Table 5.

Evidence profile table for liver effects of DEP or MEP.

Liver effects
Outcome	Available studies	Factors that increase confidence	Factors that decrease confidence	Confidence judgement for outcome	Confidence judgement for overall hazard
Organ weight	High Confidence: Fujii et al. (2005), Gray et al. (2000), NTP (1995), RTI International (1984), Kwack et al. (2009), Kwack et al. (2010), Shiraishi et al. (2006) Medium Confidence Moody and Reddy (1978), Oishi and Hiraga (1980), Brown et al. (1978) Low Confidence: Mapuskar et al. (2007), Pereira et al. (2006, 2007c, 2007d, 2008b), Pereira and Rao (2006a, 2007), Setti Ahmed et al. (2018), Sonde et al. (2000)	• Consistency across most higher dose studies • Biological plausibility	• Inconsistent findings in low dose studies • Low magnitude of effect	⊕⊕◯ MODERATE Dose-related increases in relative liver weight were observed in most studies that used higher dose levels of DEP, with statistically significant changes only observed at the highest doses tested (Fujii et al. 2005, Brown et al. 1978, NTP 1995, Moody and Reddy 1978, RTI International 1984, Oishi and Hiraga 1980). However, no effects on liver weight were observed in four high confidence rat studies (Gray et al. 2000, Kwack et al. 2009, 2010; Shiraishi et al. 2006) and effects on liver weight were inconsistent across low confidence studies.	⊕⊕◯ MODERATE Based on evidence of increased liver weight, histopathological effects, and biochemical changes that are indicative of hepatic effects. However, evidence for histopathological and biochemical effects was primarily found in low dose studies that had concerns for bias and sensitivity.
Histopathology	High Confidence: NTP (1995) Medium confidence: Fujii et al. (2005), Shiraishi et al. (2006), Moody and Reddy (1978) Low confidence: Brown et al. (1978), Mapuskar et al. (2007), Pereira et al. (2006, 2007a, 2007c, 2008), Pereira and Rao (2006a, 2008b), Sinkar and Rao (2007)	• Biological plausibility	• Unexplained inconsistency • Quantitative results are generally not provided • Concerns for bias and sensitivity in low dose studies that observed effects	◯◯◯ INDETERMINAT Reports of intracellular vacuolations, degenerative changes in centrilobular and periportal areas, and necrosis were observed in low confidence low dose studies ranging from 0.57 mg/kg-day to 6.25 mg/kg- day, although these studies did not provide quantitative data. Mild or no effects on liver histopathology were observed in studies that used higher dose levels.E
Biochemistry	High Confidence: Fujii et al. (2005), NTP (1995), Kwack et al. (2009), Kwack et al. (2010) Medium Confidence: Moody and Reddy (1978), Moody and Reddy (1982), Shiraishi et al. (2006) Low confidence: Mapuskar et al., 2007; Pereira et al., 2006, 2007a, 2007b, 2008, Pereira and Rao, 2006a, 2006b, 2008b; Sinkar and Rao, 2007; Sonde et al., 2000	• Biological plausibility	• Unexplained inconsistency • Concerns for bias and sensitivity in low dose studies that observed effects	⊕◯◯ SLIGHT High confidence studies observed limited evidence of effects on biochemical markers of liver damage, whereas low confidence low dose studies (0.57–6.25 mg/kg-day) reported dose-related increases in serum enzyme levels (e.g. ALT, AST, SOD) in both sexes of rats and mice across generations following oral exposures of at least 120 days. Alterations in triglycerides, glucose, cholesterol, and liver glycogen levels were also reported primarily in the low confidence studies.