Evaluation of developmental toxicity studies of glyphosate with attention to cardiovascular development

Figures & data

Table 1. Maternal and developmental NOAELs from six sufficient rabbit developmental toxicity studies of glyphosate.

Study	No. of animals per group	Exposure period	Doses (mg/kg/day)	Maternal NOAEL (mg/kg/day)	Offspring NOAEL (mg/kg/day)
Moxon (1995)	20	GD 7–19†	0, 100, 175, 300	100	175
Coles & Doleman (1996)	18	GD 7–19	0, 50, 200, 400	200	≥400
Brooker et al. (1991a)	16–20	GD 7–19	0, 50, 150, 450	50	150
Hojo (1995)	18	GD 7–19†	0, 10, 100, 300	100	≥300
Tasker et al. (1980a)	16–17	GD 6–27	0, 75, 175, 350	75	≥175
Suresh (1993)	15–26	GD 6–18	0, 20, 100, 500	100	≥100
Bhide & Patil (1989)	15	GD 6–18	0, 125, 250, 500	–‡	–‡

†Moxon (1995) designated the day of insemination as GD 1 and Hojo (1995) designated the day after insemination as GD 0. The exposure periods here have been adjusted to be comparable to the other studies which used GD 0 as the day of insemination.

‡Due to significant limitations in study design and data reporting, this study was considered inadequate for determining NOAELs.

Figure 1. Division of the outflow tract by the aorticopulmonary (spiral) septum. In the top diagram, the aorticopulmonary septum is forming by the growth and merging of the conotruncal ridges in the walls of the outflow tract. This process divides the outflow tract into the atrioventricular canals (precursors of the aorta and pulmonary artery). In the lower diagram, the spiral septum has completed the separation of the outflow tract into the equally sized aorta (for systemic circulation) and pulmonary artery (for the pulmonary circulation). The most inferior part of the spiral septum will contribute to the upper membranous portion of the IV septum. (Modified from DeSesso & Venkat, 2010).

Table 2. Combined and grouped (number and percentage) cardiovascular malformations from six rabbit developmental toxicity studies.

Dose (mg/kg/day)	0	10	20	50	75	100	150	175	200	300	350	400	450	500
Total number of fetuses evaluated at each dose	770	130	78	261	114	374	112	200	119	256	38	134	95	28
Defects related to displaced aorticopulmonary (spiral) septum including ventricular septal defects	1^B (0.1%)					1^H (0.3%)	1^B (0.9%)						4^B (5.0%)
Dilated heart			4^S (5.1%)			4^S (1.1%)								2^S (7.1%)
Dilated ventricles	1^S (0.1%)					1^S (0.2%)								1^S (3.6%)
Cardiomegaly						1^S (0.2%)
Single heart ventricle, thickened ventricle walls						1^M (0.2%)				1^M (0.4%)
Retroesophageal right subclavian artery							3^B (2.7%)						2^B (2.1%)
“Seal-shaped” heart	1^S (0.1%)					1^S (0.2%)
Acephalic animal with heart defects				1^B (0.4%)					1^C (0.8%)
Cebocephalic animal with heart defects	1^M (0.1%)

B = Brooker et al. (1991a); C = Coles & Doleman (1996); H = Hojo (1995); M = Moxon (1996); S = Suresh (1993).

Table 3. Maternal and developmental NOAELs from six sufficient rat developmental toxicity studies of glyphosate.

Study	No. of animals per group	Exposure period	Doses (mg/kg/day)	Maternal NOAEL (mg/kg/day)	Offspring NOAEL(mg/kg/day)
Moxon (2002)	22–24	GD 6–15†	0, 250, 500, 1000	≥1000	≥1000
Wood (1996)	22–25	GD 6–15	0, 100, 500, 1000	≥1000	≥1000
Hatakenaka (1995)	22–24	GD 6–15	0, 30, 300, 1000	300	≥1000
Brooker et al. (1991a)	23–25	GD 6–15	0, 300, 1000, 3500	1000	1000
Suresh (1991)	20–30	GD 6–15	0, 1000	≥1000	≥1000
Tasker et al. (1980b)	20–23	GD 6–19	0, 300, 1000, 3500	1000	1000

†Moxon (1995) designated the day of finding sperm as GD 1. The exposure period here has been adjusted to be comparable to the other studies which used GD 0 as the day of insemination.

