Table 3.

Evidence profile table for female reproductive effects of DEP.

Female reproductive effects
Outcome	Available studies	Factors that increase confidence	Factors that decrease confidence	Confidence judgement for outcome	Confidence judgement for overall hazard
Pregnancy outcomes	High Confidence: Fujii et al. (2005), RTI International (1984) Low Confidence: Manservisi et al. (2015)	• Minimal concern for bias and sensitivity in most studies	• Few studies • Small magnitude of effect in high confidence studies	⊕◯◯ SLIGHT Statistically significantly decreased gestation length (Fujii et al. 2005) and decreased litter size (RTI International 1984) were observed in F1 parental females in two high confidence studies, and increased litter size was observed in one low confidence study (Manservisi et al. 2015). Otherwise, no effects were observed.	⊕◯◯ SLIGHT Based on few reported effects across studies, including effects on gestation length, litter size, and organ weights or histopathology.
Maternal body weight	High Confidence: NTP (1988) Medium Confidence: Howdeshell et al. (2008), Hardin et al. (1987), Gray et al. (2000), Fujii et al. (2005) Low Confidence: Furr et al. (2014), Procter & Gamble (1994)	• Minimal concerns for bias and sensitivity in two studies that observed effects	• Unexplained inconsistency	◯◯◯ INDETERMINATE NTP (1988) reported a trend towards decreased maternal body weight gain (corrected for gravid uterine weight), whereas Fujii et al. (2005) reported increased maternal body weight gain in F0 females. Otherwise, no effects on maternal body weight gain were observed in rats, mice, or rabbits.
Reproductive organ weights	High Confidence: Fujii et al. (2005), RTI International (1984), Procter & Gamble (1994), NTP (1988), Shiraishi et al. (2006) Low Confidence: Brown et al., 1978; Pereira et al., 2007d		• Concerns for bias and sensitivity in one out of two studies that observed effects	⊕◯◯ SLIGHT Decreased absolute and relative uterine weights was observed in F1 and F2 weanling rats in a high confidence two-generation study (Fujii et al. 2005), although the effect was not observed in adult F1 animals so may be transient. A significant decrease in relative ovary weights was reported in a low confidence study in F0 and F1 adult rats (Pereira et al., 2007c). Otherwise, no organ weight changes were observed.
Histopathology	High Confidence: Procter & Gamble (1994) Medium Confidence: Fujii et al. (2005), Shiraishi et al. (2006) Low Confidence: Manservisi et al. (2015)		• Concerns for bias and sensitivity in the only study that observed effects	⊕◯◯ SLIGHT A reduction in the size of the lobular structures of the mammary gland was observed in a low confidence study in parous F1 female rats (Manservisi et al. 2015). Otherwise, no histopathological changes were observed in ovaries, uteri, vaginas, or mammary glands.
Hormones	High Confidence: Shiraishi et al. (2006)	• Minimal concern for bias and sensitivity	• Single study	◯◯◯ INDETERMINATE No effects were observed on steroid hormone or gonadotropin levels in female rats after subchronic exposure (Shiraishi et al. 2006).
Estrous cyclicity	High Confidence: Fujii et al. (2005) Low Confidence: Shiraishi et al. (2006)	• Minimal concern for bias and sensitivity	• Few studies	◯◯◯ INDETERMINATE No effects were observed on estrous cyclicity in F0 or F1 females in a two-generation study (Fujii et al. 2005) or after subchronic exposure (Shiraishi et al. 2006).
Female morphological development	High Confidence: Fujii et al. 2005, Gray et al. 2000	• Minimal concern for bias and sensitivity	• Single study	◯◯◯ INDETERMINATE A statistically significant delay in the age at vaginal opening was observed in F1 rats in a two-generation study, likely related to decreased growth. No DEP- related effects on AGD were observed in F1 or F2 animals in this study (Fujii et al. 2005).