Review of genotoxicity studies of glyphosate and glyphosate-based formulations

Figures & data

Figure 1. Chemical structure of glyphosate, (N-(phosphonomethyl)glycine, CAS 1071-83-6): (a) neutral form; (b) ionic form.

Table 1. Bacterial reversion assays.

			Treatment¶			Results∥
Test material/Solvent*	Strains†	S9‡	Method	Maximum	Com§	Toxicity	Mutagenicity	References
Glyphosate and glyphosate salts
Regulatory studies
G (98.6%) (W)	0,9,5,7	AR 4% (PI) 6.6% (PR)	PI, PR	2500 µg (−S9) 5000 µg (+S9)	C	T(R)	neg	Jensen (1991a)
G (96.0%) (W)	0,9,5,7,8	AR 10%	PI	1000 µg	>HL, C, P	T(R)	neg#	Suresh (1993a)
G (95.68%) (W)	0,9,5,7,PU	PBR 10%	PR	5000 µg	C	T(R)	neg	Akanuma (1995b)
G (95.6%) (D)	0,9,5,7,PK,PUK	PNR 10%	PI, PR	5000 µg	C	T(R)	neg**	Callander (1996)
G (95.3%) (W)	0,9,5,7,PU	AR 10%	PI	5000 µg	C	T(R)	neg	Thompson (1996)
GK (60%) (W)	0,9,5,7,PK,PUK	PNR 10%	PI, PR	5000 µg	C	T(R)	neg††	Callander (1999)
GI (612.7 g/kg) (W)	0,9,5,7 a	AR 10%^†	PI	5000 µg	>HL, S	T(R)	neg‡‡	Ranzani (2000)
G (95.1%) (W)	0,9,5,7,PU	PNR 10%	PI, PR	5000 µg	C	T(R)	neg	Sokolowski (2007a)
G (97.7%) (W)	0,9,5,7,PU	PNR 10%	PI, PR	5000 µg	C	PI,T(BR) PR,T(R)	neg	Sokolowski (2007b)
G (95.0%) (W)	0,9,5,7,PU	PNR 10%	PI, PR	5000 µg	C	PI,T(BR) PR,T(R)	neg	Sokolowski (2007c)
G (980.1 g/kg) (D)	0,9,5,7,2	AR ?%	PI	5000 µg	S	N	neg¶¶	Ribeiro do Val (2007)
G (980.5 g/kg) (D)	0,9,5,7a,2	AR 5%	PI	1000 µg	>HL, S	T(R)	neg§§	Miyaji (2008)
G (98.8 % w/w) (W)	0,9,5,7,2	AR 5%	PI, PR	3160 µg	C	T(BR)	neg∥∥	Flugge (2009a)
G (96.66% w/w) (D)	0,9,5.7,PU	PNR 10%	PI, PR	5000 µg	C	T(R)	neg	Sokolowski (2009a)
G (96.3%) (W)	0,9,5.7,PK,PUK	PNR 10%	PI, PR	5000 µg	C	T(R)	neg	Sokolowski (2009b)
G (96.4%) (W)	0,9,5,7,2	AR 5%	PI, PR	3160 µg	C	T(BR)	neg∥∥	Flugge (2010b)
G (96.0%) (D)	0,9,5,7,PU	PNR 5%	PI, PR	5000 µg	C	T(R)	neg	Schreib (2010)
G (982 g/kg) (D)	0,9,5,7,2	PNR 5%	PI, PR	5000 µg	C	PI,T(BR) PR,T(R)	neg	Wallner (2010)
GBFs
Literature study
Perzocyd 10 SL (?)##	0,9,7a,2	AR ?%##	PI	200 µg?##	?##	?##	neg##	Chruscielska et al. (2000)
Regulatory Studies
MON 78239 (36.6%a.e. GK) (W)	0,9,5,7,PU	AR 10%	PI	3330 µg (−S9)$ 5000 µg ( + S9)	C	T(BR)	neg^	Mecchi (2003a)
MON 78634 (65.2%a.e. GA) (W)	0,9,5,7,PU	AR 10%	PI	3330 µg$	C	T(BR)	neg	Mecchi (2003b)
FSG 3090-H1 (360 g/L G) (W)	0,9,5,7,2	AR 5%	PI, PR	316 µg (PI, PR + S9) 100 µg (PR −S9)	C	T(BR)	neg	Uhde (2004)
MON 78910 (30.3%a.e.) (W)	0,9,5,7,PU	AR 10%	PI	3330 µg (−S9) 5000 µg (+S9)	C	T(BR)	neg	Xu (2006)
MON 79672 (68.2%a.e. GA) (D)	0,9,5,7,2	AR? 4%	PI	2000 µg	>HL, S	T(R)	neg	Lope (2008)
MON 79864 (38.7%a.e.) (W)	0,9,5,7,PU	AR 10%	PI	5000 µg	C	T(BR)	neg	Mecchi (2008a)
MON 76313 (30.9%a.e.) (W)	0,9,5,7,PU	AR 10%	PI	5000 µg	C	T(BR)	neg	Mecchi (2008b)
MON 76171 (31.1%a.e.) (W)	0,9,5,7,PU	AR 10%	PI	5000 µg	C	T(BR)	neg	Mecchi (2008c)
Glyphosate liquid formulation (480 g/L GI) (W)	0,9,5,7,2	AR 5%	PI	200 µg	S	N	neg	Camolesi (2009)
MON 76190 (53.2%a.e. GM) (D)	0,9,5,7,2	AR? 4%	PI	2000 µg	>HL, S	T(R)	neg	Catoyra (2009)
MON 79991 (71.6%a.e.) (W)	0,9,5,7,PU	AR 10%	PI	5000 µg	C	T(R)	neg	Mecchi (2009a)
MON 76138 (38.5%a.e.) (W)	0,9,5,7,PU	AR 10%	PI	5000 µg	C	T(BR)	neg	Mecchi (2009b)
MON 77280 (495.29 g/La.e.) (W)	0,9,5,7,2	AR 5%	PI	200 µg	S	N	neg	Camolesi (2010)
TROP M (Glyphosate 480) (48.46% GI) (W)	0,9,5,7,2	AR 5%	PI, PR	1000 µg (PI) 31.6 µg (PR)	C	T(BR)	neg	Flugge (2010a)
Glyphosate 757 g/kg granular form (76.1% GA) (W)	0,9,5,7,2	AR 5%	PI, PR	100 µg (PI) 10 µg (PR)	C	T(BR)	neg	Flugge (2010d)