Table A1. Maternal and fetal outcome data for New Zealand white rabbits treated with glyphosate on gestational days 7–19† (Moxon 1996).

	0 mg/kg/day	100 mg/kg/day	175 mg/kg/day	300 mg/kg/day
Maternal data
No. animals on study	20	20	20	20
No. non-gravid	2	0	1	1
No. gravid does dead or sacrificed in extremis	1	2	2	2
No. that aborted	1	2	1	2
Embryo/fetal data
Total No. litters examined‡	17	18	17	17
Mean No. corpora lutea	10.8 ± 2.2	11.0 ± 1.6	11.1 ± 1.3	11.2 ± 1.4
Mean No. implantations	9.65 ± 2.06	9.00 ± 1.78	9.12 ± 2.50	9.82 ± 1.88
Mean % pre-implantation loss	10.7 ± 11.0	18.2 ± 11.1	18.1 ± 20.8	12.8 ± 11.9
Mean No. embryo/fetal death	NR	NR	NR	NR
Mean No. viable fetuses	8.41 ± 1.80	8.17 ± 2.20	7.94 ± 2.19	8.47 ± 2.32
Mean % post-implantation loss	11.7 ± 12.0	9.5 ± 16.7	12.1 ± 9.7	13.6 ± 16.6
Mean fetal body weight (g)	44.4 ± 4.3	43.3 ± 3.9	43.2 ± 5.7	40.7 ± 7.8*
Total fetuses (litters) with malformations
Major external/visceral	2 (2)	1 (1)	0 (0)	2 (2)
Minor external/visceral	12 (8)	7 (5)	9 (8)	11 (7)
Major skeletal	3 (2)	0 (0)	0 (0)	1 (1)
Minor skeletal	58 (16)	82 (18)**	59 (16)	79 (17)**
Total fetuses (litters) with variations
External/visceral	0	0	0	0
Cardiovascular	1 (1)	1 (1)	0	1 (1)
Skeletal	119 (17)	129 (18)	116 (17)	132 (17)**

NR = Not reported.

†Moxon (1995) designated the day of insemination as GD 1. The exposure period here has been adjusted to be comparable to the other studies which used GD 0 as the day of insemination. See text for details.

‡Includes litters that were aborted in the analysis.

*p < 0.05, ANOVA; litter is statistical unit.

**p < 0.05, Fisher’s exact test.

Table A2. Maternal and fetal outcome data for New Zealand white rabbits treated with glyphosate on gestational days 7–19 (Coles & Doleman, 1996).

	0 mg/kg/day	50 mg/kg/day	200 mg/kg/day	400 mg/kg/day
Maternal data
No. animals on study	18	18	18	18
No. non-gravid	3	0	2	1
No. gravid does dead or sacrificed in extremis	1	0	1	2†
No. that aborted	0	0	0	0
Embryo/fetal data
Total No. litters examined	14	18	15	15
Mean No. corpora lutea	10.9 ± 2.2	10.5 ± 2.4	10.7 ± 2.1	11.5 ± 1.8
Mean No. implantations	9.5 ± 2.5	9.1 ± 2.3	8.9 ± 2.5	10.3 ± 2.3
Mean % pre-implantation loss	12.5 ± 18.2	13.6 ± 9.4	16.4 ± 15.5	9.3 ± 12.5
Mean No. embryo/fetal death	0.36 ± 0.63	0.33 ± 0.77	1.00 ± 1.00*	1.40 ± 2.35
Mean No. viable fetuses	9.1 ± 2.5	8.7 ± 2.4	7.9 ± 2.5	8.9 ± 2.6
Mean % post-implantation loss	3.7 ± 6.5	3.6 ± 8.5	11.5 ± 11.4*	12.1 ± 18.6
Mean fetal body weight (g)	41.5 ± 5.5	39.4 ± 5.6	41.7 ± 4.5	38.2 ± 5.2
Total fetuses (litters) with malformations	1 (1)	3 (2)	2 (2)	1 (1)
Total fetuses (litters) with cardiovascular malformations	0	0	1 (1)	0
Total fetuses (litters) with variations‡	41 (13)	50 (17)	39 (15)	51 (14)

†At least one of these deaths/sacrifices at 400 mg/kg/day was likely treatment-related.

