 21.   GLYPHOSATE    FINAL    
Page 62 of 87 
  Table 21. Results from in vivo  genotoxicity assays1. 
Author Assay Type Species/strain Purity Highest 
conc. Results Comments 
Bolognesi et 
al. 
(1997) Micronucleus 
test Male mice (strain 
not provided) 99.9% 300 mg/kg Positive  Two IP injections of 
½ dose; 3 mice/dose 
Durward, R. (2006) Micronucleus 
test Young adult male 
and female albino 
Crl:CD‐
1TM(ICR)BR mice 95.7% 600 mg/kg Negative  Single IP injection; 
Significant increase in % PCEs per 1000 
erythrocytes was 
observed in the 24-hour; however not 
48‐hour at 600 mg/kg 
Flügge, C. 
(2009) Micronucleus 
test Male and female CD 
rats 98.8% 2000 mg/kg Negative Single dose; oral 
gavage 
Fox and 
Mackay 
(1996) Micronucleus 
test Male and female 
CD-1 BR mice 95.6%2 5000 mg/kg Negative  Single dose; oral 
gavage 
Honavar, N. 
(2005) Micronucleus 
test Male and female 
NMRI mice 97.73% 2000 mg/kg Negative  Single dose; oral 
gavage 
Honavar, N. 
(2008) Micronucleus 
test NMRI male mice 99.1% 2000 mg/kg Negative Single dose; oral 
gavage 
Jensen, J.C.  
(1991) Micronucleus 
test Young adult male 
and female NMRI 
SPF mice 98.6% 5000 mg/kg Negative  Single dose; oral 
gavage 
Manas et al.  
(2009) Micronucleus  BALB/C mice 96% 200 mg/kg Positive Two IP doses, 1 day 
apart 
NTP (1992) Micronucleus 
test Male and female 
B6C3F 1 mice  99% 11,379 
mg/kg/day Negative Dietary admin., 13 
weeks 
Suresh, T.P. 
(1993) Micronucleus 
test Young Swiss albino 
male and female 
mice 98.6% 5000 mg/kg Males: 
Negative 
Females:  Positive   Two doses 1 day 
apart; oral gavage 
Suresh, T.P. (1994) Mouse Bone 
Marrow 
Chromosome Aberration Male and female 
Swiss albino mice 96.8% 5000 mg/kg Negative Two doses, 24 hours 
apart; oral gavage 
Suresh, T.P. (1992) Rodent 
dominant 
lethal test Male and female 
Wistar rats 96.8% 500 mg/kg 
(single dose); 
100 mg/kg (5 daily doses) Negative  
Wrenn 
(1980) Rodent 
dominant 
lethal test Mouse; gavage 98.7% 2000 mg/kg Negative  
1. Studies cited in Williams et al., (2000), Kier and Kirkland (2013), or IARC monograph. 
2. Glyphosate acid 
3. IP= intraperitoneal injection  
  GLYPHOSATE    FINAL    
Page 63 of 87 
   
5. Other genotoxicity assays 
 
Inconsistent responses were reported in a num ber of assays designed to detect DNA damage, 
including sister chromatid exchange (SCE) assay, unscheduled DNA synthesis assay, and the 
comet assay (also known as the single cell electro phoresis assay). Positive  responses in these 
assays do not necessarily indica te a chemical is DNA-reactive ( i.e. mutagenic), but rather that 
DNA damage occurred under conditions of the as say. Glyphosate was also negative in two Rec- 
DNA repair tests in B. subtilis . The results of these genotoxicity studies are presented in Table 22. 
 
Table 22. Additional genotoxi city assays of glyphosate  
Authors Assay Type Cell Type Purity Highest test 
conc. Results 
Bolognesi et al.  
(1997) Sister chromatid 
exchange (SCE) Human peripheral blood 
(in vitro ) 99.9% 1000 ug/mL Positive 
Lioi et al.  
(1998a) SCE Human peripheral blood 
(in vitro ) >98% 1.4 mg/L Equivocal 
Lioi et al.  
(1998b) SCE Bovine peripheral blood 
(in vitro ) >98% 2.9 mg/L Equivocal 
Li and Long 
(1988) Unscheduled 
DNA synthesis 
(UDS) Rat hepatocytes ( in vitro  
exposure) 98% 0.125 mg/mL Negative  
Rossberger,(1994) UDS Primary rat hepatocytes 98% 111.69 mM Negative 
Bolognesi et al.  
(1997) DNA Damage 
/reactivity/UDS Mouse; IP administration 99.9% 300 mg/kg Equivocal 
Bolognesi et al. 
(1997) DNA 
Damage/reactivit
y/UDS Mouse; IP; alkaline 
solution of extracted 
DNA 99.9% 300 mg/kg Positive 
Alvarez-Moya et al. 
(2014) Comet assay Human lymphocytes 96%2700 µM Positive 
Lueken et al.   
(2004) Comet assay Human fibroblasts GM 
5757 98.4% 75 mM Negative  
Manas et al. (2009) Comet assay Liver Hep-2 cells 96% 7.5 mM  Positive 
Mladinic et al.  
(2009) Comet assay Human lymphocytes 98% 580 ug/mL 
(toxic); approximatel
y 3.43 mM   Positive 
Rossberger, S. 
(1994) DNA repair test  Male SD rat primary 
hepatocytes >98% 111.69 mM Negative 
Akanuma, M. 
(1995)  DNA repair test 
(Rec- assay) Bacillus subtilis  M45 
rec-/ H17 rec+ 95.68%2 240 ug/disk Negative 
Li and Long 
(1988) DNA repair test 
(Rec assay) B. subtilis  H17, rec+; 
M45, rec- 98% 2 mg/disk Negative 
1. Studies cited in Williams et al., (2000), Kier and Kirkland (2013), or IARC monograph. 
2. Glyphosate acid  
 GLYPHOSATE    FINAL    
Page 64 of 87 
  6. Conclusions 
 
In summary, glyphosate was not mutage nic in bacteria or mammalian cells in vitro . Additionally, 
glyphosate did not induce chromosomal aberrations in vitro . Although some studies in the open 
literature reported positive findings  for micronuclei induction in r odents, these findings were not 
replicated in the major ity of the rodent micronuclei or chro mosomal aberration studies considered 
in this assessment by the CARC. Some positive resu lts were reported in SCE and comet assays in 
the open literature; however, there is no convinc ing evidence that the DNA damage is a direct 
effect of glyphosate exposure, but rather may be secondary to cytotoxici ty or oxidative damage. 
   
C. Structure-Activity Relationship 
 
At present there are no structura lly related pesticides registered by the agency which resemble 
glyphosate. Sulfosate, the trimethylsulfonium salt of glyphosate (also known as glyphosate-
trimesium) is a 1:1 molar salt of N-(phosphonomethyl) glycine anion (PMG) and the 
trimethylsulfonium cation (TMS). Sulfosate was eval uated for its carcinogenic potential following 
dietary administration to male and female mice at 0, 10, 1000 or 8000 ppm (equivalent to 0, 16, 
159 or 1341 mg/kg/day, respectively) for 18 months, and in male and female Sprague-Dawley rats 
at 0, 100, 500, or 1000 ppm (equivalent to 0, 5.4, 27 or 557 mg/kg/day, respectively) for two years. 
There was no evidence of carcinogenicity in either  species. Sulfosate is classified as a Group E 
Chemical: “Not Likely to be Carcinogenic to Hu mans” based on the absence of carcinogenicity in 
mice and rats in two acceptable st udies. Based on the available muta genicity studies, there is no 
concern for mutagenicity (TXR Nos. 0006452 and 0011156).  
D. Subchronic and Chronic Toxicity Studies 
 
1. Subchronic Toxicity 
 
In a 90-day feeding study (MRID No. 00036803) CD -1 mice were fed diets containing 0, 250, 500 
or 2500 mg/kg/day of glyphosate for three months. Body weight gains of the high-dose males and 
females were about 24% and 18% lower, respective ly, than those of the controls. Body weight 
gains of the low-dose and mid-dose groups were comparable to those of the controls. For systemic 
toxicity, the NOAEL is 500 mg/kg/day and the LOAEL is 2500 mg/kg/da y, based on decreased 
body weight gain in both sexes.  In a 90-day feeding study (MRID No. 40559401), Spra gue-Dawley rats were fed diets containing 
0, 63, 317, and 1267 mg/kg/day of glyphosate, re spectively in males and 0, 84, 404 and 1623 
mg/kg/day of glyphosate, respectively, in females.  Treatment-related findings were: (1) increased 
serum phosphorus and potassium in all treated groups, males and females; (2) increased serum 
glucose in the mid-dose and high-dose males; (3 ) increased blood urea nitrogen (BUN) and serum 
alkaline phosphatase in the high- dose males; and (4) occurrence of pancreatic lesions in the high-
dose males (pancreas was not examined at th e low-dose and mid-dose groups). Based on these 
findings, the systemic NOAEL is <1000 ppm (not determined definitively) for both sexes. GLYPHOSATE    FINAL    
Page 65 of 87 
   