*Test material and solvent used: G, glyphosate technical (acid); GK potassium salt of glyphosate; GI, isopropylamine salt of glyphosate; GA, monoammonium salt of glyphosate. First entry in () for glyphosate or glyphosate salts indicates purity or concentration. First entry in ( ) for GBFs indicates active ingredient, if available, and ingredient concentration. a.e. after % indicates concentration is in acid equivalents. Second entry in ( ) indicates test material solvent: (W), water; (D), dimethyl sulfoxide.

†Test strains used: 0, TA100; 9, TA98; 5, TA1535; 7, TA1537;7a, TA97a; 2, TA102; 8, TA1538; PU, E. coli WP2 (uvrA); PUK, E. coli WP2 [pKM101]; PK, E. coli WP2 [pKM101].

‡S9 metabolic activation system: AR, Aroclor-induced rat liver; PNR, phenobarbital- and napthoflavone-induced rat liver; PBR, phenobarbital- and benzoflavone-induced rat liver; percentage number indicates percentage of S9 in S9 Mix.

¶Treatment conditions: Method – treatment methodology: PI, plate incorporation; PR, preincubation. Maximum – maximum amount per plate tested. In some cases differences between treatment conditions were used as indicated.

§Comments on assay:. >HL, more than half-log (√10) for one or more dose intervals; C, confirmatory experiment reported; S, single experiment reported; P, positive controls that didn't require S9 were used for two strains (TA1535 and TA1537) with S9.

∥Results reported for:

Toxicity: T, toxic effects at maximum concentration or lower; (R), reduced revertants/plate; (B), reduced background lawn; (BR), reduced revertants/plate and background lawn; N, no toxic effects.

Mutagenicity: overall judgment of assay result for test material: neg, negative; individual study increases in revertants/plate or statistical findings are indicated as individual footnotes.

#Statistically significant increase for TA100 (+S9) reported in text but not indicated in data tables. Increases were less than two-fold over control and judged not to indicate a treatment-related effect.

**Statistically significant increases in revertants/plate in one experiment for TA100 +S9, WP2 [pKM101] +S9, TA98 −S9 and WP2 (pKM101) −S9. Increases were less than two-fold, not reproducible in separate experiments and not consistent with a dose–response (e.g. occurring at mid-dose levels). Increases were less than two-fold over control and judged not to indicate a treatment-related effect.

††Statistically significant increases in revertants/plate for several strain/S9 combinations. Increases were all less than two-fold over control values, not reproducible and not consistent with a dose–response and judged not to indicate treatment-related effects.

‡‡Statistically significant increases in revertants/plate for TA98 +S9 and TA100 +S9. Increases were all less than two-fold, not consistent with a dose-response and judged not to indicate treatment- related effects.

¶¶Statistically significant ANOVA with increases for lowest dose levels for TA1537 +S9. Increases were all less and two-fold, not consistent with a dose-response and judged not to indicate treatment- related effects.

§§Statistically significant increases for TA98 +S9 (low to mid doses) and for TA100 +S9 at one dose. Increases were judged not to indicate treatment-related effects because they were less and two-fold and not consistent with a dose–response.

∥∥Statistical analysis suggested in text but not clearly evident in data tables.

##Not clearly indicated in the publication. Numerical data for revertants/plate not presented but summarized as “−“ for the lack of mutagenic activity.

$5000 µg/plate maximum dose level for WP2uvrA --S9 and in one experiment for TA98 and TA1535 −S9 (Mecchi, 2003a).

^Several dose levels exceeded control revertants/plate by more than three-fold in one experiment for TA98 −S9 and TA1535 −S9. There was no dose–response and the result was not observed in a second experiment. The result was considered due to a low control values rather than a treatment-related response.

Table 2. In vitro mammalian cell assays of glyphosate, glyphosate salt solutions and GBFs.

