Table 2.

Evidence profile table for male reproductive effects of DIBP or MIBP

Male Reproductive Effects
Outcome		Available studies	Factors that increase confidence	Factors that decrease confidence	Confidence judgement for outcome	Confidence judgement for overall hazard
Gestational (F1) Exposure	Testosterone	High confidence: Borch et al., 2006 Furr et al., 2014 Hannas et al., 2011 Hannas et al., 2012 Howdeshell et al., 2008 Saillenfait et al., 2017 Medium confidence: Wang et al., 2017	Consistency Dose-response gradient Effect size Biological plausibility (support from mechanistic evidence) Minimal concerns for bias and sensitivity		⊕⊕⊕ ROBUST A dose-related decrease in testicular T levels or production (up to −96% compared to control) was observed in all studies in rats and mice that evaluated this outcome. Several of these studies also demonstrated decreased testicular expression of genes and proteins in the steroidogenesis pathway in both rats and mice, which provides support for biological plausibility.	⊕⊕⊕ ROBUST Supported by consistency and coherence across outcomes, with mechanistic evidence (e.g. decreased testicular expression of steroidogenic enzymes and INSL3 in F1 males) providing support for biological plausibility. The greatest weight of evidence came from gestational exposure studies, whereas postnatal exposure studies were limited by risk of bias and Male sensitivity concerns.
	Male morphological development	High confidence: Borch et al., 2006 Saillenfait et al., 2006 Saillenfait et al., 2008 Saillenfait et al., 2017 Medium confidence: Wang et al., 2017	Consistency within rat studies Dose-response gradient Effect size Biological plausibility Minimal concerns for bias and sensitivity		⊕⊕⊕ ROBUST All rat studies observed a dose-related increase in effects consistent with decreased T and INSL3, including increased time to puberty, decreased AGD, nipple retention, cryptorchidism, nonscrotal testis, hypospadias, and exposed os penis. No effects on AGD were observed in mice (Wang et al., 2017).
	Reproductive organ weight	High confidence: Saillenfait et al., 2008 Medium confidence: Wang et al., 2017	Dose-response gradient and minimal concern for bias and sensitivity in the study by Saillenfait et al., 2008 Biological plausibility Coherence with postnatal exposure studies	Few studies	⊕⊕◯ MODERATE Decreased reproductive organ weights were observed in rats (Saillenfait et al., 2008), whereas a consistent trend in testis weight was not observed in mice (Wang et al., 2017); it is not clear whether this is related to differences in species or study designs. This effect is consistent with decreased T.
	Testicular histology or sperm evaluation	High confidence: Saillenfait et al., 2008 Medium confidence: Borch et al., 2006 Wang et al., 2017	Consistency Dose-response gradient Effect size Biological plausibility		⊕⊕⊕ ROBUST Adverse effects on the testis and/or sperm were observed in rats and mice, including a dose-related increased incidence of pathological lesions of the testis (Borch et al., 2006, Saillenfait et al., 2008), epididymal oligo- or azoopermia (Saillenfait et al., 2008), and decreased sperm concentration and motility (Wang et al., 2017).
Postnatal (Weanling or Peripubertal) Exposure	Testosterone	Medium confidence: Oishi and Hiraga, 1980a Oishi and Hiraga, 1980c * Oishi and Hiraga, 1980d * Low confidence: Oishi and Hiraga, 1980b	Biological plausibility	Concerns for bias and sensitivity in some studies Unexplained inconsistency	◯◯◯ INDETERMINATE A dose-related increase in androgen levels was observed in two rat studies (Oishi and Hiraga, 1980b, c), whereas androgen levels were decreased or not changed in two mouse studies (Oishi and Hiraga, 1980a, d).
	Reproductive organ weight	Medium confidence: Oishi and Hiraga, 1980b Oishi and Hiraga, 1980c* U. Rochester, 1954 Low confidence: Oishi and Hiraga, 1980a Oishi and Hiraga, 1980d* Foster et al., 1981* Zhu et al., 2010	Consistency within rat studies Biological plausibility Coherence with gestational exposure studies	Concerns for bias and sensitivity in some studies	⊕⊕⊕ ROBUST In rats, a dose-related decrease in absolute testis weight was consistently observed (Oishi and Hiraga, 1980b, c; Foster et al., 1981; University of Rochester, 1954). In weanling mice, Zhu et al. (2010) observed decreased absolute testis weight in the highest dose group. In peripubertal mice, Oishi and Hiraga (1980a, d) observed increased relative testis weight, which is considered a less reliable metric compared to absolute testis weight.
	Testicular histology/sperm evaluation	Low confidence: Oishi and Hiraga, 1980b Foster et al., 1981 *	Consistency Biological plausibility Coherence with gestational exposure studies	Concerns for bias and sensitivity Few studies	⊕⊕◯ MODERATE Rats were found to have increased testicular atrophy (Foster et al., 1981) and decreased spermatocytes and spermatogonia (Oishi and Hiraga, 1980a).

^*indicates MIBP study