2. Chronic Toxicity 
 
(i) Rats 
 
A chronic feeding/carcinogenicity study (MRI D No. 00093879) was conducted using male and 
female Sprague-Dawley rats which were fed di ets containing 0, 30, 100, or 300 ppm of glyphosate 
for 26 months. These levels were equivalent  to 0, 3, 10, and 34 mg of glyphosate/kg/day, 
respectively. There were no effects based on a ny of the parameters examined (toxic signs, 
mortality, body weights, food consumption, hema tology, clinical chemistry, urinalysis, organ 
weights and organ/tissue pathology ). Therefore, the NOAEL for sy stemic toxicity is 300 ppm 
(males: 31 mg/kg/day and females: 34 mg/kg/day). 
 A second chronic feeding/carcinogenicity st udy (MRID No. 41643801) was conducted using male 
and female Sprague-Dawley rats which were  fed diets containing 0, 2000, 8000, or 20,000 ppm of 
glyphosate for two years. These levels were equivalent to 0, 89, 362, or 940 mg/kg/day, 
respectively, for the males and 0, 113, 457, or 1183 mg/kg/day, respectively, for the females. 
Treatment-related effects observed only in the high-dose group included: (1) decreased body 
weight gain in females; and (2) increased incide nce of cataracts and lens abnormalities, decreased 
urinary pH, increased absolute liver  weight, and increased liver wei ght/brain weight ratio (relative 
liver weight) in males. No significant systemic effects were observed in the low-dose and mid-dose 
male and female groups. Therefore, the NOAEL for systemic toxicity is 8000 ppm 
(males: 362 mg/kg/day and females: 457 mg/kg/day) and the LOAEL is 20,000. 
 In a combined chronic toxicity/carci nogenicity study (MRID No. 49631701), glyphosate 
(98.9% a.i.) was administered to 85 Sprague-Dawley rats/sex/dose in the di et for 104 weeks  ater 
0, 10, 100, 300, and 1000 mg/kg/day to both sexes over the course on the study. Designated for the 
toxicity portion of the study were 35 rats/sex /dose with the remai nder designated for the 
oncogenicity portion of the study. Ther e were no statistical differenc es between treated and control 
groups in survival rates. Pale feces were obs erved during weeks 16–104 in both sexes at the high 
dose and in females from the low-mid and high-mid  dose levels. No treatment-related effect was 
observed in food consumption, hematology, ophthal mology, and gross pathology data. Males from 
the high-dose group had statisti cally lower mean body weight (P ≤0.01) by 5% to 11% beginning 
Week 2 of the study until Week 104, and at term ination was 10% lower (-14% weight gain). 
Females at the high dose had sta tistically lower body weight (P ≤0.05) by 5% to 12% beginning 
Week 20 through Week 80 (with several exceptions ), and at termination was 8% lower (-11% 
weight gain). Statistically increased ALP activitie s (+46% to +72%) were obs erved in males at the 
high dose throughout the study except for the 51 week interval wh en the mean value was 31% 
higher than control. Elevated ALP activities were  observed in females at  the high dose (+34% to 
+53%) throughout the study, and through most of the study at the high-mid dose by +20% to 
+67%, though not always statistica lly significant. Urinalysis data  showed reduced pH (5.5–6) in 
males at the high dose throughout the study.   GLYPHOSATE    FINAL    
Page 66 of 87 
  The absolute liver weight was decreased significantly in females at the high dose after 52 weeks, 
but after correcting for final body weight the differe nce was statistically significant at the three 
highest doses. The parotid salivary gland weight was increased signi ficantly in males at the three 
highest doses (56–111%) after 52 weeks, but not af ter 104 weeks. The combined weight of the 
sublingual and submaxillary salivary glands wa s significantly increased by 13% (22% after 
correcting for body weight) at the high dose after 52 weeks. In females, the parotid gland was not 
affected but the sublingual and submaxillary combined weight was significantly higher by about 
15%. The changes in salivary gland weights were  accompanied by increased incidence of mild to 
severe parotid salivary gland cell alterations and slight to moderate mandi bular salivary gland cell 
alterations were observed in both sexes at the 52-week and 104-week intervals. The lesions were 
described as cells and/or acini that appeared larger and staine d in a weakly basophilic manner 
without showing a tendency toward proliferative or degenerative ch anges over time. In males, the 
increased incidence and severity of lesions  in the parotid gland were significant (P ≤0.01) at 100, 
300, and 1000 mg/kg bw/day at 52 weeks, and si gnificant at 300 and 1000 mg/kg bw/day at 104 
weeks. The increased incidence of lesions in the mandibular gland were  significant at 300 and 
1000 mg/kg bw/day at 52 weeks and significant (P ≤0.001) at 100, 300, and 1000 mg/kg bw/day at 
104 weeks. In females, the increased incidence of  parotid lesions was significant at 300 and 1000 
mg/kg bw/day at 52 weeks, and significant at 100, 300, and 1000 mg/kg bw/day at 104 weeks. The 
increased incidence in the mandibular gland lesi ons was significant at th e high dose at both 52 and 
104 weeks. The incidence and/or severity of kidney nephropathy decreased in males at 100, 300, 
and 1000 mg/kg bw/day at 52 weeks and at the hi gh dose at 104 weeks. Urothelial hyperplasia 
significantly decreased in females from the hi gh dose group at both the 52-week and 104-week 
intervals. The LOAEL in male and female Sp rague-Dawley rats administered glyphosate for 104 
weeks in the diet was 100 mg/kg bw/day base d on microscopic lesions  in the parotid and 
mandibular salivary glands. The NOAEL wa s 10 mg/kg bw/day (MRID No. 49631701). 
 In another chronic toxicity/c arcinogenicity study (MRID No. 49704601) , groups of 52 male and 52 
female Alpk:APSD (Wistar-derived) rats were fed diets containing glypho sate at 0, 2000, 6000, or 
20,000 ppm for two years. These doses were equi valent to 0, 121, 361 or 1214 mg/kg/day in males 
and 0, 145, 437, or 1498 mg/kg/day in females, re spectively. Treatment-related findings were 
confined to the liver and kidneys at the highest dose (20,000 ppm). In both se xes, treatment-related 
changes manifested as papillary necrosis, pros tatitis, periodontal inflam mation, urinary acidosis, 
and hematuria. The LOAEL was 20,000 ppm (1214 mg/kg/day in males and 1498 mg/kg/day in 
females) and the NOAEL was 6000 ppm (361 mg/kg/da y in males and 437 mg/kg/day in females) 
 
(ii) Mice 
 
In a carcinogenicity study (MRID No. 00251007), glyphosate (Technical, 99.7% a.i.) was 
administered to groups of 50 male and 50 female CD -1 mice/sex/dose in the diet at dose levels of 
0, 1000, 5000, or 30,000 ppm (approximately equivale nt to 0, 161, 835, 4945 mg/kg bw/day for 
males and 0, 195, 968, and 6069 mg/kg bw/day for fema les) for 24 months. Cage-side and detailed 
clinical observations were done. Body weight and food intake were monitored throughout the 
study. Water consumption was measured during mont hs 12 and 24. Erythrocyte, as well as total GLYPHOSATE    FINAL    
Page 67 of 87 
  white cell counts and differentials, were done at months 12, 18, and 24. Tissues and organs were 
collected from all mice whether dying during the study or at terminal sacrifice. Microscopic 
analyses were done on all collected tissues.  No treatment-related effects were found on surviv al, body weight, food or water consumption, or 
hematology parameters of treated male or fema le mice. The terminal body weight of high-dose 
males was significantly decreased 9% while the absolute liver weight of high-dose males was 
significantly decreased 16%; however, no significa nt treatment-related effects were found on the 
liver-to-body-weight ratio. The abso lute testes weight of high- dose male mice was increased 7%, 
while the relative to body testes weight was increased 17. Neither we re statistically significant, and 
no microscopic histologi cal correlates were found. The incide nces of centrilobular hepatocyte 
hypertrophy were slightly, but not  significantly increased in high- dose male mice. Centrilobular 
hepatocyte necrosis was signi ficantly higher in high-dose male s (10/50** (20%) vs. control 2/49 
(4%), P≤0.01). No significant increases in centrilobular hepatocyte hypertrophy or necrosis were 
observed in treated female mice; however, proxima l tubular epithelial bas ophilia was significantly 
increased in high-dose females (9/ 50 (18%) vs control 0/50 (0%), P ≤0.01). No other microscopic 
treatment-related effects were found. Based on increased centrilobula r hepatocellular necrosis in 
high-dose males and proximal tubul ar epithelial basophilia in hi gh-dose females, the systemic 
LOAEL for male and female CD-1 mice was 30,000 ppm (approximately 4945 mg/kg bw/day for 
males and 6069 mg/kg bw/day for females). The NOAEL for the study was 835 mg/kg bw/day for males and 968 mg/kg bw/day for females) (MRID No. 00251007).  In another carcinogenicity study (MRID No. 49631702), glyphosate (97.5–100.2% a.i.) was 
administered to groups of 50 CD-1 mice/sex/do se in the diet at doses of 0, 100, 300, or 1000 
mg/kg/day for 104 weeks. Mortality, body weight , body weight gain, and food consumption were 
monitored throughout the study. WBC differential counts were done during Weeks 52, 77, and 102 
of the study. Organ weights were measured a nd tissues collected for microscopic analyses. 
Treatment of male and female mice for 104 weeks did not increase mortality and did not decrease 
body weight, body weight gain or food consumption. No treatment-relate d clinical signs of toxicity 
were observed and no effects were found on WBC di fferential counts. Treatment did increase the 
absolute and relative thymus weights of male  and female mice treated with 300 or 1000 mg/kg 
bw/day approximately 2–3-fold, but only the results  of male mice were st atistically increased. 
However, no treatment-related effects were found microscopically. At necropsy, the incidence of 
lung masses was slightly increased in high-dose ma le mice, but were considered coincidental. 
Microscopically, there was a slight , but statistically significant increase in mineral deposition in 
the brains of mid- and high-dose male mice. A non-significant increase was observed in female 
mice. Kidney cysts were also slight ly but statistically increased in  low- and mid-dose males, but no 
increase of cortical tubular eo sinophilic droplets was found in fema le mice. The significance of 
these findings is questionable since they did not  follow a dose-response. The systemic NOAEL for 
glyphosate in male and female CD-1 mice treat ed up to 104 weeks was 1000 mg/kg bw/day. A 
LOAEL was not identified (MRID No. 49631702).   GLYPHOSATE    FINAL    
Page 68 of 87 
  V.  COMMITTEE’S ASSESSMENT OF THE WEIGHT-OF-THE-EVIDENCE  
 
A. Evidence for Carcinogenicity in Humans 
 
The CARC evaluated one cohort st udy and seven nested case-control studies based on the cohort 
study population and twenty-five case-control studi es that examined the association between 
glyphosate exposure and one or more cancer outcomes. 
 
