Analysis of public oral toxicity data from REACH registrations 2008-2014

Abstract

Summary The European Chemicals Agency, ECHA, made available a total of 13,832 oral toxicity studies for 8,568 substances up to December 2014. 75% of studies were from the retired OECD Test Guideline 401 (11% TG 420, 11% TG 423 and 1.5% TG 425). Concordance across guidelines, evaluated by comparing LD50 values ≥ 2,000 or < 2,000 mg/ kg bodyweight from chemicals tested multiple times between different guidelines, was at least 75% and for their own repetition more than 90%. In 2009, Bulgheroni et al. created a simple model for predicting acute oral toxicity using no observed adverse effect levels (NOAEL) from 28-day repeated dose toxicity studies in rats. This was reproduced here for 1,625 substances. In 2014, Taylor et al. suggested no added value of the 90-day repeated dose oral toxicity test given the availability of a low 28-day study with some constraints. We confirm that the 28-day NOAEL is predictive (albeit imperfectly) of 90-day NOAELs, however, the suggested constraints did not affect predictivity. 1,059 substances with acute oral toxicity data (268 positives, 791 negatives, all Klimisch score 1) were used for modeling: The Chemical Development Kit was used to generate 27 molecular descriptors and a similarity-informed multilayer perceptron showing 71% sensitivity and 72% specificity. Additionally, the k-nearest neighbors (KNN) algorithm indicated that similarity-based approaches alone may be poor predictors of acute oral toxicity, but can be used to inform the multilayer perceptron model, where this was the feature with the highest information value.

Rebooting the generally recognized as safe (GRAS) approach for food additive safety in the US

“…in the 28-day test is a strong predictor for non-toxicity in the 90-day study. Luechtefeld et al (2016) confirmed in a much larger dataset that the 28-day NOAEL is predictive (albeit imperfectly) of 90-day NOAELs, however, the constraints suggested by Taylor et al did not affect predictivity. The interrelationship of 28-day and 90-day NOAEL is also used very pragmatically within the European REACH legislation in line with ECHA's test guidance to estimate from a 28-day study a 90-day derived no-effect level (DNEL) using an assessment factor of 3 (ECETOC, 2010).…”

“…The interrelationship of 28-day and 90-day NOAEL is also used very pragmatically within the European REACH legislation in line with ECHA's test guidance to estimate from a 28-day study a 90-day derived no-effect level (DNEL) using an assessment factor of 3 (ECETOC, 2010). Luechtefeld et al (2016) used the dataset also to test this assumption. 133 substances had both 90-day and 28-day key studies.…”

Thresholds of Toxicological Concern – Setting a threshold for testing below which there is little concern

“…The author has argued elsewhere that the statement that everything is poisonous is quite misleading as not all substances can produce toxic effects in animals in doses that can be practically applied (Luechtefeld et al, 2016a). For example, only about 20% of substances are acutely toxic up to the common limit of 2 g/kg bodyweight (Luechtefeld et al, 2016b). Imagine a human swallowing 100 to 200 g of pure chemical… But Paracelsus is right about the fact that for those chemicals that are poisonous, it is would adequately cover neurotoxicity, developmental toxicity, endocrinological effects, and immunotoxicity.…”

Alternative acute oral toxicity assessment under REACH based on sub-acute toxicity values

“…Prediction models based on sub-acute toxicity data or in vitro cytotoxicity tests have been suggested and developed. According to the respective authors, these models may replace in vivo acute toxicity studies partly or -in the future -in total (Creton et al, 2010;Chapman et al, 2010;Indans et al, 1998;Kinsner-Ovaskainen et al, 2013;Robinson et al, 2008;Seidle et al, 2011;Bulgheroni et al, 2009;Luechtefeld et al, 2016;Graepel et.al. 2016).…”

“…Furthermore, according to the JRC, information on repeated dose toxicity might be useful in supporting classification and labelling for acute systemic toxicity. Luechtefeld et al (2016) analyzed REACH registration data of [2009][2010][2011][2012][2013][2014] to develop a number of prediction models for oral systemic toxicity. Those authors came to the conclusion that "a lack of toxicity in a 28-day study is a relatively good predictor that a chemical will be non-toxic acutely."…”