iSafeRat®: HA-QSARs studies for REACH endpoints
Kreatis replacing experimentation for reach - REACH alternative laboratory testing
Kreatis - an alternative to experimentation for REACH - REACH alternative experimentation

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KREATiS - iSafeRat - QSAR REACH alternative

iSafeRat® (in Silico Algorithms For Environmental Risk And Toxicity) is the name given to the toolbox containing the set of High Accuracy QSAR (HA-QSAR) modules produced by KREATiS. Initially designed to meet the REACH requirements to fulfil endpoints of regulatory dossier, iSafeRat® aims to be the most reliable and accurate in silico approach to replace all kind of experimental studies.

When you order a HA-QSAR study from KREATiS you get a complete service: each requested endpoint is scrutinised individually by our staff to verify applicability domain, to examine any data you provide and then to use the appropriate iSafeRat® algorithm to provide you with the best result. In certain cases more than one way can be used to calculate an endpoint.

The aim of KREATiS is to provide an endpoint value with an accuracy equal to (or even better than) that obtained by the best available experimental technique available for that endpoint following OECD Guideline methods but for a fraction of the price of a laboratory study.

Each endpoint value that you order will be provided in a full report format containing a project and study number, information on the substance provided by the client, a brief explanation of how the prediction was made, the result and confidence limits and in Annex a full QSAR Model Report (QMRF) and QSAR Prediction Report (QPRF) necessary for successful REACH submission of your endpoint to ECHA.

If required a complete Robust summary for the endpoint can be prepared by KREATiS and will be sent to you in i5z format. The cost of this service will be provided to you in the quote upon request.

ENDPOINTS:

  • OCTANOL/WATER PARTITION COEFFICIENT (LOG KOW)
  • WATER SOLUBILITY
  • Vapour pressure
  • Acute Fish toxicity
  • Acute daphnid toxicity
  • Algae toxicity
  • CHRONIC FISH TOXICITY
  • CHRONIC DAPHNID TOXICITY
  • Aquatic toxicity for mixtures
  • TOXICITY TO MICROORGANISMS
  • SKIN IRRITATION
  • EYE IRRITATION
  • SKIN SENSITISATION

OCTANOL/WATER PARTITION COEFFICIENT (LOG KOW)

iSafeRat® KOW study can test the hydrophobicity (as log KOW) of a substance

Study/studies replaced and value reported:
  • OECD 107 (Partition coefficient (n-octanol/water): Shake flask method)
  • OECD 117 (Partition coefficient (n-octanol/water): High Performance Liquid Chromatography (HPLC) method)
  • OECD 123 (Partition coefficient (n-octanol/water): Slow-stirring method
Domain:
  • organic chemicals with H, C, N, O, S (and some halogenated compounds)
  • log KOW between 0 and 10 and possibly higher
Methodology:
  • Core-Centred Substitution Approach
  • from high quality water solubility and ecotoxicity data provided by the client (Holistic Approach)
Accuracy:

As accurate as an OECD 107 study
(uncertainty measure on develoment - expected summer 2019)

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WATER SOLUBILITY

iSafeRat® SOL study can test the water solubility (in mg/L, at 25°C) of a substance

Study/studies replaced and value reported:
  • OECD 105 (Water solubility: Shake flask method)
  • modified OECD 105 (Water solubility: slow stirring method)
Domain:
  • organic chemicals with H, C, N, O, S (and some halogenated compounds)
  • water solubility between 1 mol/L and 0.01 µmol/L and possibly lower
Methodology:
  • simple linear regression between Water Solubility and log KOW
  • from high quality ecotoxicity data provided by the client (Holistic Approach)
Accuracy:

As accurate as a modified OECD 105 slow stirring study (Thomas & Burosse, 2012, see downloads)
95%-Confidence Intervals
 

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Vapour pressure

iSafeRat® VAP study can test the vapour pressure (in Pa, at 25°C) of a substance
(alternative units available on request)

Study/studies replaced and value reported:
  • OECD 104 (Vapour Pressure)
Domain:
  • organic chemicals with H, C, N, O, S (and some halogenated compounds)
  • vapour pressure between 10-2 Pa to 105 Pa
Methodology:
  • simple linear regression between Vapour Pressure and Boiling Point
Accuracy:

As accurate as an OECD 104 study
95%-Confidence Intervals

 

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Acute Fish toxicity

iSafeRat® fishLC50 study can test 96h-acute toxicity on fish (in mg/L) of a substance

Study/studies replaced and value reported:
  • OECD 203 (Fish Acute Toxicity Test)
  • OECD 236 (Fish Embryo Acute Toxicity (FET) Test)
Domain:

Currently, the ecotoxicity module of the iSafeRat® HA-QSAR models can reliably predict the acute toxicity to fish for chemicals with the following mechanisms of action of toxicity (MechoA):

  • non-polar narcosis (MechoA 1.1)
  • polar narcosis of alkyl-/alkoxy-phenols (MechoA 1.2)
  • polar narcosis of aliphatic amines (MechoA 1.2 & 5.2)
  • mono-/poly-esters whose hydrolysis products are narcotics (MechoA 2.1)
  • hard electrophile reactivity (MechoA 3.1)
  • RedOx cycling of primary thiols (MechoA 4.4)
  • proton release of carboxylic acids (MechoA 5.2)

with log KOW between 0 and ca. 5 (and possibly higher), i.e. the point at which acute toxicity is no longer found below the limit of solubility.

Methodology:
  • simple linear regression between subcooled liquid water solubility and toxicity (Mackay et al., 2009; Thomas et al., 2015)
Accuracy:

As accurate as an OECD 203 study (in terms of finding true toxicity)
95%-Confidence Intervals

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Acute daphnid toxicity

iSafeRat® daphEC50 study can determine 48h-acute toxicity to daphnids (in mg/L) based on mobility for a substance

Study/studies replaced and value reported:
  • OECD 202 (Daphnia sp., Acute Immobilisation Test)
Domain:

Currently, the ecotoxicity module of the iSafeRat® HA-QSAR models can reliably predict the acute toxicity to daphnids for chemicals with the following mechanisms of action of toxicity (MechoA):

  • non-polar narcosis (MechoA 1.1)
  • polar narcosis of alkyl-/alkoxy-phenols (MechoA 1.2)
  • polar narcosis of aliphatic amines (MechoA 1.2 & 5.2)
  • cationic narcosis of quaternary ammoniums (MechoA 1.3)
  • mono-/poly-esters whose hydrolysis products are narcotics (MechoA 2.1)
  • hard electrophile reactivity (MechoA 3.1)
  • RedOx cycling of primary thiols (MechoA 4.4)
  • proton release of carboxylic acids (MechoA 5.2)

 

with log KOW between 0 and ca. 5 (and possibly higher), i.e. the point at which acute toxicity is no longer found below the limit of solubility.

Methodology:
  • simple linear regression between subcooled liquid solubility and toxicity (Mackay et al. 2009, Thomas et al. 2015)
Accuracy:

As accurate as an OECD 202 study (in terms of finding true toxicity)
95%-Confidence Intervals

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Algae toxicity

iSafeRat® algEC50 and iSafeRat® algNOEC studies can test 72h-toxicity (as inhibition of growth) on algae (in mg/L) of a substance

Study/studies replaced and value reported:
  • OECD 201 (Freshwater Alga and Cyanobacteria, Growth Inhibition Test)
Domain:

Currently, the ecotoxicity module of the iSafeRat® HA-QSAR models can reliably predict the toxicity to algae for chemicals with the following mechanisms of action of toxicity (MechoA):

  • non-polar narcosis (MechoA 1.1)
  • polar narcosis of alkyl-/alkoxy-phenols (MechoA 1.2)
  • polar narcosis of aliphatic amines (MechoA 1.2 & 5.2)
  • cationic narcosis of quaternary ammoniums (MechoA 1.3)
  • mono-/poly-esters whose hydrolysis products are narcotics (MechoA 2.1)
  • hard electrophile reactivity (MechoA 3.1)
  • RedOx cycling of primary thiols (MechoA 4.4)
  • proton release of carboxylic acids (MechoA 5.2)

with log KOW between 0 and ca. 5 (and possibly higher), i.e. the point at which toxicity is no longer found below the limit of solubility.

Note: iSafeRat® algNOEC is only available for compounds with MechoA 1.1 and 2.1

Methodology:
  • simple linear regression with subcooled liquid water solubility (Mackay et al. 2009, Thomas et al. 2015)
Accuracy:

As accurate as an OECD 201 study (in terms of finding true toxicity)
95%-Confidence Intervals

Note: In certain studies on algae the test substance may be lost due to metabolisation or adsorption by the algal cells. The iSafeRat® value will equate to the ErC50 (or NOEC) value obtained in a study where the substance was maintained over the whole study whether or not this can be achieved experimentally.