‡Fetuses with both malformations and variations are included in the malformations tally; fetuses with only variations are captured here.

*p < 0.05, Kruskal–Wallis followed by the Mann–Whitney U test; litter was the statistical unit.

Table A3. Maternal and fetal outcome data for New Zealand white rabbits treated with glyphosate on gestational days 7–19 (Brooker et al., 1991a).

	0 mg/kg/day	50 mg/kg/day	150 mg/kg/day	450 mg/kg/day
Maternal data
No. animals on study	19	19	16	20
No. excluded from study	1	0	0	1
No. non-gravid	0	6	1	5
No. gravid does dead or sacrificed in extremis	0	0	0	1
No. that aborted	0	1	0	0
Embryo/fetal data
Total No. litters examined	18	12†	15‡	13
Mean No. corpora lutea¶	11.5	12.4	11.7	11.3
Mean No. implantations¶	9.7	10.5	9.0	9.2
Mean % pre-implantation loss¶	14.6	15.4	23.4	18.8
Mean No. embryo/fetal death¶	0.6	1.8*	1.5*	1.8**
Mean No. viable fetuses¶	9.1	8.7	7.5	7.3
Mean % post-implantation loss§	5.7 ± 7.2	19.5 ± 19.8*	15.3 ± 17.2*	21.0 ± 11.8**
Mean fetal body weight (gms)¶	43.9	43.3	44.0	44.5
Total fetuses (litters) with malformations	3 (3)	3 (3)	5 (3)	6 (5)
Total fetuses (litters) with cardiovascular malformations||	1 (1)	1 (1)	4 (3)	5 (4)
Total fetuses (litters) with variations “anomalies”	29 (13)	26 (9)	26 (11)	16 (10)

†Analysis does not includes the one litter that was aborted at this dose.

‡Includes one female which aborted one embryonic death – referred to as “partial abortion”.

¶Standard deviation was not provided.

§Standard deviation values calculated from individual animal data in Brooker et al. (1991a).

||Exclusion of retroesophageal right subclavian artery reduces the numbers to 1 (1), 1 (1), 1 (1) and 4 (4) for 0, 50, 150 and 450 mg/kg/day, respectively.

*p < 0.05; **p < 0.01., Kruskal–Wallis test followed by non-parametric equivalent of Williams’ test; litter was the statistical unit.

Table A4. Types and incidence of malformations by individual fetus (Brooker et al., 1991a).

	0 mg/kg/day	50 mg/kg/day	150 mg/kg/day	450 mg/kg/day
No. fetuses examined	163	104	112	95
Narrow ascending aorta, dorsally displaced pulmonary trunk, IV septal defect	1		1	1
Dilated ascending aorta/aortic arch, narrow pulmonary trunk; IV septal defect with enlarged left, reduced right ventricle				2
Retroesophageal right subclavian artery† (1 fetus at 150 mg/kg/day also had forelimb flexure; 1 fetus at 450 mg/kg/day with IV septal defect)			3	2
Acephaly; single dilated arterial trunk and carotid artery; right-sided descending aorta; IV septal defect, forelimb flexure and hindlimb brachydactyly		1
Sacral meningocoele occulta with slightly flattened cranium and minimal protrusion in occipital region	1
Bilateral small eye (areas of retinal folding and dysplasia)		1
Hydrocephaly and cebocephaly with fused and reduced nasals and premaxillae, fused nares, absent upper incisors			1
Cleft palate; forelimb flexure and brachydactyly				1
Reduced and fused thoracic vertebral arches with absent centrum; connected, branched and absent ribs	1
Spina bifida with lumbar kyphosis and flattened cranium; malrotated hindlimb		1

†Retroesophageal right subclavian artery is considered a variation by other laboratories. Removing this endpoint as a malformation would reduce the number of fetuses in this group to one fetus with forelimb flexure at 150 mg/kg/day and one fetus with IV septal defect at 450 mg/kg/day.

Table A5. Maternal and fetal outcome data for Japanese white rabbits treated with glyphosate on gestational days 7–19† (Hojo, 1995).

