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

Gissi, Andrea

doi:10.14573/altex.1609121

Cited by 12 publications

(9 citation statements)

References 8 publications

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“…Three 3R approaches to improve acute oral toxicity testing have been discussed. [1][2][3][4] Based on the possibility of human exposure, the inhalation route is used in addition to the oral or dermal route. Triggers for the need of testing a compound through inhalation are for example volatility or the particle size distribution, as well as the use of the compound.…”

Section: Introductionmentioning

confidence: 99%

Reduction of Acute Inhalation Toxicity Testing in Rats: The Contact Angle of Organic Pigments Predicts Their Suffocation Potential

HofmannThomas

Ma-HockLan

TeubnerWera

et al. 2018

Applied In Vitro Toxicology

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Determination of acute inhalation toxicity is requested for hazard assessment of substances. In the regulatoryrequired test, otherwise toxicologically inert solid (dust) aerosols have to be tested up to a very high concentration limit of 5 mg/L of air. By testing a series of organic pigments at this concentration, we found that some pigments were well tolerated (hence, resulting in an LC 50 >5 mg/L). For other pigments, we identified obstruction of the airways with subsequent suffocation as the cause of death at this concentration. In these cases, Organization for Economic Cooperation and Development TG 436 requires that additional animals are tested at 1 mg/L air. However, the mortality of animals at the high concentration could have been avoided if the suffocation by obstruction of the airways was predictable. Hence, we investigated the correlation of several physicochemical characteristics with the observed mortality. Test substances with the highest contact angle, a measure of hydrophobicity, produced mortality at high concentrations, whereas the more hydrophilic compounds did not. Therefore, the contact angle of test substances may serve as a predictive parameter for suffocation potential. We propose conducting this characterization before in vivo testing to reduce the number and suffering of animals until further in vitro and in silico approaches are developed to completely replace animal testing.

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Section: Introductionmentioning

confidence: 99%

Reduction of Acute Inhalation Toxicity Testing in Rats: The Contact Angle of Organic Pigments Predicts Their Suffocation Potential

HofmannThomas

Ma-HockLan

TeubnerWera

et al. 2018

Applied In Vitro Toxicology

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“…This WoE adaptation proposed by ECHA (ECHA 2017b ) applies to low toxicity substances (i.e., those that are not to be classified for acute oral toxicity). Further considerations regarding these adaptation rules are also discussed in Buesen et al 2018 ; Gissi et al 2017 , 2018 ; Graepel et al 2016 .…”

Section: Current Eu Regulatory Requirements Of Relevance For the Safety Assessment Of Chemicals And Cosmetic Productsmentioning

confidence: 99%

Current EU regulatory requirements for the assessment of chemicals and cosmetic products: challenges and opportunities for introducing new approach methodologies

et al. 2021

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The EU Directive 2010/63/EU on the protection of animals used for scientific purposes and other EU regulations, such as REACH and the Cosmetic Products Regulation advocate for a change in the way toxicity testing is conducted. Whilst the Cosmetic Products Regulation bans animal testing altogether, REACH aims for a progressive shift from in vivo testing towards quantitative in vitro and computational approaches. Several endpoints can already be addressed using non-animal approaches including skin corrosion and irritation, serious eye damage and irritation, skin sensitisation, and mutagenicity and genotoxicity. However, for systemic effects such as acute toxicity, repeated dose toxicity and reproductive and developmental toxicity, evaluation of chemicals under REACH still heavily relies on animal tests. Here we summarise current EU regulatory requirements for the human health assessment of chemicals under REACH and the Cosmetic Products Regulation, considering the more critical endpoints and identifying the main challenges in introducing alternative methods into regulatory testing practice. This supports a recent initiative taken by the International Cooperation on Alternative Test Methods (ICATM) to summarise current regulatory requirements specific for the assessment of chemicals and cosmetic products for several human health-related endpoints, with the aim of comparing different jurisdictions and coordinating the promotion and ultimately the implementation of non-animal approaches worldwide. Recent initiatives undertaken at European level to promote the 3Rs and the use of alternative methods in current regulatory practice are also discussed.

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“…The number of fragments of the given descriptor space depends on selected fragmentation scheme. It varied from 387 (IIAB(2-2), atom centred fragments with radius 1) to 31623 (IIAB (2)(3)(4)(5), atom centred fragments with radius 5), with an average of 7974 (SI, section 1).…”

Section: Encoding Of Chemical Structuresmentioning

confidence: 99%

“…Until 2002, the reference guideline was OECD 401, however it was abolished for animal welfare reasons. Nowadays, more advanced guidelines are available which demand much less testing on animals and are likely to produce more reliable results [2]. Currently used guidelines are: OECD 420 (fixed dose procedure), OECD 423 (acute toxic class method), OECD 425 (up and down procedure) [3].…”

Section: Introductionmentioning

confidence: 99%

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Consensus models to predict oral rat acute toxicity and validation on a dataset coming from the industrial context

Lunghini

Marcou

Azam

et al. 2019

SAR and QSAR in Environmental Research

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We report predictive models of acute oral systemic toxicity representing a follow-up of our previous work in the framework of the NICEATM project. It includes the update of original models through the addition of new data and an external validation of the models using a dataset relevant for the chemical industry context. A regression model for LD 50 and multi-class classification model for toxicity classes according to the Global Harmonized System categories were prepared. ISIDA descriptors were used to encode molecular structures. Machine learning algorithms included support vector machine (SVM), random forest (RF) and naïve Bayesian. Selected individual models were combined in consensus. The different datasets were compared using the generative topographic mapping approach. It appeared that the NICEATM datasets were lacking some relevant chemotypes for chemical industry. The new models trained on enlarged data sets have applicability domains (AD) sufficiently large to accommodate industrial compounds. The fraction of compounds inside the models' AD increased from 58% (NICEATM model) to 94% (new model). The increase of training sets improved models' prediction performance: RMSE values decreased from 0.56 to 0.47 and balanced accuracies increased from 0.69 to 0.71 for NICEATM and new models, respectively.

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

Cited by 12 publications

References 8 publications

Reduction of Acute Inhalation Toxicity Testing in Rats: The Contact Angle of Organic Pigments Predicts Their Suffocation Potential

Reduction of Acute Inhalation Toxicity Testing in Rats: The Contact Angle of Organic Pigments Predicts Their Suffocation Potential

Current EU regulatory requirements for the assessment of chemicals and cosmetic products: challenges and opportunities for introducing new approach methodologies

Consensus models to predict oral rat acute toxicity and validation on a dataset coming from the industrial context

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