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CHRONIC FISH TOXICITY

iSafeRat® fishEC10 study can test 32d-chronic toxicity on fish (in mg/L) of a substance

Study/studies replaced and value reported:
  • OECD 210 (Fish, Early-life Stage Toxicity Test)
Domain:

Currently, the ecotoxicity module of the iSafeRat® HA-QSAR models can reliably predict the chronic toxicity to fish for chemicals with the following mechanisms of action of toxicity (MechoA):

  • non-polar narcosis (MechoA 1.1)
  • mono-/poly-esters whose hydrolysis products are narcotics (MechoA 2.1)

 

with log KOW between 0 and ca. 5.5 (and possibly higher), i.e. the point at which toxicity is no longer found below the limit of solubility.

Methodology:
  • simple linear regression with subcooled liquid water solubility (Mackay et al., 2009; Thomas et al., 2015)
Accuracy:

As accurate as an OECD 210 study (in terms of finding true toxicity)
95%-Confidence Intervals

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CHRONIC DAPHNID TOXICITY

iSafeRat® daphEC10 study can test 21d-chronic toxicity to daphnids (in mg/L) of a substance

Note: The iSafeRat® daphEC10 study will provide a calculated EC10 value (QSAR based on reproduction effects further to a 21-day study on daphnids using measured concentrations).

Study/studies replaced and value reported:
  • OECD 211 (Daphnia magna Reproduction Test)
Domain:

Currently, the ecotoxicity module of the iSafeRat® HA-QSAR models can reliably predict the chronic toxicity to daphnids for chemicals with the following mechanisms of action of toxicity (MechoA):

  • non-polar narcosis (MechoA 1.1)
  • mono-/poly-esters whose hydrolysis products are narcotics (MechoA 2.1)

 

with log KOW between 0 and ca. 6 (and possibly higher), i.e. the point at which toxicity is no longer found below the limit of solubility.

Methodology:
  • simple linear regression with subcooled liquid water solubility (Mackay et al. 2009, Thomas et al. 2015)
Accuracy:

As accurate as an OECD 211 study (in terms of finding true toxicity)
95%-Confidence Intervals

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Aquatic toxicity for mixtures

As opposed to the other High Accuracy-QSAR models this is a multistep calculation method requiring knowledge of the toxicity properties of each constituent. These can initially be calculated using one of the above ecotoxicity acute modules. Currently KREATiS can accurately predict mixture toxicity (e.g. Natural Complex Substances) for up to 29 constituents. Even if your mixture contains more, it may be possible to get a high quality prediction based on the major constituents and those expected to have the highest toxicity.

iSafeRat® fishLL50 WAF, daphEL50 WAF or algErL50 WAF study can test the acute toxicity on fish, daphnid or agae (in mg/L) of the Water Accommodated Fraction (WAF) of a substance (expressed as the lethal or effective loading rate, L/EL50, in mg/L)

Note. The calculation method is also available to get the chronic result (based on the loading rate once again).

Study/studies replaced and value reported:
  • OECD 203 (Fish Acute Toxicity Test)
  • OECD 210 (Fish, Early-life Stage Toxicity Test)
  • OECD 236 (Fish Embryo Acute Toxicity (FET) Test)
  • OECD 202 (Daphnia sp., Acute Immobilisation Test)
  • OECD 211 (Daphnia magna Reproduction Test)
  • OECD 201 (Freshwater Alga and Cyanobacteria, Growth Inhibition Test)

using WAF method (following OECD Guidance No. 23 Guidance on Aquatic testing of difficult substances and mixtures)

Domain:
  • mixture consituents should share the same Mechanism of Action (MechoA), ideally MechoA 1.1 (non-polar narcotics)
  • with log KOW between 0 and ca. 5 (and possibly higher), i.e. the point at which toxicity is no longer found below the limit of solubility
Methodology:

The toxicity of mixtuures to aquatic organisms was determined using a calculation method based on toxic additivity principle. That means the toxic parts of each constituent are added up. Therefore the constituents considered within the mixture should act with a similar MechoA. To maximise accuracy of the prediction, the concentration of each constituent in the mixture should be known and is used as inputs into the model.

  1. First a thermodynamic approach is used to calculate the influence of each constituent on the solubility of the others allowing the concentration of each constituent within the mixture to be determined (i.e. providing the “loading rate”).
  2. In the second step, the non-bioavailable fraction is removed to determine the true concentration of each constituent exerting toxicity.
  3. Then, the bioavailable concentrations of each constituent is converted into chemical activity prior to be summed.
  4. Finally, the loading rate is adjusted until the value of the sum of activities of the bioavailable fractions is equal to the fraction-weighted average of toxic activity of each constituent. This can be seen as a mechanistic description of the process which occurs in an experimental WAF study.