			Treatment¶							Results
				Time∥
Test material*	Endpt†	Cell type‡	S9§	−S9	+S9	Dose levels/ Replicates./ Ind. expts. #	Maximum dose**	pH††	Score‡‡	Tox¶¶	Mutagenicity§§	References
Gene mutation
Glyphosate and glyphosate salts
Regulatory studies
G (98.6%) (M)	TK	ML		4 (48)		4/2/C	5000 µg/mL (≈29.6 mM)	NI	NA	CE−	neg	Jensen (1991b)
			AR 30%		3 (48)	4/2/C	4200 µg/mL (≈24.8 mM)	NI	NA	CE−	neg
G (95.6% w/w) (D)	TK	ML	PNR 5%	4 (48)	4 (48)	3 and 4/2/C	1000 µg/mL (≈5.9 mM)	pH	NA	RS−	neg	Clay (1996)
Chromosomal aberration or micronucleus
Glyphosate and glyphosate salts
Literature studies
GI (62%) (W)	CB MN	BL	none	24		5/?/C	0.56 mM	NI	1000BN (NC)	CBPI−	neg	Piesova (2004)
	CB MN	BL	none	48		5/?/C	0.56 mM	NI	1000BN (NC)	CBPI−	equiv∥∥
GI (62%) (W)	CB MN	BL	AR 10%	2 (20?)	2 (20?)	5/?/C	0.56 mM	NI	1000BN (NC)	CBPI−	neg	Piesova (2005)
	CB MN	BL	none	48		5/?/C	0.56 mM	NI	1000BN (NC)	CBPI−	equiv∥∥
GI (62%) (W)	CA (1)	BL	none	24		6/?/C	1.12 mM	NI	350–900 M (NC)	NI	neg##	Holeckova (2006)
GI (62%) (W)	CA	BL	none	24		6/?/C	1.12 mM	NI	100 M (NC)	MI+	neg	Sivikova & Dianovsky (2006)
G (96%) (M)	CA	HL	none	48		3 (>HL)/?/C	6 mM	pHa	100 M	MI−	neg	Manas et al. (2009)
G (98%) (P)	CB MN	HL		4 (72?) $		5 (>HL)/2/C	580 µg/mL (≈3.43 mM)	pHa	1000BN (NC)	EA+ NE+ NB+ CBPI−	equiv^	Mladinic et al. (2009a)
	CB MN	HL	H 10%		4 (72?) $	5 (>HL)/2/C	580 µg/mL (≈3.43 mM)	pHa	1000BN (NC)	EA+ NE+ NB+ CBPI−	pos
G (98%) (P)	CB MN	HL		4 (72?) $		5 (>HL)/2/C	580 µg/mL (≈3.43 mM)	pHa	2000BN (NC)	CBPI− NB+	equiv^^	Mladinic et al. (2009b)
			H 10%		4 (72?) $	5 (>HL)/2/C	580 µg/mL (3.43 mM)	pHa	2000BN (NC)	CBPI− NB+	pos
G (95%) (M)	CB MN	TR146	none	20 min. (48)		3/3/S	20 mg/L (≈0.12 mM)	NI	>3000BN (NC)	AP+ NE+ NB+	pos	Koller et al. (2012)
Regulatory studies
G (95.3% w/w) (M)	CA	CHL	AR 5%	6 (24), 24, 48	6 (24)	3/2/S	1250 µg/mL (≈7.39 mM)	pH	200 M	RG−	neg	Wright (1996)
G (95.6%) (M)	CA	HL	PNR 25%	20	3 (20)	3 (>HL)/2/C	1250 µg/mL (≈7.39 mM)	pH	200 M	MI+(−S9)	neg	Fox (1998)
				44	3 (44)	1/2/S	1250 µg/mL (≈7.39 mM)	pH	200 M	MI−	neg
G (95.68%) (H,M)	CA	CHL	PBR 30%	6 (24)	6 (24)	3/2/S	1000 µg/mL (≈5.92 mM)	pHn	200 M	MI−	neg	Matsumoto (1995)
				24		3/2/S	500 µg/mL (≈2.96 mM)	pHn	200 M	MI−	neg
				48		3/2/S	500 µg/mL (≈2.96 mM)	pHn	200 M	MI−	neg
GBFs
Literature studies
herbazed (84% G) (M)	CA	MS	none	24		3 (>HL)/5/S	50 mM$$	NI	500 M	VC+	pos	Amer et al. (2006)
Roundup™ Ultra Max (450 g/L G) (M)	CB MN	TR146	none	20 min (48)		3/3/S	20 mg/L glyphosate (≈0.12 mM)	NI	>3000BN (NC)	AP+ NE+ NB+	pos	Koller et al. (2012)

*Test material and solvent used: G, glyphosate technical (acid); GK, potassium salt of glyphosate; GI, isopropylamine salt of glyphosate; GA, monoammonium salt of glyphosate. First entry in ( ) for glyphosate indicates percent purity or concentration. First entry in ( ) for GBFs indicates active ingredient and ingredient concentration. Second ( ) entry indicates test material solvent: (W) water; (D) dimethyl sulfoxide; (M) culture medium; (H) Hanks balanced salt solution; (P), phosphate buffered saline.