1. Cancer at Multiple Sites 
 
Several case-control studies repo rted no association for cancer of  the oral cavity, colon, rectum, 
colorectum, lung, pancreas, kidne y, bladder, prostate, breast or  melanoma from exposure to 
glyphosate (De Roos et al., 2005; Engle et al., 2005; Lee et al., 2007; Andreotti et al., 2009; and 
Dennis et al., 2010). 
 In single case-control studies, no associations  were found for cancers of the esophagus, stomach, 
prostate or soft-tissue sarcoma fr om exposure to glyphosate (Alavanja et al., 2003; Lee et al. , 
2004; Band et al. , 2011; Pahwa, et al., 2011; Koutros et al.,  2013). No association for childhood 
cancer was found from maternal or pate rnal exposure to glyphosate (Flower et al., 2004). 
 
2. Brain Cancer 
 
A case-control study in Nebraska and the Upper Midwest Health case-control study in Iowa, 
Michigan, Minnesota and Wisconsin  did not find any no association of glyphosate with adult brain 
cancer, specifically for gliomas (Ruder et al., 2004; Carreon et al., 2005; and Lee et al., 2005). 
 
3. Leukemia 
 
No significant association with leukemia was reported in a case-control study in Iowa and 
Minnesota (Brown et al., 1990) or in the AHS cohort (De Roos et al., 2005). A Swedish case-
control study reported a non- statistically significant elevated ri sk for hairy cell leukemia. However, 
the authors stipulated that this risk should be interpreted with caution si nce it was based on only 4 
glyphosate-exposed cases (Nordstrom et al., 1998). 
 
4. Multiple Myeloma 
 
No significant association for multiple myelom a from exposure to glyphosate was found in three 
separate population-based case-control studi es: one in Iowa and Minnesota (Brown et al., 1993) 
and the other in Iowa and North Carolina, USA (De Roos et al., 2005; Sorhan 2015); and the third 
study in Canada (Pahwa et al., 2012; Kachuri et al., 2013), and in a hospital-based case-control 
study in France (Orsi et al., 2009). A cohort study found no associ ation with glyphosate exposure 
and monoclonal gammopathy of undetermined signi ficance, a pre-clinical marker of multiple 
myeloma progression (Landgren et al., 2009). GLYPHOSATE    FINAL    
Page 69 of 87 
   
5. Non-Hodgkin Lymphoma 
 
There is conflicting evidence for an association between glyphos ate exposure and NHL; seven 
case-control studies reported no association in th e U.S, Canada, and France, while two case-control 
studies from Sweden repor ted positive association. 
 No association between glyphosate exposure and NHL was found in four population-based case-
control studies in the United Stat es: in Iowa and Minnesota (Cantor et al., 1992); in Iowa, 
Nebraska and Minnesota (Lee et al., 2004a); in Iowa, Nebraska, Mi nnesota and Kansas (De Roos 
et al., 2003) and in the AHS cohort with 57,311 licensed pesticide applicators in Iowa and North 
Carolina (De Roos et al., 2005). 
 Similarly, no association between  glyphosate exposure and NHL was seen in two population-based 
case-control studies conducted in va rious Canadian provinces (McDuffie et al., 2001; Hohenadel 
et al.,  2011).  
 
A hospital based case-control study from France did not find an association between glyphosate 
exposure and NHL (Orsi et al., 2009). 
  The first report of an association between gl yphosate exposure and NHL was in a population-based 
case-control study from Sweden (OR=23.3; 95% CI=0.40–13.0); however, this  finding was based 
on only 4 glyphosate-exposed cases and 3 controls (Hardell and Erickson, 1999). 
 In a 2002 follow-up study, data from two case-co ntrol studies in Sweden, one on NHL and the 
other on hairy cell leukemia, were pooled and analyzed. A univariate analysis showed an increased 
risk (OR=3.04; 1.08–8.52); however, when study site, vita l status, and exposure to other pesticides 
were taken into account in a multivariate an alysis, risk declined (OR=1.85; 95% CI=0.55–6.20) 
(Hardell et al., 2002). 
 In another case-control study in Sweden, among the 29 glyphosate-exposed cases, a multivariate 
analyses showed a statistically  significantly increased risk  for NHL (OR=1.51; 95% CI=0.77–2.94) 
and B-cell lymphoma (OR=1.87;  95% CI=0.998–3.51) (Erickson et al., 2008). 
 A meta-analysis of the six studies (De Roos et al.,  2003; 2005; McDuffie et al., 2001; Hardell et 
al., 2002; Erickson et al., 2008; and Orsi et al., 2009) that showed an association between 
glyphosate exposure and NHL, resulted in a meta-ri sk ratio of 1.5 (95% CI=1.1–2.0) (Schinasi and 
Leon, 2014). 
In an attempt to address the noted power/sample  size issues and after co nsidering the adjusted 
estimates of the two Swedish stud ies, IARC performed a meta-analysi s of the data and estimated a 
meta-risk ratio of 1.3 (95% CI=1.03–1.65) (IARC, 2015).  GLYPHOSATE    FINAL    
Page 70 of 87 
  In summary, the epidemiological evidence at this time does not support a causal relationship 
between glyphosate exposure and solid tumors. There is also no evidence to support a causal 
relationship between glyphosate exposure and no n-solid tumors: leukemia, multiple myeloma or 
Hodgkin lymphoma. The epidemiological  evidence at this time is inc onclusive for a causal or clear 
associative relationship between glyphosate exposu re and NHL. Multiple case-control studies and 
one prospective cohort study found no associatio n with NHL; whereas, results from a small 
number of case-control studies (mostly in Sweden) did suggest an association. Most of the studies 
in the database were underpowered, suffered fr om small sample size of cancer cases with 
glyphosate exposure, and risk/odds ratios with large confidence inte rvals. Additionally, some of 
the studies had biases associat ed with recall and missing data . The CARC recognizes the meta-
analysis conducted by IARC to try to address th e power/sample size issues. However, given the 
limitations of the studies used, a different weig hting scheme could easily change the meta-risk 
ratio. Thus, while the epidemiologic literature to  date does not support ca usal association, the 
CARC recommends that the literature continue to  be monitored for studies related to glyphosate 
and risk of NHL.  
 
 
B. Evidence for Carcinogenicity in Experimental Animals 
 
1. Evidence for Carcinogenicity in Rats 
  
A total of seven chronic toxicity /carcinogenicity studies in Wistar or Sprague-Dawley strain rats 
were available for review. In these studies, glyphosa te was administered in th e diet to both sexes at 
doses ranging from 3.0 mg/kg/day to 1500 mg/kg/day for 2-years. 
 
(i) Testes 
 
In Sprague-Dawley rats (MRID No. 00093879), ther e was a non-dose-related increase in the 
incidences of interstitial cell tumors in the test es of males at 3 mg/kg/ day (6%), 10 mg/kg/day (2%) 
and 30 mg/kg/day (12%; P=0.013) when compared to  controls (0%). The CARC reaffirmed the 
previous conclusion that these tumors are not treatment related based on the following 
considerations: 1) lack of dose-response ; 2) absence of pre- neoplastic lesions ( i.e., interstitial cell 
hyperplasia); 3) the incidences were  within the normal biological vari ation seen for this tumor type 
in this strain of rats; 4) the incidences in the c oncurrent controls (0%) was not representative of the 
normal background incidences noted in the histor ical control animals (mean, 4.5; range, 3.4% to 
6.7%;) and 5) this finding is not replicated in the other studies in the same strain of rats ( i.e., no 
interstitial cell tumors were se en when tested up to 1100 mg/kg/ day). The CARC concluded that 
the interstitial cell tumors are not treatment-related.  GLYPHOSATE    FINAL    
Page 71 of 87 
  (ii) Pancreas 
 
Benign pancreatic islet cell tumors were seen in male Sprague-Dawle y rats in two studies. In the 
first study (MRID No. 00093879), th ere was no dose response or statistical si gnificance; the 
incidences for adenomas were: 0%, 10%, 4% a nd 4% at the control, low, mid, and high dose 
groups. Carcinomas were seen in one rat at the high dose. In the second study (MRID No. 
41643801), there was a statistically significant increase in adenomas at the lowest (100 mg/kg/day) 
and the highest (1000 mg/kg/day) doses compared  to controls: lowest dose, 8/45 (18%; P=0.018); 
intermediate dose, 5/49 (10%); and highest dose,  7/48 (15%; P=0.042) versus  controls, 1/43 (2%). 
The CARC reaffirmed the previous  conclusion that the benign pancreatic islet cell tumors are not 
treatment-related due to lack of dose-response, absence of pr e-neoplastic lesions, lack of 
progression to malignancy, and incidences within th e historical control ra nge (0–17%) reported for 
this tumor in this strain of rats. This neoplas m was not seen in the ot her five studies. The CARC 
concluded that the pancreatic isle t tumors are not treatment-related. 
 
(iii) Liver 
 
In male Sprague-Dawley rats (MRID No. 41643801), th ere was a statistically significant positive 
trend in the incidence of he patocellular adenomas (P=0.016). The CARC concluded that the 
minimal increase in adenomas is not treatment-re lated due lack of statistical significance in 
pairwise comparison, absence of pre-neoplasti c lesions, no progression to malignancy, and the 
incidences were within the historical c ontrol range (1.4–18.3%) of the testing laboratory. 
 In male Wistar rats (MRID No. 49704601), there was a statistically significant trend (P=0.00804) 
and pairwise significance for the increase in hepatocellular adenomas  at the highest (1214 
mg/kg/day) dose compared to controls: lowest do se, 2/52 (4%); intermediate dose, 0/52 (0%); and 
highest dose, 5/52 (10%; P=0.02826) versus contro ls, 0/52 (0%). The CARC concluded that this 
increase is not attributable to treatment based on the following considera tions: 1) absence of dose-
response relationship; 2) lack of  progression to malignancy; 3) no evidence of pre-neoplastic 
lesions; 4) the incidences were within the historical cont rol range (0–11.5%). 
 