	0 mg/kg/day	10 mg/kg/day	100 mg/kg/day	300 mg/kg/day
Maternal data
No. animals on study	18	18	18	18
No. non-gravid	0	0	0	0
No. gravid does dead or sacrificed in extremis	0	0	0	1
No. that aborted	0	2	0	2
No. with only resorptions	0	1	2	1
Embryo/fetal data
Total No. litters examined‡	18	15	16	14
Mean No. corpora lutea	10.2 ± 2.0	11.7 ± 2.2	12.1 ± 2.0	10.1 ± 2.3
Mean No. implantations	8.5 ± 2.8	9.8 ± 2.9	10.4 ± 2.9	8.6 ± 3.3
Mean % pre-implantation loss¶	17.8 ± 22.4	16.6 ± 17.0	15.2 ± 18.0	14.6 ± 25.2
Mean No. embryo/fetal death¶	0.7	1.1	1.0	0.6
Mean No. viable fetuses	7.8 ± 2.4	8.7 ± 3.2	9.4 ± 2.7	8.0 ± 3.2
Mean % post-implantation loss§	7.1 ± 8.8	13.8 ± 14.1	8.7 ± 10.5	6.5 ± 9.8
Mean fetal body weight (g) MALES	35.8 ± 8.1	37.3 ± 5.4	36.7 ± 3.3	36.2 ± 5.4
Mean fetal body weight (g) females	35.7 ± 6.7	36.1 ± 5.1	36.0 ± 3.9	34.9 ± 4.4
Malformations and variations
Total # litters (%) with malformations	1 (5.6)	3 (20.0)	3 (18.8)	5* (35.7)
Total # litters (%) with variations	16 (88.9)	14 (93.3)	16 (100.0)	8* (57.1)
Total # Fetuses (%) with malformations
External	0 (0.0)	0 (0.0)	2 (1.3)	0 (0.0)
Visceral	0 (0.0)	1 (0.8)	3 (2.0)	0 (0.0)
Cardiovascular	0	0	1 (1)	0
Skeletal	1 (0.7)	4 (3.1)	6 (4.0)	5 (5.4)
Total # Fetuses (%) with variations
Visceral	4 (2.9)	5 (3.8)	5 (3.3)	1 (0.9)
Skeletal	40 (28.6)	32 (24.6)	61* (40.7)	31 (27.7)

†Day of insemination adjusted to GD0 for comparison with other studies. See text for details.

‡Analysis does not include the litters that were aborted.

¶Mean and standard deviations not reported. Calculated from individual animal data in Hojo (1995).

§Standard deviations calculated from individual animal data in Hojo (1995).

*p < 0.05, Fisher’s exact test; litter is the statistical unit.

Table A6. Maternal and fetal outcome data for Dutch belted rabbits treated with glyphosate on gestational days 6–27 (Tasker et al., 1980a).

	0 mg/kg/day	75 mg/kg/day	175 mg/kg/day	350 mg/kg/day
Maternal data
No. animals on study	16	16	16	17
No. non-gravid	2	0	2	0
No. gravid does dead or sacrificed in extremis	0	1	2	10
No. that aborted	2	0	1	1
Embryo/fetal data
Total No. litters examined†	12	15	11	6
Mean No. corpora lutea	9.0 ± 2.13	10.1 ± 1.64	10.5 ± 3.45	8.5 ± 1.87
Mean No. implantations	5.9 ± 2.39	8.0 ± 1.81	6.1 ± 2.84	7.2 ± 2.93
Mean % pre-implantation loss	NR	NR	NR	NR
Mean No. embryo/fetal deaths	NR	NR	NR	NR
Mean No. viable fetuses/litter	5.3 ± 2.73	7.6 ± 1.84*	5.9 ± 2.77	6.3 ± 2.25
Mean % post-implantation loss‡	16.7 ± 23.0	4.9 ± 8.0	2.5 ± 5.8	18.7 ± 13.5
Mean fetal body weight (g)	33.4 ± 7.27	30.9 ± 4.43	29.9 ± 7.21	29.3 ± 4.82
Total fetuses (litters) with malformations¶
External and visceral	0	0	0	2 (1)
Cardiovascular	0	0	0	0
Skeletal	0	3 (3)	2 (2)	0

NR = Not reported.

†Analysis does not include the litters that were aborted.

‡Calculated from individual animal data in Tasker et al. (1980a).

¶The incidences of variations were not reported in this study.