†Assay endpoint: TK, gene mutation at the TK locus; CA, chromosomal aberration; CA (1), chromosomal aberration (FISH analysis of chromosome 1 for acentric fragments); CB MN, cytokinesis block micronucleus

‡ML, L5178Y mouse lymphoma; CHL, Chinese hamster lung; HL, human peripheral blood lymphocytes; BL, bovine peripheral blood lymphocytes; TR146, human buccal epithelial cell line; MS, mouse spleen cells

¶In cases where treatments differ in the presence and absence of exogenous metabolic activation treatment parameters are presented on separate lines.

§Type of S9 used with %S9 homogenate in S9 Mix indicated in ( ): AR, Aroclor-induced rat liver; PNR, phenobarbital/naphthoflavone-induced rat liver; PBR, phenobarbital/5,6-benzoflavone-induced rat liver; H, human liver; ?, S9 not clearly indicated; none, no experiments conducted with exogenous mammalian metabolic activation.

∥Duration of treatment in hours with total time or times to harvest in hours from treatment in ( ) if treatment was not continuous. min indicates minutes of treatment for one study.

#First number: number of analyzable treatment dose levels with (>HL) indicating spacing between one or more treatment levels greater than half-log; second number: number of replicates cultures for each treatment with ? indicating that number of replicates is not clear; third character: C, confirmatory experiments reported for cell lines or multiple donors for lymphocytes; S, no confirmatory experiment reported.

**Maximum dose level tested and scored with calculated mM in ( ) for glyphosate.

††Assessment or consideration of pH effects of test material: NI, no measurement or control of pH reported; pH, large pH effects noted at higher concentrations and maximum set to minimize pH effects; pHn, effects on pH noted but not used to set maximum treatment concentration; pHa, pH adjusted.

‡‡Number of cells or metaphases scored per treatment level/time point for chromosomal aberration and micronucleus assays. M, metaphases; BN, binucleated cells. (NC) indicates that coding of slides for scoring was not explicitly indicated. In some cases coding was not explicitly indicated but may have been implied by a reference citation. NA, not applicable.

¶¶Measurement of cytotoxicity with + indicating effects on endpoint at one or more treatment levels and -indicating no effects on endpoint up to maximum treatment level: CE, cloning efficiency; RS, relative survival; RG, relative growth; MI, mitotic index; CBPI, cytokinesis block proliferation index; EA, early apoptosis; NE, necrosis ; AP, apoptosis; NB, nuclear buds; LDH, LDH release (cell integrity); NR, neutral red (vital stain); VC, viable cell staining; NI, no concurrent cytotoxicity measurement reported.

§§ Evaluation of mutagenicity or chromosomal effects: neg, negative; pos, positive; equiv, equivocal. Evaluation different from publication or report indicated with individual footnote.

∥∥Statistically significant increases observed at a single different dose for each of two donors. Publications indicate dose responses were not observed and effects were weak or minimal with 48 h treatment.

##No positive control reported.

$Lymphocytes apparently treated before exposure to mitogenic stimulus.

^Small increases in MN frequency in binucleate cells observed for a wide range of dose levels (3.5–580 µg/mL) but not statistically significant.

^^No statistically significant increases in MN frequency for any dose level. Statistically significant correlation observed between dose and MN frequency but approximately the same small increase was observed over a very wide range of doses (3.5–580 μg/mL) and this is considered to be questionable as a biologically plausible dose response.

$$Calculated from the stated concentration of 5 × 10⁻⁵ M glyphosate/mL.

Table 3. In vivo mammalian chromosomal effect studies.