The CARC noted that survival was better at the high dose (25/52; 13%) compared to the controls 
(16/52; 8.3%) which could be reason for the slig htly higher incidence (5/52) of age-related 
background tumors like liver adenomas  in the absence of any associat ed lesions. Furthermore, with 
a weak genotoxic effect one woul d expect to see an effect on car cinomas (or at least adenomas/ 
carcinomas, combined) and shorter latency period, which were not observed in this study. With a 
weak cytotoxic or mitogenic effect one would e xpect to see an increase in foci and other non-
neoplastic lesions. In addition, as discussed above, only a linear tr end (no pairwise) was seen for 
this tumor type in another strain (Sprague-Dawley)  for rats where the incidences were still within 
the historical control range. Also, liver tumors were not seen in the ot her four studies. This 
provides additional evidence for lack of an actua l carcinogenic response in the liver. The CARC 
concluded that the liver tumo rs are not treatment-related. 
 GLYPHOSATE    FINAL    
Page 72 of 87 
  (iv) Thyroid 
 
In Sprague-Dawley rats (MRID No. 41643801), there was a statistically significant positive trend 
in the incidence of thyroid C- cell tumors in females (P=0.031).  The CARC concluded that the 
minimal increase is not treatment-related due to lack of statistical si gnificance in pairwise 
comparison, no progression to carcinomas, no increas e in severity of gr ade or incidence of 
hyperplasia, and the incidences were within the historical control range (3.3–10%). The CARC 
concluded that the thyroid tumors in fe male rats are not treatment-related. 
 
In summary, dietary administration of gly phosate at doses ranging from 3.0 to 1500 
mg/kg/day for up to two years produced no evid ence of carcinogenic response to treatment in 
male or female Sprague-Dawley or Wistar rats.   
2. Evidence for Carcinogenicity in Mice 
 
Four carcinogenicity studies in CD-1 mice were available for revi ew. In these studies, glyphosate 
was administered in the diet to both sexes at doses ranging fro m 85 mg/kg/day to 4800 mg/kg/day 
for 18–24 months. In one study there were no stat istically significant or otherwise notable 
increases in the occurrence of any tumor types. Tumors observed in the other three studies are 
discussed below.   
(i) Kidney 
 
Kidney (renal tubular) tumors were seen in male CD-1 mice in one study (MRID No. 00251007). 
The incidences of adenomas was 1/49 (2%), 0/49 (0%), 0/50 (0%), and 1/50 (2%) in the control (0 
mg/k/day), low- (157 mg/kg/day), mid- (814 mg /kg/day) and high-dose (4945 mg/kg/day) groups, 
respectively. The incidence of carcinomas was 0/ 49 (0%), 0/49 (0%), 1/50 (2%) and 2/50 (4%) in 
the control, low-, mid- and high-dose groups, respectively. The incidence of adenomas or 
carcinoma (combined) was 1/49 (2%), 0/50 (0%), 1/ 50 (2%), and 3/50 (6%) in  the control, low-, 
mid-, and high-dose groups, respectively. None of th ese differences showed statistical significance. 
  The CARC reaffirmed the previ ous conclusion that the kidney tu mors are not treatment-related 
based on the following weight-of-evidence consider ations: a) lack of dose-related trend or 
statistical significance in pairwise  comparisons; b) lack of non-ne oplastic renal tubular lesions ( e.g. 
tubular necrosis/regeneration, hyperplasia, or bas ophilia); c) the examinati on of multiple sections 
of kidneys from all groups resulted  in no additional neoplasms; this fact is particul arly important 
since not only were the original sections closely scrutinized by more than one pathologist, but 
additional sections as well; and d) the difference in incidence between high-dose group (3/50) and 
the control group (1/49) was minimal, especially considering the very hi gh concentration given 
(4 x time the limit dose).   
  GLYPHOSATE    FINAL    
Page 73 of 87 
  Furthermore, the Pathology Work Group conclude d that the renal tumors were not treatment-
related since none of the treatment groups differed fr om the controls for a linear trend or pairwise 
statistical significance, there wa s no treatment-related nephrotoxic lesions including pre-neoplastic 
changes, and multiple renal tumors were not seen in any animal.  In addition, the CARC noted that renal tumors we re not observed when tested at a similar dose 
(4348 mg/kg/day) in this strain of mice in another study(Arysta, 1997b)  or in two other studies at 
the limit dose (MRID No. 49631702, Nufarm, 2009b). If re ally treatment-related, it is unlikely that 
the same tumor would not have been detected at  higher incidences in CD-1 mice with top doses 
>1000 – 4000 mg/kg/day.  
(ii) Lung adenocarcinoma 
 
There was a dose-dependent increase in the incide nce of bronchiolar-alveo lar adenocarcinoma of 
the lung in male CD-1 mice (Nufarm, 2009b). There was a positive trend (P=0.02906) in the 
incidence of lung adenocarcinomas : 5/51 (10%), 5/51 (10%), 7/51 ( 14%) and 11/51 (22 %) at the 0, 
85, 267 or 946 mg/kg/day groups, respectively. The CARC  determined that th is increase is not 
treatment-related due to lack of  statistical signific ance in pairwise comparison, absence of pre-
neoplastic lesions in the lung ( e.g., bronchiolar-alveolar hyperplasia),  and incidences in all treated 
groups within the background range (1.42–26%) for this tumor in this strain and age of mice. Also, 
lung tumors were not seen when tested at a comp arable dose (1000 mg/kg/day)  or at considerably 
higher doses (4116–4945 mg/kg/day) in this strain of mice in the ot her three studies (MRID Nos. 
00251007; 49631702; Arysta, 1997b).  
(iii) Lymphoma/Lymphosarcomas 
 
There was a dose-dependent and statistically signi ficant increase in the incidence of malignant 
lymphomas in male mice (Nufarm, 2009b). The in cidence was: 0/51 (0%;  trend P=0.006633), 1/51 
(2%), 2/51 (4%) and 5/51 (10%; P=0.02820) at the 0, 85, 267 or 946 mg/kg/day groups, 
respectively. The CARC determined that this incr ease is not treatment-related since the incidences 
in the concurrent controls (0%) were not representative of the normal background incidences noted 
in the historical controls (mean, 4.5%; range, 1.5% to 21.7%), and the apparent statistical 
significance of the pairwise comparison of the high  dose group with the concurrent control might 
have been attributable to this factor rather than an actual carcinogenic response. Also, this 
neoplasm was not seen in other studies in this strain of mice. For example, in the study by 
Knezevich and Hogan 1983 (MRID No. 00251007), there was no significant difference in the incidence of lymphomas between  control and high-dose groups (P=1.00 for males, P=0.12 for 
females). In the study by Atkinson et al. (1993) (MRID No. 496317), th e incidence values in 
“lymphoreticular/ hematopoietic tissue” were not significantly different between control and high-
dose groups (males: 4 in controls, 6 in high-dose group; females: 14 in co ntrols, 13 in high-dose 
group). In the Arysta  1997 study (Greim et al., 2015), the incidence of lymphoma in males was 
2/50, 2/50, 0/51, 6/50 in the control, low, mid and high dose groups, respectively. There were no 
statistically significant pairwise differen ces observed in any of these studies. GLYPHOSATE    FINAL    
Page 74 of 87 
   
(iv) Hemangioscarcomas 
 
Hemangiosarcomas were seen in multiple organs incl uding, liver, spleen, and prostate in males and 
liver and uterus in female CD-1 mice (MRID No. 49631702). There was a positive trend 
(P=0.00296) in the incidence of hemangiosarcomas in male mice: 0/47 (0 %), 0/46 (0%), 0/50 (0%) 
and 4/45 (9%) at the 0, 100, 300 and 1000 mg/kg/day groups, respectively. The hemangiosarcomas 
were present in the liver, spleen or prostate in the high dose males. In females, this neoplasm was 
seen in one female at the low dose (uterus) and in one high dose (spl een). The CARC did not 
consider the hemangiosarcomas in males to be treatment-related based on the following 
considerations: 1) there was no pairwise significance; 2) lack  of dose-response; 3) the incidence 
was near the upper limit (0–8%) of the bac kground rate at the pe rforming laboratory; 
4) hemangiosarcomas are commonly observed in mi ce as spontaneous tumors and are generally 
more common in males in CD-1 strain mice; 5) there was not a significant increase in 
hemangiosarcomas seen in the other three mouse st udies; and 6) if really treatment-related, it is 
unlikely that the same tumor would not have been de tected at higher incidences in CD-1 mice with 
top doses >1000-4000 mg/kg/day. 
 
In summary, dietary administration of gly phosate at doses ranging from 85 to 4945 
mg/kg/day for up to two years produced no evid ence of carcinogenic response to treatment in 
male or female CD-1 mice. 
    