*p < 0.05, ANOVA followed by t-test for multiple comparisons; litter is the statistical unit.

Table A7. Maternal and fetal outcome data for New Zealand white rabbits treated with glyphosate on gestational days 6–18 (Suresh, 1993).

	0 mg/kg/day	20 mg/kg/day	100 mg/kg/day	500 mg/kg/day
Maternal data
No. animals on study	26	17	16	15
No. non-gravid	4	4	0	1
No. gravid does dead or sacrificed in extremis	2	0	4	8
No. that aborted	NR	NR	NR	NR
No. with only resorptions	0	0	0	1
Embryo/fetal data
Total No. litters examined	20	13	12	6†
Mean No. corpora lutea	11 ± 2.8	10 ± 2.4	10 ± 1.9	9 ± 2.0
Mean No. implantations	8 ± 2.0	8 ± 1.5	9 ± 1.8	6 ± 2.4
Mean % pre-implantation loss‡	48	29	20	37
Mean No. embryo/fetal death‡	0.90	1.38	2.00	1.67
Mean No. viable fetuses	6.7	6.1	6.4	5.6
Mean % post-implantation loss¶	13.5 ± 14.3	18.6 ± 13.1	23.4 ± 23.8	23.2 ± 39.0
Mean fetal body weight (g)	32 ± 5.3	35 ± 3.7#	35 ± 2.4#	33 ± 4.9
“Abnormal fetuses” (n; %)	1 (1)	2 (3)	0	0
Total fetuses (litters) with malformations
External	2 (2)	2 (1)	1 (1)	0 (0)
Visceral	4 (3)	6 (3)	6 (4)	8 (2)*
Cardiovascular	2 (2)	4 (3)	6 (4)	6 (2)
Skeletal	11 (4)	5 (3)	0 (0)	1 (1)
Total fetuses (litters) with minor malformations and variations§
External	0	0	1 (1)	0
Visceral	NR (9)	NR (5)	NR (7)	NR (2)
Skeletal	NR (20)	NR (13)	NR (11)	NR (5)

NR = Not reported.

†Only five litters were evaluated for developmental toxicity at 500 mg/kg/day; includes single litter that was aborted at this dose in the analysis.

‡Standard deviation not reported.

¶Calculated from data provided in Suresh, 1993; values do not exactly match those presented in the study report.

§Incidence was not reported by individual fetus; rather, the incidence of each type of defect was reported, but more than one may have been seen in the same fetus.

#Significantly higher than control by ANOVA followed by Dunnett’s test; litter is the statistical unit.

*Significantly different from control by chi-square test.

Table A8. Types and incidence of individual malformations† (Suresh, 1993).

	0 mg/kg/day	20 mg/kg/day	100 mg/kg/day	500 mg/kg/day
No. fetuses examined	133‡	78	77	28
Acephaly, abdominal hernia, external nares absent, shortened upper jaw, tail short & kinky, dorsal displacement of genital tubercle; multiple associated skeletal malformations	1 (1)
Acrania, open eyelids, kinky tail, arthrogryposis and adactyly (one with microglossia, short upper jaw, thoracic and abdominal hernia, hemimelia, malformed skull, missing cervical centrum and arch; one with cleft palate and oligodactyly)		2 (1)
Seal-shaped heart	1 (1)
Cardiomegaly and seal-shaped-heart			1 (1)
Dilated heart		4 (3)*	4 (2)*	5 (2)*
Dilated ventricle¶	1 (1)		1 (1)	1 (1)
Cleft palate	1 (1)
Forelimb arthyrogryposis			1 (1)
Liver hematoma				1 (1)
Gall bladder absent				1 (1)
Hydronephrosis	1 (1)	1 (1)
Dilated ureter		1 (1)
Fused sternebrae		1 (1)
Malformed sternebrae	1 (1)	1 (1)
Displaced sternebrae	1 (1)
Missing ribs	4 (3)
Bifurcated ribs	2 (2)
Missing thoracic arch and centrum	3 (3)
Extra lumbar arch and centrum				1 (1)

†Single fetuses may be represented more than once.

‡One fetus was not examined for skeletal malformations.

¶It is unclear from the study report if the dilated ventricles are of the heart or brain. For the purposes of this review, it is assumed that this description relates to the ventricles of the heart.