			Treatment‡
Test material*	Endpt†	Strain/Species	Veh	Rte	No/Sex	Grps	Schedule	Maximum dose	Scoring¶	Results§ Tox	Mutagenicity	References
Glyphosate and glyphosate salts
Literature MN studies
G	BM MN	C3H mice	W	i.p.	6M	1	S (24, 48C, 72)	300	1000P (NC)	M−, R−	neg	Chruscielska et al. (2000)
G (96%)	BM MN	BalbC mice	S?	i.p.	5M 5F	3	T (24)	200	1000E(NC)	M−, C−, R−	pos||	Manas et al. (2009)
Regulatory MN studies
G (98.6%)	BM MN	NMRI SPF mice	0.5% CMC	p.o.	5M 5F	1	S (24, 48C, 72)	5000	2000P *N	M−, R−	neg	Jensen (1991c)
G (96.8%)	BM MN	Swiss mice	PO	p.o.	5M 5F	3 (>HL)	T (24)	5000	≈2000E (NC) ≈1000P	M−, C−, R−	inc#	Suresh (1993b)
G (95.6% w/w)	BM MN	CD-1 mice	PS	p.o.	5M 5F	1	S (24, 48)	5000	2000P	M−, C−, R−	neg	Fox & Mackay (1996)
GK (59.3%)	BM MN	CD-1 mice	W	p.o.	5M	1	S (24, 48)	2000	2000P	M−, C−, R−	neg**	Jones (1999)
G (954.9 g/kg)	BM MN	Swiss albino mice	W	i.p.	5M 5F	3	T (24)	562.5	1000P 1000N	M−, R−	neg	Marques (1999)
GI (612.7 g/kg)	BM MN	Swiss albino mice	W	i.p.	5M††5F††	3	T (24)	3024	1000P *N	M+, R−	neg	Gava (2000)
G (97.73%)	BM MN	NMRI mice	PEG 400	p.o.	5M 5F	3	S (24, 48 H)	2000	2000P	M−, C−, R−	neg	Honarvar (2005)
G (95.7% w/w)	BM MN	Crl:CD-1®(ICR) BR mice	PBS	i.p.	7M	3	S (24, 48 CH)	600	2000P	M−, C+, R+	neg‡‡	Durward (2006)
G (980.1 g/kg)	BM MN	Swiss mice	W	p.o.	6M	3	T (24)	30	3000P	M−, R−	neg¶¶	Zoriki Hosomi (2007)
G (99.1% w/w)	BM MN	NMRI mice	0.5% CMC	p.o.	5M	3 (24 h)	S (24, 48 CH)	2000	2000P	M−, C−, R−	neg	Honarvar (2008)
G (980.0 g/kg)	BM MN	Swiss albino mice	CO	i.p.	5M 5F	3	T (24)	62.5	2000P *N	M−, R−	neg	Costa (2008)
G (98.8% w/w)	BM MN	Crl(CD)(SD) rats	0.8% HPMC	p.o.	5M 5F	3	S (24, 48 CH)	2000	2000P	M−, C−, R−	neg	Flugge (2009b)
Regulatory CA study
G (96.8%)	BM CA	Swiss albino mice	PO	p.o.	5M 5F	1	T (24)	5000	50M	M−, C+, MI−	neg	Suresh (1994)
GBFs
Published studies
Perzocyd 10 SL	BM MN	C3H mice	W	i.p.	6M	1	S (24, 48C, 72)	90	1000P (NC)	M−, R−	neg	Chruscielska et al. (2000)
Roundup™ 69	BM MN	mice	NI	i.p.	6M	3	T (25)	200	1000P (NC) 1000N	M−, R−	neg	Coutinho do Nascimento & Grisolia (2000)
Roundup (480 g/L GI)	BM MN	Swiss mice	W?	i.p.	8M 8F	3	T (24)	200	2000E(P) NC	M−, R−	neg	Grisolia (2002)
Roundup (480 g/L GI)	BM CA	New Zealand white rabbits	W	d.w.	5M	2§§	60 days	750 ppm	50M (NC)	M−	pos	Helal & Moussa (2005)
Herbazed (84% G)	BM CA	Swiss mice	NI	i.p.	5M	1	1, 3, 5d (24)	50 gly?	100M (NC)	M−	inc∥∥	Amer et al. (2006)
Herbazed (84% G)	SC CA	Swiss mice	NI	i.p.	5M	1	1, 3, 5d (24)	50 gly?	100M (NC)	M−	pos
Herbazed (84% G)	BM CA	Swiss mice	NI	p.o.	5M	2	1, 7, 14, 21d (24)	100 gly?	100M (NC)	M−	pos
Herbazed (84% G)	SC CA	Swiss mice	NI	p.o.	5M	2	1, 7, 14, 21d (24)	100 gly?	100M (NC)	M−	pos
Roundup	BM CA	C57BL mice	W	p.o.	8M	1	S (6, 24, 48, 72, 96, 120)	1080	50M	M−	neg	Dimitrov et al. (2006)
	BM MN	C57BL mice	W	p.o.	8M	1	S (24, 48, 72, 96, 120)	1080	500P	M−, R−	neg	Dimitrov et al. (2006)
Roundup (41% GI)	BM CA	Swiss mice	DMSO	i.p.	5M	2	S (24, 48, 72)	50 gly?	75M (NC)	M−, MI+	pos	Prasad et al. (2009)
	BM MN	Swiss mice	DMSO	i.p.	5M	2	S (24, 48, 72)	50 gly?	2000(P) (NC)	M−, MI+	pos
Regulatory studies
MON 78239 (36.6%a.e. GK)	BM MN	Crl:CD-1®(ICR) BR mice	W	p.o.	5M	3	S (24, 48CH)	2000	2000P	M−, C−, R−	neg##	Erexson (2003a)
MON 78634 (65.2%a.e.)	BM MN	Crl:CD-1®(ICR) BR mice	W	p.o.	5M	3	S (24, 48CH)	2000	2000P	M−, C−, R−	neg	Erexson (2003b)
MON 78910 (30.3%a.e.)	BM MN	CD-1I^®(ICR)BR mice	W	p.o.	5M	3	S (24, 48CH)	2000	2000P	M−, C−, R−	neg	Erexson (2006)
MON 79864 (38.7%a.e.)	BM MN	Hsd:ICR(CD-1 mice	W	p.o.	5M	3	S (24, 48CH)	2000	2000P	M−, C+, P−	neg##	Xu (2008a)
MON 76171 (31.1%a.e.)	BM MN	CD-1^®(ICR)BR mice	W	p.o.	5M	3	S (24, 48CH)	2000	2000P	M−, C−, R−	neg	Xu (2008b)
MON 79991 (71.6%a.e.)	BM MN	CD-1^®(ICR)BR mice	W	p.o.	5M	3	S (24, 48CH)	2000	2000P	M−, C−, R+?	neg	Xu (2009a)
MON 76138 (38.5%a.e.)	BM MN	CD-1^®(ICR)BR mice	W	p.o.	5M	3	S (24, 48CH)	2000	2000P	M−, C−, R−	neg	Xu (2009b)
MON 76313 (30.9%a.e.)	BM MN	Hsd:ICR(CD-1) mice	W	p.o.	5M	3	S (24, 48CH)	2000	2000P	M−, C−, R−	neg	Xu (2009c)
A17035A (280.7 g/L G)	BM MN	Swiss mice	W	p.o.	6M	1	T (24)	2000	3000P	M−, C−, R−	neg	Negro Silva (2009)
TROP M (483.6 g/l GI)	BM MN	NMRI mice	.8% CMC	p.o.	5M 5F	3	S (24, 48CH)	2000	2000P	M−, C−, R−	neg	Flugge (2010c)
Glyphosate 757 g/kg formulation (69.1%a.e. G)	BM MN	Crl(CD)(SD) rat	0.8% HPMC	p.o.	5M 5F	3	S (24, 48CH)	2000	2000P	M−, C−, R−	neg	Flugge (2010e)
Glyphosate SL (499.35 g/L G)	BM MN	Swiss mice	W	p.o.	6M	1	T (24)	2000	3000P	M−, C−, R−	neg	Negro Silva (2011)