C. Discussion 
 
When determining the carcinogenic potential of chemicals, the IARC iden tifies a cancer “hazard” 
if an agent ( e.g., chemical) is capable of causing cancer under some circumstance and the agent is 
termed “carcinogenic” if it is capable of increasi ng the incidence of malignant neoplasms, reducing 
their latency, or increasing their severity or multiplicity. The IARC also considers that there is 
“sufficient evidence of carcinogenicity”  based on the occurrence of  increased tumors (benign, 
malignant, or combination) in: 1) two or more sp ecies of animals; 2) two or more independent 
studies in one species; and/or 3) an increased inci dence of tumors in both se xes of a single species. 
Furthermore, a single study in one species and sex might be considered to provide sufficient 
evidence of carcinogenicity when malignant neoplasms occur to an unusual degree with regard to 
incidence, site, type of tumor or age at onset, or when there are strong findings of tumors at 
multiple sites (IARC Preamble, 2006).  In March 2015, the IARC evaluated the carci nogenic potential of  glyphosate. The IARC 
determined that there was a positive trend in th e incidence of a rare tumor type, renal tubular 
carcinoma and renal tubule adenoma or carcinoma (combined) in males in one feeding study in 
CD-1 mice. A second study reported a positive tre nd for hemangiosarcomas in male CD-1 mice. 
Thus, in accordance with one of the preamble criter ia, “the occurrence of tumors in two studies in 
one species,” IARC determined that there is “sufficient evidence” in experimental animals for the carcinogenicity of glyphosate (IARC, 2015). GLYPHOSATE    FINAL    
Page 75 of 87 
  In contrast, the USEPA’s carcinogenicity clas sification is based on weight-of-evidence 
considerations in accordance with the agency’s 2005 Guidelines for Carcinogen Risk Assessment. 
The cancer guideline emphasizes the importance of weighing all of the evidence in reaching 
conclusions about the human carcino genic potential of agents. This  evaluation is accomplished in a 
single integrative step after asse ssing all of the indivi dual lines of evidence. Evidence considered 
includes tumor findings, or lack th ereof, in humans and laboratory animals; an agent’s chemical 
and physical properties; its stru cture-activity relationships (SAR s) as compared with other 
carcinogenic agents; and studies addressing potential car cinogenic processes and mode(s) of 
action, either in vivo or in vitro . Data from epidemio logical studies are ge nerally preferred for 
characterizing human cancer hazard and risk. Howe ver, all of the inform ation discussed above 
could provide valuable insight in to the possible mode(s) of acti on and likelihood of human cancer 
hazard and risk (USEPA, 2005).  Conclusions for evidence of carci nogenicity are based on the comb ined strength and coherence of 
inferences appropriately  drawn from all of the available information. The following observations 
add significance to the tumor findings: tumors in  multiple species, strains, or both sexes; dose-
related increases; progression of lesions from pr e-neoplastic to benign to  malignant; proportion of 
malignant tumors; reduced latency of neoplasti c lesions; and both biolog ical and statistical 
significance of the findings (USEPA, 2005).  The IARC attributed the kidney tumors observed in male CD-1 mice at the high dose in the 
feeding study (MRID No. 00251007) to treatment sinc e they are rare and there was borderline 
significance in trend test (P=0.034 for carcinoma and P=0.037 for combined adenoma or 
carcinoma) in a Cochran-Armitage trend test. However, as shown in Table 14, the agency’s statistical analyses did not show a significan t trend for either carcinoma (P=0.06345) or the 
combined adenoma or carcinoma (P=0.06483). In a Fi sher’s exact test, when compared to the 
concurrent control, there was no pairwise significance for any tumor type (adenoma, carcinoma, or 
combined). There were no pre-neoplastic rena l tubular lesions such as tubular necrosis/ 
regeneration, hyperplasia or hypertrophy, despite a high dose level (4945 mg /kg/day) that was 
approximately 5-fold higher than the limit dos e (1000 mg/kg/day) recommended by the agency’s 
guidelines. Examination of multiple sections of  kidneys from all animals by more than one 
pathologist did not result in any additional neoplasms. Although the highest dose tested (4945 
mg/kg/day) was approximately 5-fold higher th an the limit dose (1000 mg/kg/day) recommended 
by the agency’s guideline, the incidence of the kidney tumors was minimal (1/50 adenomas and 
2/50 carcinomas) compared to controls (1/49 ad enomas). An evaluation by the PWG concluded 
that the renal tumors are not treatment-related since there were  no compound related nephrotoxic 
lesions, including pre-neoplastic changes, multiple tumors were not found in any animals, and 
there was no evidence of a significant linear tr end at the 0.5 level in a one-tailed Cochran-
Armitage test or pairwise significance in a Fish er’s exact test. Furthermore, kidney tumors were 
not seen when tested at lower (85 to 1000 mg/kg/day) doses or at  a comparable (4116 mg/kg/day) 
dose in this strain of mice in the other three studies. Thus, the totality of data available from 4 carcinogenicity studies provides a strong support for the conclusion th at the kidney tumors seen in 
one study is not the result of a car cinogenic response to glyphosate. GLYPHOSATE    FINAL    
Page 76 of 87 
   
The IARC attributed the hemangiosarcomas observe d in male CD-1 mice at the high dose in 
separate feeding study (MRID No. 49631702) to treatment due to th e positive trend (P<0.001) in a 
Cochran-Armitage trend test. As shown in Table 16, the agency’s statistical analyses also showed 
a positive trend (P=0.00296) in the trend test. In the Fisher’s exact test , there was no pairwise 
significance when compared to controls. In contra st with the IARC, the CARC did not consider the 
hemangiosarcomas to be treatment-relate d based on the following weight-of-evidence 
considerations: 1) there was no pairwise significance; 2) lack  of dose-response; 3) the incidence 
was near the upper limit (0–8%) of the bac kground rate at the pe rforming laboratory; 
4) hemangiosarcomas are commonly observed as spont aneous tumors in male CD-1 strain mice; 
and 5) hemangiosarcomas were not seen when tested at comparable doses (946–1467 mg/kg/day) 
or at considerably higher doses (4116–4945 mg/kg/day) in this strain  of mice in the other studies 
(MRID No.00251007, Arysta, 1997b, Nufarm, 2009b). It is  noted that JMPR in their evaluation 
also concluded that the hemangiosarcomas are not treatment-related ow ing to lack of dose-
response relationship, lack of stat istical significance and incidences  within the historical control 
range (JMPR, 2004).  
Hemangiosarcomas have similar histopathological features in rodents and humans but differ in 
both incidence and tissue site. In human populations , hemangiosarcomas have an incidence rate of 
approximately 0.2 new cases/100,000 people (0.0002%) (1996–2000, US National Cancer 
Institute–SEER Database) and account for <1% of  all human sarcomas. The historical background 
incidence of hemangiosarcomas in B6C3F1 and CD -1 mice relative to the incidence rate in 
humans has thus been estimated to be approximately 10,000-fold higher than in people (Pegg et 
al., 2012). The most common sites for spontaneous he mangiosarcomas in rodents are liver, spleen, 
bone marrow, and to a lesser extent in lym ph nodes and skin (see references in Pegg et al.  (2012). 
In male mice, liver and spleen tend to be th e most common sites. Human hemangiosarcoma is 
most commonly reported in skin (Weiss et al., 2001). Primary liver hemangiosarcoma in humans 
has been linked to chemical exposure, notably  thorotrast and vinyl chloride, which are both 
considered genotoxic carcinogens. There are severa l examples of induction of hemangiosarcomas 
by non-genotoxic agents in mice, but no clear examples of hemangiosarcoma induction by non-
genotoxic agents in human populations (Cohen et al.,  2009). Several studies have looked at 
potential mode of action (MOA) for these tumo rs in mice in response to various drugs or 
chemicals. These MOAs generally relate to hypoxia  or vascular toxicity  as early key events. 
 
1. Mutagenicity 
 
Glyphosate was not mutagenic in bacteria or mammalian cells in vitro . Additionally, glyphosate 
did not induce chromosomal aberrations in vitro . Although some studies in the open literature 
reported positive findings for micronuclei induction in rodents, these findings were not replicated 
in the majority of the rodent micronucleus assa y studies. There is no convincing evidence that the 
DNA damage is a direct effect of glyphosate, but under some c onditions may be secondary to 
cytotoxicity or oxidative damage. Furthermore, the chemical structure of glyphosate, with its 
absence of alkyl groups also prov ides SAR support for the lack of  mutagenic/genotoxic potential. GLYPHOSATE    FINAL    
Page 77 of 87 
   
IARC concluded that “there is strong evidence that exposure to glyphosate or glyphosate-based 
formulations is genotoxic”; howev er, the IARC analysis included studies that tested glyphosate-
formulated products as well as studies where the test material  was not well-characterized ( i.e., no 
purity information was provided). The CARC did not  include such studies in their evaluation.  
The IARC analysis also focused on DNA damage as an endpoint ( e.g., comet assay); however, 
DNA damage is often reversible and can result from events that  are secondary to toxicity 
(cytotoxicity), as opposed to permanent DNA change s which are detected in tests for mutations 
and chromosomal damage ( e.g. chromosomal aberrations or mi cronuclei induction). The studies 
that IARC cited, where positive findings were reported for chromosomal damage, had study 
limitations confounding the interpreta tion of the results. In additi on, these positive findings were 
not reproduced in other guideline or guideline- like studies evaluating the same endpoints. This 
includes many negative studies cite d by Kier and Kirkland (2013) that were considered by CARC, 
but were not included in the IARC decision.   
2. Structure Activity Relationship 
 
Sulfosate (the trimethylsulfonium salt of glyphosate) is classified as a Group E Chemical: “Not Likely 
to be Carcinogenic to Humans,” based on the lack of evidence of carcinogenicity in mice and rats in 
two acceptable studies, and absence of mutagenicity concern.  
 
VI. CLASSIFICATION OF CARCINOGENIC POTENTIAL 
 
In accordance with the 2005 Guidelines for Carci nogen Risk Assessment, glyphosate is classified 
as “Not Likely to be Carcinogenic to Humans.”  This classification is based on the following 
weight-of-evidence considerations: 
 
 The epidemiological evidence at this time does not support a causal relationship between 
glyphosate exposure and solid tumors. There is also no evidence to support a causal 
relationship between glyphosate exposure a nd the following non-solid  tumors: leukemia, 
multiple myeloma, or Hodgkin lymphoma. The ep idemiological evidence at this time is 
inconclusive for a causal or  clear associative relations hip between glyphosate and NHL. 
Multiple case-control studies and one pros pective cohort study found no association; 
whereas, results from a small number of cas e-control studies (mostly in Sweden) did 
suggest an association. Limitations for most of these studies include  small sample size, 
limited power, risk ratios with large confidence intervals, and recall bias as well as missing 
data. The literature will conti nue to be monitored for studies  related to glyphosate and risk 
of NHL.  
 In experimental animals, there is no eviden ce for carcinogenicity. Diet ary administration of 
glyphosate at doses ranging from 3.0 to 1500 mg /kg/day for up to two years produced no 
evidence of carcinogenic response to treatment in seven separate studies with male or 
female Sprague-Dawley or Wistar rats. Simila rly, dietary administ ration of glyphosate at GLYPHOSATE    FINAL    
Page 78 of 87 
  doses ranging from 85 to 4945 mg/kg/day for up to two years produced no evidence of 
carcinogenic response to treatment in four separa te studies with male or female CD-1 mice. 
The CARC did not consider any of the obser ved tumors in 11 carcinogenicity studies in 
rats and mice to be treatment-related since th e observed tumors did not exhibit a clear dose-
response relationship, were not s upported pre-neoplastic changes ( e.g., foci, hypertrophy, 
and hyperplasia), were not statistically signifi cant on pairwise statisti cal analysis, and/or 
were within the range of th e historical control data. 
 