*Significantly different from control by chi-square test.

Table A9. Maternal and fetal outcome data for New Zealand white rabbits treated with glyphosate on gestational days 6–18† (Bhide & Patil, 1989).

	0 mg/kg/day	125 mg/kg/day	250 mg/kg/day	500 mg/kg/day
Maternal data
No. animals on study	15	15	15	15
No. non-gravid	2	1	1	3
No. gravid does dead or sacrificed in extremis	0	0	0	0
No. that aborted	0	0	0	2
Embryo/fetal data
Total No. litters examined	13	14	14	12‡
No. litters with no live fetuses	0	0	0	2
Mean No. corpora lutea	10.0 ± 1.69	10.1 ± 1.60	10.3 ± 1.44	9.8 ± 1.57
Mean No. implantations	9.0 ± 1.20	9.3 ± 1.33	9.4 ± 1.12	8.5 ± 1.05
Mean No. early resorptions	1.7 ± 3.22	1.1 ± 2.53	1.0 ± 2.56	1.9 ± 2.43
Mean % pre-implantation loss	21.3 ± 32.4	14.9 ± 24.09	14.7 ± 24.38	13.1 ± 6.34
Mean No. embryo/fetal death	0.07 ± 0.26	0.13 ± 0.35	0.27 ± 0.59	1.4 ± 2.20
Mean No. viable fetuses	7.3 ± 3.10	8.0 ± 2.59	8.0 ± 2.48	5.2 ± 3.03
Mean % post-implantation loss	NR	NR	NR	NR
Mean fetal body weight (gms) ¶	40.6 ± 16.6	47.1 ± 0.95	47.5 ± 1.38	48.7 ± 1.87
Total fetuses (litters) with malformations§
Total fetuses (litters) with malformations||	3 (3)	6 (6)	10 (10)	20 (14)
External	1 (1)	2 (2)	3 (3)	3 (3)
Visceral	1 (1)	4 (4)	5 (5)	12 (9)
Cardiovascular	0	1 (1)	1 (1)	2 (2)
Skeletal	1 (1)	0	2 (2)	5 (2)

NR = Not reported.

†Body weights, maternal endpoints and some developmental endpoints for all 15 animals in each group appear to be included in the data. It appears that only the gravid animals were included for data on sex ratio and fetal body weight.

‡The two litters that were aborted at this dose were included in the analysis.

¶Fetal body weight data are as reported in the study report; it is unclear if all 15 does were included in this calculation.

§The incidences of variations were not reported in this study.

||The total number appears to be the sum of the fetuses and litters with external, visceral and skeletal malformations. Thus, the number of litters in the 500 mg/kg/day dose group is reported as 14 when there were only 12 litters in the group.

Table A10. Maternal and fetal outcome data from the developmental toxicity studies of glyphosate in rats.