*G, glyphosate technical acid; GK, potassium glyphosate salt. GI, isopropylamine glyphosate salt; ( ) indicates purity or concentration for glyphosate or glyphosate salts or a.i. content for GBFs. Concentration in acid equivalents indicated as a.e.

†Endpoint: BM MN , bone marrow erythrocyte micronucleus; BM CA, bone marrow chromosomal aberration; SC CA, spermatocyte chromosomal aberration.

‡Treatment:

Veh – Vehicle used: W, water; S, saline; PO, peanut oil; PS, physiological saline; PEG 400; polyethylene glycol; PBS, phospate buffered saline; CO, corn oil; HMC, DMSO, dimethylsulfoxide; CMC, carboxymethylcellulose; HPMC, hydroxypropylmethylcellulose; NI, not indicated.

Rte – Route of administration: p.o. oral (gavage); i.p., intraperitoneal injection; d.w., drinking water.

No/Sex – Number of males (M) and females (F) scored for each glyphosate or GBF treatment group.

Grps – Number of glyphosate or GBF dose level treatments scored for micronuclei or chromosomal aberrations. >HL indicates spacing between one or more treatment groups greater than half-√10.

Schedule – Treatment schedule for glyphosate treatments: S, single treatment; T, two treatments 24 h apart; d, consecutive days of treatment with a separate group for each number of days. Numbers in parentheses are harvest times in hours after treatment or last treatment with a separate group for each harvest time. Treatment or harvest conditions used specifically for other groups are indicated as C, vehicle control, H, high-dose.

Maximum dose – Maximum glyphosate or GBF treatment dose level in mg/kg body weight except for ppm which indicates amount in drinking water. gly for GBFs indicates that dose units were reported as mg/kg body weight of glyphosate.

¶Number indicates cells or metaphases scored per animal for P (PCEs), N (NCEs), E (erythrocytes), M (metaphases). *N, variable NCEs scored for micronuclei while scoring the indicated number of PCEs. E(P) indicates number of erythrocytes scored with results for PCEs reported separately. NC, coding of slides for scoring not explicitly indicated in report or publication. In some cases coding was not explicitly indicated but may have been implied by a reference citation.

§Results:

Tox – Measures of toxicity reported: M, mortality; C, clinical signs; R, PCE/NCE ratio; MI, mitotic index. A “+” after the measure indicates treatment-related effects. A “−” after the measure indicates no treatment-related effects; +? Indicates a decrease in (R) but control (R) value for the corresponding time point was unusually high. No mortality (MI-) was assumed unless mortality was indicated.

Mut – Overall evaluation of study results as negative (neg), positive (pos) or or inconclusive (inc) for treatment-related effects. Individual footnotes used to indicate statistically significant effects or difference from conclusion of publication or report authors.

∥Statistically significant increase reported for micronucleated erythrocytes. Results not reported for micronucleated PCEs.

#Statistically significant increase in MN erythrocytes for high-dose females. Control MN PCE frequencies were unusually high and historical control data not presented.

**Statistically significant increase in MN PCE frequency at 24 h only, within historical control, not judged to be treatment related.

††Only four males and four females scored for high-dose group.

‡‡Statistically significant increase in MN PCE frequency only for 24 h high-dose, within historical control, not judged to be treatment related.

¶¶Statistically significant increase for high-dose MN PCE frequency, within historical control, not judged to be treatment related.

§§Two groups treated with same level of Roundup GBF but one group also treated with vitamin E.

∥∥Increases in abnormal metaphases not statistically significant excluding gaps from aberrant cells. Authors conclude positive result based on statistically significant increases in abnormal metaphases including gaps.

##Statistically significant increase for high-dose at 48 h, within historical control, but judged to be due to a low control group value and not treatment-related.