 Based on a weight of evidence approach  from a wide range of assays both in vitro  and in 
vivo including endpoints for gene mutation, chromosomal damage, DNA damage and 
repair, there is no in vivo  genotoxic or mutagenic concern for glyphosate. 
 
 
VII. QUANTIFICATION OF CARCINOGENIC POTENTIAL 
 
Not required. 
 
VIII. BIBLIOGRAPHY  
Akanuma M. (1995a). HR-001: DNA Repair Test  (Rec-Assay). Unpublished Regulatory Study. 
Report Identification Number: IET 94-0141.  Akanuma M. (1995b). HR-001 reverse mutation test. Unpublished Regulatory Study. Report 
Identification Number: IET 94-0142.  Alavanja, M. C., Dosemeci, M., Samanic, C., Lubi n, J., Lynch, C. F., Knott, C. Blair, A. (2004). 
Pesticides and lung cancer risk in the agricultural health study cohort. Am J Epidemiol, 160 (9), 
876–885.]  Alavanja, M. C., Samanic, C., Dosemeci, M., Lubi n, J., Tarone, R., Lynch, C. F. Blair, A. (2003). 
Use of agricultural pesticides and prostate cancer risk in the Agricultural  Health Study cohort. Am 
J Epidemiol, 157 (9), 800–814.  
 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. 
 Andreotti, G., Freeman, L. E., H ou, L., Coble, J., Rusiecki, J., Hoppin, J. A., Alavanja, M. C. 
(2009). Agricultural pesticide use and pancreatic cancer risk in  the Agricultural Health Study 
Cohort. Intl. J Cancer , 124(10), 2495–2500. 
 Arysta Life Sciences (1997b). HR-001: 18-Month Oral Oncogenici ty Study in Mice. Tokyo, Japan: 
The Institute of Environmental Toxicology.  GLYPHOSATE    FINAL    
Page 79 of 87 
  Arysta Life Sciences. (1997a). HR-001: 24-Month Oral Chronic Toxicity and Oncogenicity Study 
in Rats. Kodaira-sh i, Tokyo, Japan: The Institute of Environmental Toxicology.  
 Atkinson, C., Martin, T., Hudson, P. & Robb, D. (1993a) Glyphosate: 104 week dietary 
carcinogenicity study in mice. Unpublished report No.7793, IRI project No. 438618, dated 12 
April 1991, from Inveresk Research Internati onal, Tranent, Scotland. Submitted to WHO by 
Cheminova A/S, Lemvig, Denmark. MRID 49631702.  Atkinson, C., Strutt, A.V., Henderson, W., Finc h, J. & Hudson, P. (1993b) Glyphosate: 104 week 
combined chronic feeding/oncogenicity study in rats  with 52 week interim kill (results after 104 
weeks.). Unpublished report No. 7867, IRI proj ect No. 438623, dated 7 April 1993, from Inveresk 
Research International, Tranent, Scotland. Submitted to WHO by Cheminova A/S, Lemvig, 
Denmark. MRID 49631701.  Band, P. R., Abanto, Z., Bert, J., Lang, B., Fang, R ., Gallagher, R. P., & Le, N. D. (2011). Prostate 
Cancer Risk and Exposure to Pesticid es in British Columbia Farmers. Prostate, 71 (2), 168–183. 
 
Bolognesi, C., Bonatti, S., Degan, P., Gallerani, E., Peluso, M., Rabboni, R., Roggieri, P., and 
Abbondandolo, A. (1997). Genotoxic activity of glyphosate and its technical formulation 
Roundup. J. Agric. Food Chem . 45, 1957–1962. 
  Brammer, A. (2001) Glyphosate acid: two year di etary toxicity and oncoge nicity study in rats. 
Unpublished report No. CTL/PR1111, study N o. PR1111, dated 15 March 2001, from Zeneca 
Agrochemicals, Central Toxicology Laboratory, Al derley Park, Macclesfield, Cheshire, England. 
Submitted to WHO by Syngenta Crop Protec tion AG, Basel, Switzerland. MRID 49704601. 
 Brown, L. M., Blair, A., Gibson, R., Everett, G.  D., Cantor, K. P., Schuman, L. M., Dick, F. 
(1990). Pesticide exposures and ot her agricultural risk  factors for leukemia among men in Iowa 
and Minnesota. Cancer Res, 50 (20), 6585–6591.  
 Brown, L. M., Burmeister, L. F., Everett, G. D., & Blair, A. (1993). Pesticide exposures and 
multiple myeloma in Iowa men. Cancer Causes Control, 4 (2), 153–156.  
 Callander RD. (1996). Glyphosate acid: an ev aluation of mutagenic potential using S. typhimurium 
and E. coli . Unpublished Regulatory Study. Report Identification Number: CTL/P/4874. 
 Cantor, K. P., Blair, A., Everett, G., Gibson, R ., Burmeister, L. F., Brown, L. M., Dick, F. R. 
(1992). Pesticides and other agricultural risk  factors for non-Hodgkin's lymphoma among men in 
Iowa and Minnesota. Cancer Res, 52 (9), 2447–2455.  
 Carreon, T., Butler, M. A., Ruder, A. M., Waters, M. A., Davis-King, K. E., Calvert, G. M. Brain 
Cancer Collaborative Study, G. (2005). Gliomas a nd farm pesticide exposure in women: The 
Upper Midwest Health Study. Environmental Health Perspectives, 113 (5), 546–551. GLYPHOSATE    FINAL    
Page 80 of 87 
   
Clay P. (1996). Glyphosate acid: L5178Y TK+/ – mouse lymphoma gene mutation assay. 
Unpublished Regulatory Study. Report Identification Number: CTL/P/4991. 
 Cocco P, Satta G, Dubois S, Pili C, Pilleri M, Zucca M et al. (2013) Lymphoma risk and 
occupational exposure to pesticid es: results of the Epilymph study. Occup Environ Med , 
70(2):91–8.   Cohen S, Storer R, Criswell KA, Doerrer NG, Dellarco VL, Pegg DG, Wojcinski ZW, Malarkey 
DE, Jacobs AC, Klaunig JE, Swenberg JA, Cook JC (2009). Hemangiosarcomas in rodents: mode 
of action evaluation and human relevance. To Toxicol. Sci. (2009) 111 (1): 4–18.
  
 De Roos, A. J., Blair, A., Rusiecki, J. A., Hoppi n, J. A., Svec, M., Dosemeci, M., Alavanja, M. C. 
(2005). Cancer incidence among glyphosate-exposed pesticide applicators in the Agricultural 
Health Study. Environ Health Perspect, 113 (1), 49–54.  
 De Roos, A. J., Zahm, S. H., Cant or, K. P., Weisenburger, D. D., Ho lmes, F. F., Burmeister, L. F., 
& Blair, A. (2003). Integrative asse ssment of multiple pesticides as risk factors for non-Hodgkin's 
lymphoma among men. Occup Environ Med, 60 (9), E11.  
 Dennis, L. K., Lynch, C. F., Sandler, D. P., & Al avanja, M. C. (2010). Pesticide use and cutaneous 
melanoma in pesticide applicator s in the agricultural heath study. Environ Health Perspect, 118 (6), 
812–817.   Durward R. (2006). Glyphosate technical: micronucleus test in the mouse. Unpublished 
Regulatory Study. Report Iden tification Number: 2060/014. 
 Engel, L. S., Hill, D. A., Hoppin, J. A., Lubin, J. H., Lynch, C. F., Pierce, J., Alavanja, M. C. (2005). Pesticide use and breast cancer risk among farmers' wives in the agricultural health study. 
Am J Epidemiol , 161(2), 121–135. 
 Eriksson, M., Hardell, L., Carlberg, M., & Akerman, M. (2008). Pesticide e xposure as risk factor 
for non-Hodgkin lymphoma including hi stopathological subgroup analysis. Int J Cancer, 123 (7), 
1657–1663.  EC. (2002). Review report for the active substance glyphosate. European Commission., 
Directorate E — Food Safety: plan t health, animal health and we lfare, international questions, 
E1-Plant health.  Flower, K. B., Hoppin, J. A., Lynch, C. F., Blair, A., Knott, C., Shore, D. L., & Sandler, D. P. (2004). Cancer risk and parental  pesticide application in child ren of agricultural health study 
participants. Environ Health Perspect , 112(5), 631–635.  
 GLYPHOSATE    FINAL    
Page 81 of 87 
  Flugge C. (2009a). Mutagenicity study of glyphosate TC in the Salmonella Typhimurium reverse 
mutation assay ( in vitro ). Unpublished Regulatory Study. Re port Identification Number: 23916. 
 Flugge C. (2009b). Micronucleus test  of glyphosate TC in bone marrow cells of the CD rat by oral 
administration. Unpublished Regulatory St udy. Report Identification Number: 23917. 
 Flugge C. (2010a). Mutagenicity stu dy of trop M (glyphosate 480) in the Salmonella Typhimurium 
reverse mutation assay ( in vitro ). Unpublished Regulatory Study. Re port Identification Number: 
24753.  Flugge C. (2010b). Mutagenicity study of glyphosate TC in the Salmonella Typhimurium reverse 
mutation assay ( in vitro ). Unpublished Regulatory Study. Re port Identification Number: 24880. 
 Feinchemie Schwebda. (1996). Combined Chroni c Toxicity and Carci nogenicity Study with 
Glyphosate Technical in Wist ar Rats. Bangalore, India:  Rallis India, Ltd. 
 Feinchemie Schwebda. (2001). Carcinogenicity Study with Glyphosate Technical in Swiss Albino 
Mice. Bangalore, India: Rallis India, Ltd. Gad SC, Frith CH, Goodman DG,  Boysen BG. (2008).  
 Fox V. (1998). Glyphosate acid: in vitro  cytogenetic assay in hu man lymphocytes. Unpublished 
Regulatory Study. Report Identif ication Number: CTL/P/6050. 
 Fox V, Mackay JM. (1996). Glyphosate acid: m ouse bone marrow micronucleus test. Unpublished 
Regulatory Study. Report Iden tification Number: SM0796. 
 Germany Rapporteur Member Stat e. (2015a). Glyphosate Renewal Assessment Report, Volume 1. 
Report and Proposed Decision. Revised 29th, January 2015. 
 Germany Rapporteur Member Stat e. (2015b). Glyphosate Renewal Asse ssment Report, Volume 3, 
Annex B.6.1 Toxicology and Metabolism . Revised 29th, January 2015. 
 Giknis, M. L. A., and Cliffor d, C. B. (2005). Spontaneous Neopl astic Lesions in the Crl:CD1 
(ICR) Mouse in Control Groups from 18 M onth to 2 Year Studies. Charles River. 
http://www.criver.com/files/pdfs/rms/cd1/ rm_rm_r_lesions_crlcd_1_icr_mouse.aspx  
 