Strain (#/group)	Duration of Treatment	Dose (mg/kg/day)	No. gravid females	No. maternal deaths	No. litters examined	Mean % post- implantation loss	Mean No. live fetuses	Mean fetal body wts (gms)	No. malformed fetuses (litters)	Cardiovascular malformations	Maternal toxicity	Ref.
Wistar (24)	GD 6–15^†	0	22	0	22	9.9 ± 15.5	12.9 ± 2.4	4.86 ± 0.29	1 (1)	None	None	Moxon (2002)
		250	24	0	24	4.0 ± 5.1	12.4 ± 3.4	5.02 ± 0.33	1 (1)	None	None
		500	23	0	23	7.8 ± 10.8	13.1 ± 2.7	4.95 ± 0.29	1 (1)	None	None
		1000	24	0	23	5.8 ± 8.3	12.9 ± 2.9	4.96 ± 0.27	2 (2)	None	None
Sprague–Dawley (25)	GD 6–15	0	23	0	23	4.9 ± 5.6	14.1 ± 3.3	3.81 ± 0.32	3 (3)	One IV septal defect and persistent truncus arteriosis, 1 retro- esophageal right-sided aortic arch	None	Wood (1996)
		100	24	0	24	4.4 ± 4.7	13.8 ± 2.2	3.99 ± 0.47	1 (1)	One IV septal defect	None
		500	22	0	22	6.1 ± 7.0	14.0 ± 1.8	3.76 ± 0.29	0	None	None
		1000	25	0	25	5.2 ± 6.8	14.0 ± 3.1	3.79 ± 0.40	0	None	None
Sprague–Dawley Crj:CD (24)	GD 6–15	0	23	0	23	7.0 + 6.1	13.7 ± 4.1	M: 3.6 ± 0.4 F: 3.3 ± 0.3	2 (1)	None	None	Hatakenaka (1995)^‡
		30	24	0	24	6.8 ± 7.8	15.0 ± 2.1	M: 3.6 ± 0.2 F: 3.4 ± 0.3	1 (1)	None	None
		300	24	0	24	7.4 ± 8.0	14.9 ± 2.8	M: 3.5 ± 0.4 F: 3.4 ± 0.4	3 (2)	One right aortic arch, 1 IV septal defect	None
		1000	22	0	22	8.4 ± 9.1	15.4 ± 2.1	M: 3.6 ± 0.2 F: 3.4 ± 0.2	5 (2)	One IV septal defect	Loose stool
Sprague–Dawley (25)	GD 6–15	0	23	0	23	6.1	13.7	3.96	1 (1)	None^¶	None	Brooker et al. (1991b)^§
		300	23	0	23	7.3	12.7	3.90	2 (2)	None	None
		1000	25	0	25	5.7	13.2	3.89	1 (1)	One IV septal defect	None
		3500	25	3	22	3.6	13.1	3.71^++	3 (2)	One IV septal defect	Salivation, loose feces, noisy respiration, wet coats, gasping
Wistar	GD 6–15	0	30	0	30	8	8.7	3.6 ± 0.4	External/visceral 5 (5)^|| Skeletal 17 (8) ^#	None	None	Suresh (1991)
		1000	20	0	20	11	7.9	3.7 ± 0.3	External/VIsceral 0 Skeletal 10 (6)^#	None	None
Sprague–Dawley COBS CD rats (25)	GD 6–19	0	22	0	22	4.2 ± 5.7	14.4 ± 1.3	3.5 ± 0.2	3 (3)	None	None	Tasker et al. (1980b)^$
		300	20	0	20	1.4 ± 3.5	11.9 ± 4.4*	3.7 ± 0.7	0	None	None
		1000	21	0	21	3.1 ± 5.6	14.3 ± 2.1	3.6 ± 0.2	0	None	None
		3500	23	6	16	14.3 ± 24.0^⊥	11.5 ± 4.1*	3.2 ± 0.3**	10 (3)^$	None	6/25 deaths; various signs of clinical toxicity; decreased weight gain due to weight loss on GD 6–9

^†Moxon (2002) designated the day of finding sperm as GD1. The exposure period listed here was adjusted using GD 0 as the day of finding sperm.

^‡Hatakenaka (1995) did not report a combined mean fetal weight, but rather reported the mean fetal weight for males (M) and females (F) separately. Individual animal data were not available to calculate the combined mean fetal weight. Mean post-implantation loss also was not reported but was calculated by the present authors based on data provided in the study report.

^¶One small IV septal defect was considered a variation by the authors.

^§Brooker et al. (1991b) did not provide standard deviation values for mean post-implantation loss, mean number of live fetuses, or mean fetal body weights.

^||Undescended testis and unascended kidneys were considered minor malformations by the authors but are included here.

^#Several bilobed vertebral centra and delayed ossification of various bones were reported as major malformations, but none fit the author’s definition of a major malformation. Individual fetal data were incompletely reported, so it is difficult to determine which type of defects which fetus and litter. The number of fetuses (litters) given here is taken from Table A9 in Suresh (1991).

^⊥Post-implantation loss percentages and standard deviations calculated from individual animal data in Tasker et al. (1980b); statistical significance was not calculated.

^$Includes six fetuses in one litter with a syndrome of bent tail, open eyelids, missing kidneys and ureters, and various skeletal defects and three fetuses in another litter with dwarfism. All malformations were seen in the historical controls.

^+ +p < 0.01, Kruskal–Wallis followed by distribution-free Williams’ test; litter was the statistical unit.

*p < 0.05, ANOVA followed by Dunnett’s test; statistical unit was not specified.

**p < 0.01, ANOVA followed by Dunnett’s test; statistical unit was not specified.

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