This method has been validated internally on a dozen of Natural Complex Substances for acute exposure with non-polar narcosis constituents. The methodology will soon be available in literature (Bicherel and Thomas, in prep).

Accuracy:

As accurate as a WAF experimental study following the specific guideline
(no confidence limits available)

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TOXICITY TO MICROORGANISMS

iSafeRat® asritEC50 study can test the toxicity to microorganisms of activated sludge (as EC50) of a substance

Study/studies replaced and value reported:
  • OECD 209 (Activated Sludge, Respiration Inhibition Test (Carbon and Ammonium Oxidation))
Domain:

Currently, the ecotoxicity module of the iSafeRat® HA-QSAR models can reliably predict the toxicity to microorganisms for chemicals with the following mechanisms of action of toxicity (MechoA):

  • non-polar narcosis (MechoA 1.1)
  • mono-/poly-esters whose hydrolysis products are narcotics (MechoA 2.1)

with log KOW between 0 and ca. 3 (and possibly higher), i.e. the point at which toxicity is no longer found below the limit of solubility

Methodology:
  • simple linear regression with subcooled liquid water solubility (Mackay et al., 2009; Thomas et al., 2015)
Accuracy:

As accurate as an OECD 209 study (in terms of finding true toxicity)
95%-Confidence Intervals

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SKIN IRRITATION

iSafeRat® iSafeRabbit Skin study can predict the irritant potential to the skin of a substance

Study/studies replaced and value reported:
  • OECD 404 (Acute Dermal Irritation/Corrosion)
Domain:
  • various organic chemicals
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EYE IRRITATION

iSafeRat® iSafeRabbit Eye study can predict the irritant potential to the eyes of a substance

Study/studies replaced and value reported:
  • OECD 405 (Acute Eye Irritation/Corrosion)
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SKIN SENSITISATION

iSafeRat® iSafeRabbit Sensitisation study can predict the skin sensitisation of a substance.

NOTE: This model is still under development. However a pilot version is already available on request.

Study/studies replaced and value reported:
  • OECD 406 (Skin Sensitisation)
  • OECD 429 (Skin Sensitisation: Local Lymph Node Assay)
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ENDPOINTS:

  • Physico-chemical properties
  • Environmental properties
  • Ecotoxicity endpoints
  • Human Health Endpoints
  • Endocrine Disruption potential

Physico-chemical properties

- Boiling Point (summer 2020)

- Flash Point (summer 2020)

- Melting Point

- Relative density

- Surface tension

- Flammability

- Explosive Properties

- Self-ignition temperature

- Oxidising Properties

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Environmental properties

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Ecotoxicity endpoints

KREATiS is currently working on development of new in silico models to predict these following endpoints in ecotoxicology :

- update of the acute and chonic toxicity to fish, daphnids and algae for non-polar narcotic compounds (i.e. MechoA 1.1) taking into account nitro compounds (expected end 2019)

- update of the acute and chonic toxicity to fish, daphnids and algae for polar narcotic compounds (i.e. MechoA 1.2) taking into account anilines (expected 2020)

- update of the acute and chronic toxicity to fish, daphnids and algae for reactive compounds (i.e. MechoA 3.1 and 3.2) like aldehydes, epoxides and acrylates (expected summer 2019)

- new model of the chronic toxicity to fish, daphnids and algae for acides/bases (MechoA 5.2) (expected 2020)

- updates on MechoA dedicated to pesticides (expected 2020)

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Human Health Endpoints

KREATiS is currently working on development of new in silico models to predict these following endpoints in toxicology:

- Acute Inhalation Toxicity

- Respiratory Irritation

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Endocrine Disruption potential

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Besides our intention to cover the majority of REACH annexes VII and VIII endpoints, KREATiS is currently also offering tailor-made in-silico services to meet our clients’ requirements. Whether you need a tool for screening purposes, submitting high accuracy QSAR predictions to the regulatory authorities or generating QSAR reporting formats for REACH dossiers, our dedicated team is here to help.

Just as our existing HA-QSARs have been developed and validated (following the regulatory guidelines), each of our tailored models are treated with the same level of attention to detail, data verification and statistical model validation. Depending on your request, we can also prepare a validation report to justify the robustness and, if possible, a mechanistic interpretation for your models.

Get in touch with the KREATiS team today to benefit from our tailored services. Let us know your requirements and one of our team members will contact you to discuss it further.

At KREATiS we believe in our models, and together we can find accurate answers to your questions without resorting to unnecessary experimentation.

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Knowledge & research in environment and toxicology in silico