Greim, H., Saltmiras, D., Mostert, V., Strupp, C (2015). Evaluation of carci nogenic potential of the 
herbicide glyphosate, drawing on tu mor incidence data from fourteen chronic/carcinogenicity 
rodent studies. Critical Reviews in Toxicology . 45(08.3): 185–208. 
 Hardell, L., & Eriksson, M. (1999). A case-cont rol study of non-Hodgkin lymphoma and exposure 
to pesticides. Cancer, 85 (6), 1353–1360.  
 GLYPHOSATE    FINAL    
Page 82 of 87 
  Hardell, L., Eriksson, M., & Nordstrom, M. (2002). Exposure to pesticides as risk factor for non-
Hodgkin's lymphoma and hairy cell leukemia: pool ed analysis of two Swedish case-control 
studies. Leuk Lymphoma, 43 (5), 1043–1049. 
 Hohenadel, K., Harris, S. A., McLaughlin, J. R., Spin elli, J. J., Pahwa, P., Dosman, J. A., Blair, A. 
(2011). Exposure to multiple pesticides and ri sk of non-Hodgkin lym phoma in men from six 
Canadian provinces. Int J Environ Res Public Health , 8(6), 2320–2330.  
 
Honarvar N. (2005). Micronucleus assay in bone  marrow cells of the mouse with glyphosate 
technical. Unpublished Regulatory St udy. Report Identification Number: 872000. 
 Honarvar N. (2008). Glyphosate technical – mi cronucleus assay in bone marrow cells of the 
mouse. Unpublished Regulatory Stu dy. Report Identification Number: 1158500. 
 
IARC (2015). International Agency for Resear ch on Cancer. Monograph on Glyphosate. Volume 
112 http://monographs.iarc.fr/ENG/Monographs/vol112/mono112-02.pdf   
 
Jensen JC. (1991a). Mutagenicity test: Ames Sa lmonella assay with glyphosate, batch 206-JaK-25-
1. Unpublished Regulatory Study. Repor t Identification Number: 12323. 
 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. 
 Jensen JC. (1991c). Mutagenicity test: micronuc leus test with glyphos ate, batch 206-JaK-25-1. 
Unpublished Regulatory Study. Repor t Identification Number: 12324. 
 JMPR (2006). Glyphosate. In: Joint FAO/WHO Meet ing on. Pesticides residues in food – 2004. 
Part II: Toxicological Evaluations. Geneva, World Health Organisation, pp 95-169 http:// 
www.inchem.org/documents/jmpr/jmpmono/v2004pr01.pdf   
 
Kachuri L, Demers PA, Blair A, Spinelli JJ, Pahwa M, McLaughlin JR et al.  (2013) Multiple 
pesticide exposures and the risk of multiple myeloma inCanadian men. Int J Cancer , 
133(8):1846–58.  Karunanayake CP, Spinelli JJ, McLaughlin JR , Dosman JA, Pahwa P, McDuffie HH. (2012). 
Hodgkin lymphoma and pestic ides exposure in men: a Canadian case-control study.  
J Agromedicine . 2012 Jan; 17(1):30–9.  
 Kier, L.D.; Flowers, L.J.; Hannah, L.H. (1978) Fi nal Report on Salmonella Mutagenicity Assay of 
Glyphosate: Test No. LF-78-161. MRID 00078620.  Kier, D and Kirklan, D. J (2013). Review of ge notoxicity studies of glyphosate and glyphosate-
based formulations. Critical Reviews in Toxicology . 43(4), 283–315. 
 GLYPHOSATE    FINAL    
Page 83 of 87 
  Klimisch, H.J., Andreae, M., Tilmann, U. (1977). A systematic approach for evaluating the quality 
of experimental toxicological  and ecotoxicological data. Regul. Toxicol. Pharmaco . 25:1–5. 
 Knezevich, A.L and Hogan, G. K. (1983). A ch ronic feeding study of glyphosate in mice. 
Unpublished report prepared by Bio/Dynamic Inc., dated July 21, 1983. Report No. 77-2011. EPA Accession No. 00251007 – 251009, and 251014. 
 
Koutros S, Beane Freeman LE, Lubin JH, Heltsh e SL, Andreotti G, Barry KH, DellaValle CT, 
Hoppin JA, Sandler DP, Lynch CF, Blair A, Alavanja  MC. Risk of total a nd aggressive prostate 
cancer and pesticide use in the Agricultural Health Study. Am J Epidemiol . 
2013 Jan 1;177(1):59–74.  Landgren, O., Kyle, R. A., Hoppin, J. A., Freeman, L. E. B., Cerhan, J. R., Katzmann, J. A., 
Alavanja, M. C. (2009). Pesticide exposure and risk of monoclonal gammopathy of undetermined 
significance in the Agricultural Health Study. Blood, 113 (25), 6386-6391.  
 Lankas, G.R.; Hogan, G.K. (1981) A Lifetime Feeding Study of Glyphosate (Roundup Technical) 
in Rats: Project No. 77- 2062. (Unpublished stud y received Jan 20, 1982 under 524-308; prepared 
by Bio/dynamics, Inc., submitted by Monsanto  Co., Washington, D.C.; CDL:246617-A; 246618; 
246619; 246620; 246621). MRID 00093879.  Lee, W. J., Cantor, K. P., Berzofsky, J. A., Zahn, S. H., & Blair, A. (2004a). Non-Hodgkin's 
lymphoma among asthmatics exposed to pesticides. International Journal of Cancer, 111 (2), 
298–302.   Lee, W., Lijinsky, W., Heineman, E., Markin, R., Weisenburger, D., & Ward, M. (2004b). 
Agricultural pesticide use and adenocar cinomas of the stomach and oesophagus. Occupational and 
Environmental Medicine, 61 (9), 743–749.  
 Lee, W., Colt, J., Heineman, E., McComb, R ., Weisenburger, D., Lijinsky, W., & Ward, M. 
(2005). Agricultural pesticide use and risk of glioma in  Nebraska, United States. Occupational and 
Environmental Medicine, 62 (11).  
 Lee, W. J., Sandler, D. P., Blair, A., Samanic,  C., Cross, A. J., & Alavanja, M.C.R. (2007). 
Pesticide use and colorectal cancer ri sk in the Agricultural Health Study. International Journal of 
Cancer, 121 (2), 339–346.  
 
Li, A.; Kier, L.; Folk, R. ( 1983) CHO/HGPRT Gene Mutation A ssay with Glyphosate: EHL Study 
No. ML-83-155. Final rept. MRID 00132681.  
 
Li, A. P., and Long, T. J. (1988). An evalua tion of the genotoxic potential of glyphosate. Fundam. 
Appl. Toxicol . 10, 537–546. 
 GLYPHOSATE    FINAL    
Page 84 of 87 
  Lioi, M. B., Scarfi, M. R., Santor o, A., Barbieri, R., Zeni, O., Salvemini, F., Di Berardino, D., and 
Ursini, M. V. (1998a). Cytogenetic damage and induction of pro-oxi dant state in human 
lymphocytes exposed in vitro  to gliphosate, vinclozo lin, atrazine, and DPX-E9636. Environ. Mol. 
Mutagen.  32, 39–46. 
 Lioi, M. B., Scarfi, M. R., Santor o, A., Barbieri, R., Zeni, O., Di Berardino, D., and Ursini, M. V. 
(1998b). Genotoxicity and oxidative stress induc ed by pesticide exposure in bovine lymphocyte 
cultures in vitro . Mutat. Res . 403, 13–20. 
 Manas F, Peralta L, Raviolo J, et al. (2009). Genotoxicity of gl yphosate assessed by the comet 
assay and cytogenetic tests. Environ Toxicol Phar , 28, 37–41. 
 Matsumoto K. (1995). HR-001: in vitro  cytogenetics test. Unpub lished Regulatory Study. Report 
Identification Number: IET 94-0143.  McDuffie, H. H., Pahwa, P., McLaughlin, J. R., Spin elli, J. J., Fincham, S ., Dosman, J. A., Choi, 
N. W. (2001). Non-Hodgkin's lymphoma and specifi c pesticide exposures in men: cross-Canada 
study of pesticides and health. Cancer Epidemiol Biomarkers Prev, 10 (11), 1155–1163.  
 Mink P. J., Mandel JS, Sceurman BK, Lundin JI. (2012). Epidemiologic studies of glyphosate and 
cancer: a review. Regul Toxicol Pharmacol , 63, 440–52. 
 Mladinic M, Berend S, Vrdoljak AL, et al. (2009a). Evaluation of geno me damage and its relation 
to oxidative stress induced by gl yphosate in human lymphocytes in vitro . Environ Mol Mutagen , 
50, 800–7.  Nordstrom, M., Hardell, L., Magnuson, A., Hagberg, H., & Rask-Andersen, A. (1998). 
Occupational exposures, animal exposure and smoki ng as risk factors for hairy cell leukaemia 
evaluated in a case-control study. British Journal of Cancer, 77 (11), 2048-2052.  
 Nufarm. (2009a). Glyphosate Tech nical: Dietary Combined Chronic Toxicity/Carcinogenicity in 
the Rat. Shardlow, Derbyshire, UK: Harlan Laboratories Ltd. 
 Nufarm. (2009b). Glyphosate Techni cal: Dietary Carcinogenicity St udy in the Mouse. Derbyshire, 
UK: Harlan Laboratories Ltd.  NTP (1992). Technical Report on Toxicity Studies of Glyphosate (CAS No. 1071-83-6) 
Administered in Dosed Feed to F344/N Rats an d B6C3F1 Mice, Toxicity Report Series Number 
16, NIH Publication 92-3135, July 1992. U.S. De partment of Health and Human Services, 
National Toxicology Program (NTP),  Research Triangle Park, NC. 
 
