Table 7.

Summary of the UN-GHS Weight of Evidence (WoE) elements in the EU assessment and comparison with the weight provided in the IARC assessment

UN-GHS and EU CLP WoE elements	Regulatory guidance (ECHA, 2015) and scientific support	Evaluation method in the IARC Preamble	Relevance for the glyphosate WoE
			EU assessment	Comments on IARC assessment
(a) Tumour type and background incidence	Relevance for humans, due to the relevance of the mode of action(Meek et al. 2014a, b), or tissues with no human equivalents. Spontaneous incidences and use of historical control data(Dinse and Peddada 2011; Greim et al. 2003; Keenan et al. 2008; Ma et al. 2002; Massarelli et al. 2013)	Relevance for humans, e.g. species-specific mechanism that does not operate in humans The use of historical data is mentioned	All valid studies are considered negative. No need for mode of action evaluation Historical control data from the same laboratory were considered when available	All tumours were assumed relevant for humans No information on the use of historical control data is provided except the consideration of some tumours as “rare”
(b) Multi-site responses	If observed, increases the evidence (Dybing et al. 1997)	Consistency of the results across target organ(s) and spectrum of neoplastic response	No significant incidences observed in the valid studies Consistency among studies was considered	Based on statistically significant trends for different tumour types. Assessment limited to a subset of the available studies
(c) Progression of lesions to malignancy	If observed, increases the evidence	The spectrum of neoplastic response, from preneoplastic lesions and benign tumours to malignant neoplasms	Specifically considered for individual studies	Specifically considered for individual studies
(d) Reduced tumour latency	Only relevant for unusual tumours	Sufficient for considering the agent as carcinogen	Not relevant	No indications are provided
(e) Whether responses are in single or both sexes	A consistent mode of action is required for tumours observed in only one sex	No specific indications for the evaluation of tumours occurring in a single sex are provided	Contributes to the lack of consistency assessment as no sex related mode of action is postulated	All trends were significant only in one sex, but no sex mediated mode of action is discussed
(f) Whether responses are in a single species or several species	If observed in several species increases the evidence	If observed in several species increases the evidence	No significant incidents were identified for mice or rats	Based on positive trends in both mice and rats
(g) Structural similarity to a substance(s) for which there is good evidence of carcinogenicity	Includes SAR, QSAR, read across and grouping	The possibility for using information from structurally similar agents is mentioned	Not relevant, the assessment is based on studies on glyphosate	Not relevant, the assessment is based on studies on glyphosate
(h) Routes of exposure	Includes local tumours	The exposure route should be mentioned	Assessment based on oral studies	Assessment based on oral studies
(i) Comparison of absorption, distribution, metabolism and excretion between test animals and humans	Also relevant for considering the role of metabolites	Comparison should be made when possible	Not relevant	Not relevant
(j) The possibility of a confounding effect of excessive toxicity at test doses	Effects observed only at doses exceeding the maximum tolerable dose should be checked for confounding effects of excessive toxicity	Not mentioned in the preamble. NOAELs and LOAECs for each study are not reported	Considered for tumours in mice	Effects observed only at high doses with excessive toxicity are included in the trend assessment. No additional information is provided
(k) Mode of action and its relevance for humans, such as cytotoxicity with growth stimulation, mitogenesis, immunosuppression, mutagenicity	The IPCS framework and related approaches (Boobis et al. 2006, 2008; Meek et al. 2014a; Sonich-Mullin et al. 2001) offers general guidance, IARC (1994, 1999) and ECHA (2015) list specific tumours considered not relevant for humans. Mutagenicity and genotoxicity play a key role in the assessment and in particular the assessment of non-threshold genotoxic-carcinogenic modes of action	The possible mechanism should be identified when possible. The assessment of genotoxicity is described in the preamble, in vivo data on humans and mammals have preference. No mention to the “ten key characteristic approach” is included in the preamble	The genotoxicity assessment is based on mammalian studies, and concluded as negative for glyphosate, as all studies are negative except at very high doses with confounding cytotoxicity. Genotoxicity of a co-formulant and of some glyphosate formulations cannot be ruled out, and should be addressed	The conclusion of strong evidence on genotoxicity and oxidative stress for glyphosate and glyphosate based formulations is one of the key arguments of the IARC proposal. The differences between glyphosate and glyphosate based formulations reported in several studies are presented but no further discussed