Estimation of acute oral toxicity using the No Observed Adverse Effect Level (NOAEL) from the 28 day repeated dose toxicity studies in rats

Bulgheroni, A.; Kinsner‐Ovaskainen, Agnieszka; Hoffmann, Sebastian; Hartung, Thomas; Prieto, Pilar

doi:10.1016/j.yrtph.2008.10.001

Cited by 44 publications

(33 citation statements)

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“…All studies show a positive predictive value of 33.7%. These results are in close agreement with the statistics published by Bulgheroni et al (2009), and indicate that the results are largely robust for different chemical types – lack of toxicity in a subchronic study is broadly indicative of lack of acute toxicity. If a 28-day NOAEL of 200 mg/kg per day had been used to rule out acute toxicity, then 928 previous acute oral toxicity studies could have been avoided.…”

Section: Resultssupporting

confidence: 89%

“…In 2009, Bulgheroni et al evaluated whether acute oral toxicity could be predicted (and thus made redundant) by repeat-dose 28 day toxicity data. Bulgheroni et al used authorized access to the NCD (Bulgheroni et al, 2009). In 2014, Taylor et al published an evaluation of the added value of the 90-day repeated dose oral toxicity test given the availability of a “sub-acute toxicity profile” (Taylor et al, 2014).…”

Section: Resultsmentioning

confidence: 99%

“…Bulgheroni’s analysis identified 1,791 substances with acute oral LD 50 and 28-day oral NOAEL data from the NCD (Bulgheroni et al, 2009). The evaluation indicated that a 200 mg/kg body weight (b.w.)…”

Section: Resultsmentioning

confidence: 99%

“…LD 50 estimation could be made given a NOAEL value > 200 mg/kg b.w. (Bulgheroni et al 2009). Collation of ECHA disseminated acute toxicity oral LD 50 results (OECD TG 401, 423, 420 and 425) and 28-day NOAELs (OECD 407) allows for the evaluation of this testing strategy on the extracted substances.…”

Section: Resultsmentioning

confidence: 99%

“…It was shown earlier (Bulgheroni et al, 2009) that the European New Chemicals Database (NCD) in 2008 included 4,773 substances of which 4,219 included oral toxicity data: 70.2% were Category 5 (LD 50 2,000 – 5,000 mg/kg bodyweight (b.w.)) and 16.7% were “Not classified” LD 50 > 5,000 mg/kg b.w.).…”

Section: Introductionmentioning

confidence: 99%

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

Luechtefeld

2016

ALTEX

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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.

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Section: Resultssupporting

confidence: 89%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Luechtefeld

2016

ALTEX

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Environmentally Friendly Approach to the Synthesis of 3‐[Benzylideneamino]‐2‐methylquinazolin‐4(3H)‐one Derivatives and Calculation of Their Toxicity

Molnar

Kraljević

Pavić

et al. 2023

Chemistry & Biodiversity

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Application of deep eutectic solvents in synthesis of different heterocyclic compounds was proven very efficient. These solvents are a new generation of green solvents showing excellent potential for different purposes, where they are used as environmentally acceptable substitute for toxic and volatile organic solvents. This research describes their application in the synthesis of series of quinazolinone Schiff bases in combination with microwave, ultrasound‐assisted and mechanochemical methods. First, a model reaction was performed in 20 different deep eutectic solvents to find the best solvent and then reaction conditions (solvent, temperature and reaction time) were optimized for each method. Afterwards, 40 different quinazolinone derivatives were synthesized in choline chloride/malonic acid (1 : 1) DES by each method and compared by their yields. Here we show that deep eutectic solvents can be very efficient in the synthesis of quinazolinone derivatives as an excellent substitution for volatile organic solvents. With green chemistry approach in mind, we have also performed a calculation on compounds’ toxicity and solubility, showing that most of them possess toxic and mutagenic properties with low water solubility.

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The taste of toxicity: A quantitative analysis of bitter and toxic molecules

2017

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The role of bitter taste-one of the few basic taste modalities-is commonly assumed to signal toxicity and alert animals against consuming harmful compounds. However, it is known that some toxic compounds are not bitter and that many bitter compounds have negligible toxicity while having important health benefits. Here we apply a quantitative analysis of the chemical space to shed light on the bitterness-toxicity relationship. Using the BitterDB dataset of bitter molecules, The BitterPredict prediction tool, and datasets of toxic compounds, we quantify the identity and similarity between bitter and toxic compounds. About 60% of the bitter compounds have documented toxicity and only 56% of the toxic compounds are known or predicted to be bitter. The LD value distributions suggest that most of the bitter compounds are not very toxic, but there is a somewhat higher chance of toxicity for known bitter compounds compared to known nonbitter ones. Flavonoids and alpha acids are more common in the bitter dataset compared with the toxic dataset. In contrast, alkaloids are more common in the toxic datasets compared to the bitter dataset. Interestingly, no trend linking LD values with the number of activated bitter taste receptors (TAS2Rs) subtypes is apparent in the currently available data. This is in accord with the newly discovered expression of TAS2Rs in several extra-oral tissues, in which they might be activated by yet unknown endogenous ligands and play non-gustatory physiological roles. These results suggest that bitter taste is not a very reliable marker for toxicity, and is likely to have other physiological roles. © 2017 IUBMB Life, 69(12):938-946, 2017.

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Estimation of acute oral toxicity using the No Observed Adverse Effect Level (NOAEL) from the 28 day repeated dose toxicity studies in rats

Cited by 44 publications

References 1 publication

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

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

Environmentally Friendly Approach to the Synthesis of 3‐[Benzylideneamino]‐2‐methylquinazolin‐4(3H)‐one Derivatives and Calculation of Their Toxicity

The taste of toxicity: A quantitative analysis of bitter and toxic molecules

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