Orsi, L., Delabre, L., Monnereau, A., Delval , P., Berthou, C., Fenaux, P., Clavel, J. (2009). 
Occupational exposure to pesticides and lymphoi d neoplasms among men: results of a French 
case-control study. Occupational and Environmental Medicine, 66 (5), 291–298.  GLYPHOSATE    FINAL    
Page 85 of 87 
   
Pahwa P, Karunanayake CP, Dosman JA, Spin elli JJ, McLaughlin JR, Cross-Canada Group 
(2011). Soft-tissue sarcoma and pesticides exposur e in men: results of a Canadian case-control 
study. J Occup Environ Med , 53(11):1279–86.  
 Pahwa, P., Karunanayake, C. P., Dosman, J. A., Sp inelli, J. J., McDuffie, H. H., & McLaughlin, J. 
R. (2012). Multiple myeloma and exposure to pesticides: a Canadian case-control study. J Agromedicine, 17 (1), 40–50. 
 
Pegg D, Bleavins, M, Herman J, Wojcinski Z, Graziano M, Henck J, Criswell KA, Anderson T, 
Duddy S. (2012). Hemangiosarcoma in mice administ ered pregabalin: analysis of genotoxicity, 
tumor incidence and tumor genetics. 
 Rossberger S. (1994). DNA repair test with prim ary rat hepatocytes. Unpublished Regulatory 
Study. Report Identification Number: 931564.  Ruder, A. M., Waters, M. A., Butler, M. A., Carre ón, T., Calvert, G. M., Da vis-King, K. E. Group, 
B. C. C. S. (2004). Gliomas and farm pesticide exposure in men: the upper Midwest health study. 
Arch Environ Health, 59 (12), 650–657.  
 SAP (1986), Transmittal of the Final FIFRA Scien tific Advisory Panel Reports on the February 
11-12, 1986 Meeting.  http://www.epa.gov/pesticides/chem_ search/cleared_reviews/csr_PC-
103601_24-Feb-86_209.pdf  
 
Salamon, C.; Smith, S. (1977) Report to Monsanto  Company: Dominant Lethal Study with CP 
76100 in Albino Mice: IBT No. 8533-08920. MRID 00057072.  Schinasi L, Leon M. (2014). Non-Hodgkin Lympho ma and Occupational Expos ure to Agricultural 
Pesticide Chemical Groups and Activ e Ingredients: A systematic Re view and Meta-Analysis. Int. 
J. Environ. Res. Public Health  11:4449–4527. 
 Schreib G. (2010). Reverse muta tion assay using bacteria ( Salmonella Typhimurium and 
Escherichia Coli ) with glyphosate technical. Unpublished Regulatory Study. Report Identification 
Number: 102025.  Shirasu, Y., Miriya, M., and Ota, T. (1978). The Report of Mutagenic Study with Bacteria for 
CP67573 (ET78-241). Unpublished report, The In stitute of Environmental Toxicology, 
Toxicology Division, Kodaira, Japan. MRID 00078619.  Sokolowski A. (2007a). Salmonella Typhimurium and Escherichia Coli reverse mutation assay 
with glyphosate technical. Unpublished Re gulatory Study. Report Identification Number: 
1061401.  GLYPHOSATE    FINAL    
Page 86 of 87 
  Sokolowski A. (2007b). Salmonella Typhimurium and Escherichia Coli  reverse mutation assay 
with glyphosate technical. Unpublished Re gulatory Study. Report Identification Number: 
1061402.  Sokolowski A. (2007c). Salmonella Typhimurium and Escherichia Coli  reverse mutation assay 
glyphosate technical. Unpublished Regulator y Study. Report Identification Number: 1061403. 
 Sokolowski A. (2009a). Salmonella Typhimurium and Escherichia Coli  reverse mutation assay 
with glyphosate technical U npublished Regulatory Study. Report Identification Number: 1236400. 
 Sokolowski A. (2009b). Glyphosate technical Salmonella Typhimurium and Escherichia Coli 
reverse mutation assay. Unpublished Regulat ory Study. Report Identification Number: 1264500. 
 Son WC , Gopinath C . (2004). Early occurrence of spontaneous tumors in CD-1 mice and 
Sprague-Dawley rats. Toxicol Pathol , 32, 371–4. 
 Sorahan T. (2012). Multiple myeloma and glyphosate use: a re-analysis of US Agricultural Health 
Study data. Abstract P27-02. Toxicol Lett , 211S, S127. 
 Stout, L. and Ruecker, F. (1990) Chronic Study of Glyphosate Admi nistered in Feed to Albino 
Rats: Lab Project Number: MSL-10495: R.D. 1014. MRID 41643801.  Stout, L.; Johnson, C. (1987) 90-day Study of  Glyphosate Administered in Feed to 
Sprague/Dawley Rats: Proj. ID ML-86-351/EHL 86128. MRID 40559401.  Street, R.W.; Conkin, R.A.; Edwards, G.A.; et al. (1980) A Three-Mont h Feeding Study of 
Glyphosate in Mice: Special Report # MSL- 1154. MRID 00036803
. 
 Suresh TP (1992). Dominant lethal test in Wi star rats. Unpublished Re gulatory Study. Report 
Identification Number TOXI: 888-DLT.  Suresh TP. (1993a). Mutagenicity — Salmonella Typhimurium reverse mutation assay (Ames test). 
Unpublished Regulatory Study. Report Identif ication Number: TOXI: 887-MUT.AMES. 
 Suresh TP. (1993b). Mutagenicity — micronucle us test in Swiss albino mice. Unpublished 
Regulatory Study. Report Identificat ion Number: TOXI: 889-MUT.MN. 
 Suresh TP. (1994). Genetic toxicology — in vivo  mammalian bone marrow cytogenetic test — 
chromosomal analysis. Unpublished Regulatory Study. Report Identification Number: TOXI: 890-
MUTCH.AB.  GLYPHOSATE    FINAL    
Page 87 of 87 
  Taddesse-Heath L , Chattopadhyay SK , Dillehay DL , Lander MR , Nagashfar Z , Morse HC , III , 
Hartley JW . (2000) . Lymphomas and high-level e xpression of murine leukemia viruses in CFW 
mice. J Virol , 74 , 6832–7 .  Thompson PW. (1996). Technical glyphosate re verse mutation assay (Ames test) using Salmonella 
Typhimurium and Escherichia Coli . Unpublished Regulatory Study. Re port Identification Number: 
SPL Proj. No. 434/014.  USEPA. (2005) Guidelines for Carcinogen Risk Assessment. March 2005. EPA/630/P-03/001F. 
 van de Waart, I. E. J. (1995). Evaluation of the Ability of Glyfosaat to Induce Chromosome 
Aberrations in Cultured Peripheral Huma n Lymphocytes. Unpublished report, NOTOX, 
The Netherlands.  Ward, J. M. (2006) Lymphomas and Leukemia in mice. Exp.Toxicol Pathol . 27, 377–381. 
 Weiss, S. W., Goldblum, J. R., and Enzinger, F. M. (2001). Enzinger and Weiss’s Soft Tissue 
Tumors , 4th ed., pp. 917–954. Mosby, St Louis, MO. 
 WHO/FAO. (2004). Pesticides re sidues in food – 2004. Part II T oxicological Evaluations. Joint 
meeting of the FAO Panel of Experts on pesticid e residues in food and the environment and the 
WHO Core Assessment Group (JMPR). World H ealth Organization/Food and Agriculture 
Organization of the United  Nations, Rome, Italy. 
http://www.inchem.org/documents/jmpr/jmpmono/v2004pr01.pdf . 
 
Williams GM, Kroes R, Munro IC. (2000). Safety ev aluation and risk assessment of the herbicide 
Roundup and its active ingredient, glyphosate, for humans. Regul Toxicol Pharmacol , 31, 117–65. 
 Wrenn, J. (1980). Dominant Lethal  Study in Mice. Unpublished report, International Research and 
Development Corporation, Mattawan, MI.  Wright NP. (1996). Technical glyphosate: chromosome abe rration test in CHL cells in vitro . 
Unpublished Regulatory Study. Repor t Identification Number: 434/015. 
 
Yiin JH, Ruder AM, Stewart PA, Waters  MA, Carreón T, Butler MA, Calvert GM, 
Davis-King KE, Schulte PA, Mandel JS, Morton RF, Reding DJ, Rosenman KD; Brain Cancer 
Collaborative Study Group. The Upper Midwest Health Study: a cas e-control study of pesticide 
applicators and risk of glioma. Environ Health . 2012 Jun 12; 11:39.