Table 3.

Other studies fulfilling five or six ‘checkpoints’ in Beausoleil et al. (2016) (EFSA External Report) for which well‐defined biological explanation for NMDR were subject to some uncertainty

Publication, chemical and measured effect	Dose range, No. of dose‐groups (N) excluding controls	1) Presence/shape of NMDR (checkpoint not fulfilled*)	2) Nature of measured effect	3) Biol plaus ‡	4) Role in adversity ‡	5) Probability of NMDR (%) as described by Chevillotte et al. (2017a,b)╫	Comments
Puatanachokchai et al. ( 2006 ). Impact of alpha HCH on hepatic markers in rats pre‐induced with diethylnitrosamine 1) Proliferation of GST‐P positive hepatic foci 2) Total CYP450 content in liver 3) Proliferating‐Cell‐Nuclear‐Antigen (PCNA) 4) 2α‐testosterone hydroxylase activity in liver 5) 8OHdG formation in liver 6) NADPH‐P450 reductase activity in liver 7) 16α‐testosterone hydroxylase activity in liver	0.01–500 mg/kg diet 10 week (0.001–50 mg/kg bw) N = 7 All rats had received 100 mg/kg bw i.p. diethylnitrosamine weekly 3 times before starting alpha HCH exposure	1) No (CP‐3) 2) Yes U (CP‐3) 3) Yes U (none) 4) Yes ∩ (none) 5) Yes U (none) 6) Yes U (none) 7) Yes ∩ (CP‐5)	1) Intermediate 2) Early event 3) Early event 4) Early event 5) Intermediate 6) Early event 7) Early event	?	1) Yes 2) No 3) Yes, together with cell proliferation 4) Unclear 5) Decrease is protective, increase is adverse 6) Unclear 7) Unclear	1) PNMDR 77.0 (U) 2) PNMDR 92.0 3) PNMDR 99.14 4) PNMDR 99.96 5) PNMDR 89.37 (U) 6) PNMDR 97.39 (U) 7) PNMDR 79.5 (∩)	Could be related to combined effect of the two substances Four checkpoints met for CYP2C11 mRNA expression in liver 4 and 7. Monotonic increases for other testosterone hydroxylase activities
Zhang et al. ( 2012 ). Acute effects of methylmercury i.p. on rats 1) Protein expression in cerebral cortex as marker for stress response	2–10 mg/kg bw i.p., 1x N = 6	1) Yes, ∩ but toxicity could explain the decrease in protein expression at doses > 6 mg/kg (none)	1) Early event	1) Yes	1) Unclear	1) PNMDR 72.0	Not relevant for the much lower human exposure. Furthermore, acute i.p. application
Shutoh et al. ( 2009 ). Effects of DDT on juvenile rats 1) DNA methylation, and indicators of oxidative stress (lipid peroxidation; LPO) in cerebrum	0.06–60 mg/kg bw 4 week Gavage, N = 6	1) Yes U for LPO, other changes not convincing (CP‐3)	1) Early event	1) Yes	No. Homoeostatic response to a xenobiotic	1) PNMDR 87.85
Sukata et al. ( 2002 ). Effects of DDT on rats. 1) Proliferation of GST‐P positive hepatic foci 2) mRNA IL‐1 receptor type 1 (Figure 3)	0.5–500 mg/kg diet 16 week (0.05–20 mg/kg bw) N = 8	1) No (CP‐3) 2) Yes, trend, not stat. Sign. ∩ (CP‐3)	1) Intermediate 2) ?		Rather an indication of induction of anti‐stress responses at low doses	1) PNMDR 77.35 (NMDR U) (2 cells) 2) PNMDR 83.86	1) GST‐P positive foci of different size classes were analysed 2) Similar result for other mRNA
Yuanqing et al. ( 2013 ) Effects of acetonitrile on mice. 1) AChE brain	0.156–20 mg/kg N = 8 i.p. adm	1) Yes U (CP‐3)	1) Intermediate effect, but has been used as RP	1) ?	Inhibition has been used as RP for adversity	1) PNMDR 100	Four checkpoints for AChE blood with ∩
Wildemann et al. ( 2015 ) Effects of lead acetate on rats 1) Body weight gain 2) Pulse pressure	0.004–45 mg/kg bw per day N = 8 Drinking water	1) Yes, ∩ (CP‐5) 2) Yes, U	1) Apical 2) Intermediate	?	1) Yes, body weight gain was 113 g control vs. up to 224 g treated 2–7 Yes	1) PNMDR 92.38 2) PNMDR 76.64	All the haemodynamic effects are linked. Other possible non‐monotonic responses but with less than 5 checkpoints observed for Systolic blood pressure Stroke volume Cardiac output
Zorrilla et al. ( 2009 ) Effects of triclosan on juvenile rats 1) Triiodothyronine (T3) serum	3–300 mg/kg per day N = 5 Gavage	1) Yes, ∩ (CP‐3)	1) Intermediate	1) ?	1) Yes, reduction in T3 levels during critical windows is linked to reproductive effects	1) low for NMDR (56% for MDR)	1) Due to one dose group, but very high reduction. Large variability among treatments. The main effect is for T4 and is clearly monotonic.

^*CP = checkpoint as defined in Beausoleil et al. (2016): CP‐3. Can the apparent NMDR be explained by one single potential outlying dose group? CP‐5. Is the steepness of the dose‐response curve outside the range of biologically plausible/realistic dose‐response shapes?

^ΠThe symbol U indicates an NMDR with U (or J) shape, the symbol ∩ indicates an NMDR with inverted U (or J) shape.

^‡Only addressed when a possible NMDR is confirmed under 1. Presence/shape of NMDR.

^╫The key Monte Carlo resampling results are presented, for additional results, see the publications.