Table 4. High-dose and control MN PCE frequencies for regulatory glyphosate and glyphosate salt studies.

					Micronucleated PCE per 1000 PCE mean ± std. dev.
Test material†	Sex	Dose (mg/kg bw)	Route	Harvest (h)	Control	High-dose	References
G	M	5000	p.o.	24		1.7 ± 0.6	Jensen (1991c)
				48	1.5 ± 0.7	1.1 ± 0.4
				72		0.9 ± 0.7
	F	5000		24		1.5 ± 0.7
				48	1.2 ± 0.3	1.7 ± 0.8
				72		0.8 ± 0.6
G	M	5000	p.o.	24	6.7 ± 5.5	8.8 ± 1.8	Suresh (1993b)
	F	5000		24	4.9 ± 2.7	10.4 ± 4.9*
G	M	5000	p.o.	24	1.6 ± 0.8	2.1 ± 1.6	Fox & Mackay (1996)
				48	1.7 ± 1.3	2.1 ± 1.9
	F	5000		24	1.4 ± 0.7	2.1 ± 2.5
				48	0.7 ± 0.6	0.8 ± 0.8
GK	M	2000	p.o.	24	0.2 ± 0.4	0.9 ± 0.4*	Jones (1999)
				48	0.8 ± 1.0	0.9 ± 1.0
G	M	562.5	i.p.	24	0.4 ± 0.5	0.4 ± 0.9	Marques (1999)
	F	562.5		24	0.8 ± 0.8	0.6 ± 0.5
GI	M	3024	i.p.	24	0.6 ± 0.5	0.7 ± 1.0	Gava (2000)
	F	3024			0.4 ± 0.5	0.7 ± 1.0
G	M	2000	p.o.	24	0.9 ± 0.6	0.9 ± 0.7	Honarvar (2005)
	F	2000		24	0.7 ± 0.8	0.6 ± 0.7
	M	2000		48		1.5 ± 1.0
	F	2000		48		1.1 ± 0.9
G	M	600	i.p.	24	0.6 ± 0.6	1.9 ± 0.7*	Durward (2006)
				48	1.0 ± 1.2	0.9 ± 1.1
G	M	30	p.o.	24	0.6 ± 0.3	1.4 ± 0.4*	Zoriki Hosomi (2007)
G	M	2000	p.o.	24	0.7 ± 0.7	0.7 ± 0.4	Honarvar (2008)
		2000		48	0.7 ± 0.6	0.8 ± 0.6
G	M	62.5	i.p.	24	0.0 ± 0.0	0.3 ± 0.7	Costa (2008)
	F	62.5		24	0.0 ± 0.0	0.0 ± 0.0
G	M (rat)	2000	p.o.	24	0.8 ± 0.6	0.6 ± 0.4	Flugge (2009b)
				48	1.0 ± 0.9	0.8 ± 0.4
	F (rat)	2000		24	0.9 ± 0.2	0.4 ± 0.4
				48	1.1 ± 0.7	0.4 ± 0.4

*Statistically significant increase over control value.

†G, glyphosate technical acid; GK, potassium salt of glyphosate; GI, isopropylamine salt of glyphosate.

Table 5. Blood erythrocyte micronucleus assays in non-mammalian systems.

Test system	Test material	Maximum dose*	Result	Comment†	Reference
Oreochromis niloticus (fish)	Roundup 69	170 mg/kg i.p. (maximum tolerated)	Equivocal‡		Coutinho do Nascimento & Grisolia (2000)
T. rendalli (fish)	Roundup™ formulation	170 mg/kg (abdominal injection)	Positive		Grisolia (2002)
Carassius auratus (fish)	Roundup™ formulation	15 ppm glyphosate in water (2, 4 and 6 d)	Positive		Cavas & Konen (2007)
Prochilodus lineatus (fish)	Roundup™ formulation	10 mg/L in water (6, 24 and 96 h)	Negative	NC	Cavalcante et al. (2008)
Caiman eggs/hatchlings	Roundup® Full II formulation	1750 µg/egg	Positive		Poletta et al. (2009)
Caiman eggs/hatchlings	Roundup® Full II formulation	Nest sprayed 3% (3 L/100 L water/ha)	Positive		Poletta et al. (2011)
O. cordobae (amphibian)	Roundup formulation	100 mg a.i./L	Equivocal¶		Bosch et al. (2011)
R. arenarum (amphibian)		800 mg a.i./L	Equivocal§
Corydoras paleatus (fish)	Roundup®formulation	6.67 µg/L in water (3.2 µg/L a.e.) (3, 6 and 9 d)	Negative	PC, NC	de Castilhos Ghisi & Cestari (2012)

*a.e., concentration in glyphosate acid equivalents.; a.i. concentration of active ingredient.

†PC, no concurrent positive control; NC, independent coding of slides for scoring not explicitly indicated for visually scored slides. In some cases coding may have been implied by reference citation.

‡Statistically significant increase in micronucleated erythrocyte frequency only at mid-dose level.

¶Increase in micronucleated erythrocyte frequency not statistically significant for single group surviving treatment; authors appear to conclude increase may have been treatment-related.

§Authors appear to conclude increases in micronucleated erythrocytes were treatment-related. No statistically significant differences were observed among the experimental groups by the analysis of variance. A statistically significant positive correlation between concentration and micronucleated erythrocyte frequency but this analysis apparently omitted the high-dose group.

Table 6. DNA damage assays of glyphosate, glyphosate salts and GBFs in in vitro and in vivo mammalian systems.

Endpoint	Test system	Test material	Maximum dose	Result	Comment*	References
In vitro studies glyphosate and glyphosate salts
Literature studies
Comet	GM38 human fibroblasts	glyphosate (technical)	6.5 mM	Positive	MA, PH, NC	Monroy et al. (2005)
	HT1080 human fibrosarcoma	glyphosate (technical)	6.5 mM	Positive	MA, PH, NC	Monroy et al. (2005)
SCE	bovine lymphocytes	glyphosate (62% Isopropylamine salt)	1.12 mM (toxic)	Positive (−S9) Equivocal (+S9)	PH, NC	Sivikova & Dianovsky (2006)
Comet	Hep-2 cells	glyphosate (analytical, 96%)	7.5 mM (limited by toxicity)	Positive	MA, PH?, NC	Manas et al. (2009)
Comet	Human lymphocytes	Glyphosate (technical, 98%)	580 µg/mL (toxic) ≈3.43 mM)	Positive (−S9) Positive (+S9)	NC	Mladinic et al. (2009a)
Comet	TR146 human buccal epithelial	Glyphosate (95%)	2000 mg/L ≈11.8 mM)	Positive	MA, PH, NC	Koller et al. (2012)
Regulatory study
UDS	Primary rat hepatocyte	Glyphosate (>98%)	111.69 mM	Negative	PH	Rossberger (1994)
In vitro studies GBF
Literature studies
SCE	mouse spleen cells	herbazed formulation (84% glyphosate)	50 mM glyphosate‡	Positive	MA, PH, TO, NC	Amer et al. (2006)
Comet	TR146 human buccal epithelial	Roundup™ Ultra Max	200 mg/L glyphosate (≈1.18 mM)	Positive	MA, PH, NC	Koller et al. (2012)
In vivo studies GBF
Literature studies
Bone marrow SCE	Mouse	herbazed formulation (84% glyphosate)	200 mg/kg p.o. glyphosate	Positive	NC	Amer et al. (2006)

*MA, Mammalian metabolic activation system not used; PH, no indication of pH or osmolality control; TO, no concurrent measurement of toxicity reported or toxicity not observed for highest dose level; NC, independent coding of slides for scoring not explicitly indicated.

‡Calculated from the stated concentration of 5 × 10⁻⁵ M glyphosate/mL.

Table 7. DNA damage assays of glyphosate, glyphosate and GBF’s in non-mammalian systems.

Endpoint	Test system	Test material	Maximum dose	Result	Comment†	References
In vitro studies glyphosate and glyphosate salts
Literature studies
Comet	Tradescantia flowers and nuclei	Glyphosate (technical, 96%)	0.7 mM	Positive	NC	Alvarez-Moya et al. (2011)
Comet	Oyster sperm	Glyphosate	5 µg/L (≈0.03 µM)	Negative	NC	Akcha et al. (2012)
Regulatory study
Rec assay	B. subtilis	Glyphosate 95.68%)	240 µg/disk	Negative		Akanuma (1995a)
In vitro studies GBF’s
Literature studies
SOS*	E. coli	Roundup™ BIO formulation	0.25 µg/sample	Positive		Raipulis (2009)
Sperm Comet	Oyster	Roundup Express®	5 µg/L glyphosate (≈0.03 uM)	Negative	NC	Akcha et al. (2012)
In vivo studies GBF’s
Literature studies
Comet	Freshwater mussel larvae	Roundup™ formulation	5 mg/L glyphosate	Negative	NC	Conners & Black (2004)
Erythrocyte Comet	Carassius auratus (fish)	Roundup™ formulation	15 ppm glyphosate in water (2, 4 and 6 d)	Positive		Cavas & Konen (2007)
Erythrocyte and gill cell Comet	Prochilodus lineatus (fish)	Roundup™ formulation	10 mg/L in water (6, 24 and 96 h)	Positive		Cavalcante et al. (2008)
Erythrocyte	Caiman eggs /hatchlings	Roundup® Full	1750 µg/egg	Positive		Poletta et al. (2009)
Comet		II formulation
Erythrocyte	Anguilla	Roundup™ formulation	116 µg/L	Positive	NC	Guilherme et al. (2010)
Comet	anguilla (eel)		(1 and 3 d)
Erythrocyte	Caiman eggs /hatchlings	Roundup® Full	Nest sprayed	Positive		Poletta et al. (2011)
Comet		II formulation	3% (3 L/100 L water/ha)
Liver and gill cell	Anguilla	Roundup® Ultra	116 µg/L	Positive	NC	Guilherme et al. (2012)
Comet	anguilla (eel)		(1 and 3 d)
Erythocyte Comet	Corydoras paleatus (fish)	Roundup™ formulation	6.67 μg/L (3, 6 and 9 d)	Positive	NC	de Castilhos Ghisi & Cestari (2012)

^aSOS response DNA damage assay.

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