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
  • Acute toxicity for fish, daphnids or algae 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: non-ionic linear/cyclic, aliphatic/olefinic/aromatic, oxygenated (or not) compounds and thiols (except for epoxydes, peroxydes and polyalcohols)
  • log KOW between 0 and 10 and possibly higher
Methodology:
  • Core-Centred Contribution Fragment Approach (see tutorial)
  • GSE (see tutorial) from high quality solubility study result provided by the client
Accuracy:

As accurate as an OECD 107 study
(confidence limits on develoment)

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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: non-ionic linear/cyclic, aliphatic/olefinic/aromatic, oxygenated/chlorinated (or not) compounds and thiols (except for epoxydes, peroxydes and polyalcohols)
  • water solubility between 1 mol/L and 0.01 µmol/L and possibly lower
Methodology:
  • Solubility-KOW Equation (SKE)
  • Reverse iSafeRat® ecotox (determined from acute toxicity data on fish, daphnid or algae) (see tutorial)
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: linear/cyclic, aliphatic, mono/poly-unsaturated, aromatic, oxygenated or not compounds (except for aldehydes, epoxydes and peroxydes)
  • vapour pressure between 10-2 Pa to 105 Pa
Methodology:
  • Vapour Pressure-Boiling Point Equation (VPBP/E)
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:
  • non-polar narcotics (MOA 1 according to Verhaar et al., 2000): this mode of action covers non-ionic organic chemicals (e.g. alkanes, alcohols, ketones, ethers, macrocyclics...)
  • alkyl- and alkoxy-phenols as polar narcotics (MOA 2 according to Verhaar et al., 2000)
  • mono- and poly-esters (e.g. acetates, lactates, lactones, methacrylates, phthalates)
  • aldehydes
  • epoxydes
  • primary thiols
  • carboxylic acids (on development)

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:
  • regression with sub-cooled liquid solubility (Mackay et al., 2009; Thomas et al., 2013) (for tutorial click here)
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 test 48h-acute toxicity on daphnid (in mg/L) of a substance

Study/studies replaced and value reported:
  • OECD 202 (Daphnia sp., Acute Immobilisation Test)
Domain:
  • non-polar narcotics (MOA 1 according to Verhaar et al., 2000): this mode of action covers non-ionic organic chemicals (e.g. alkanes, alcohols, ketones, ethers, macrocyclics...)
  • alkyl- and alkoxy-phenols as polar narcotics (MOA 2 according to Verhaar et al., 2000)
  • mono- and poly-esters (e.g. acetates, lactates, lactones, methacrylates, phthalates)
  • aldehydes
  • epoxydes
  • primary thiols
  • carboxylic acids (on development)

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:
  • regression with sub-cooled liquid solubility (Mackay et al. 2009, Thomas et al. 2013) (see tutorial).
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:
  • non-polar narcotics (MOA 1 according to Verhaar et al., 2000): this mode of action covers non-ionic organic chemicals (e.g. alkanes, alcohols, ketones, ethers, macrocyclics...)
  • alkyl- and alkoxy-phenols as polar narcotics (MOA 2 according to Verhaar et al., 2000)
  • mono- and poly-esters (e.g. acetates, lactates, lactones, methacrylates, phthalates)
  • aldehydes
  • epoxydes
  • primary thiols
  • carboxylic acids (on development)

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.

Note: iSafeRat® algNOEC is only available for non-polar narcotics and esters.

Methodology:
  • regression with sub-cooled liquid solubility (Mackay et al. 2009, Thomas et al. 2013) (see tutorial)
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 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® fishNOEC study can test 28d-chronic toxicity on fish (in mg/L) of a substance

Note: The iSafeRat® fishNOEC study will provide a calculated NOEC value (QSAR based on growth effects further to a 28-day study on fish using measured concentrations).

Study/studies replaced and value reported:
  • OECD 210 (Fish, Early-life Stage Toxicity Test)
Domain:
  • non-polar narcotics (MOA 1 according to Verhaar et al., 2000): this mode of action covers non-ionic organic chemicals (e.g. alkanes, alcohols, ketones, ethers, macrocyclics...)

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

Methodology:
  • regression with sub-cooled liquid solubility (Mackay et al., 2009; Thomas et al., 2013) (for tutorial click here)
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® daphNOEC study can test 21d-chronic toxicity to daphnids (in mg/L) of a substance

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

Study/studies replaced and value reported:
  • OECD 211 (Daphnia magna Reproduction Test)
Domain:
  • non-polar narcotics (MOA 1 according to Verhaar et al., 2000): this mode of action covers non-ionic organic chemicals (e.g. alkanes, alcohols, ketones, ethers, macrocyclics...)
  • mono- and poly-esters (e.g. acetates, lactates, lactones, methacrylates, phthalates)

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

Methodology:
  • regression with sub-cooled liquid solubility (Mackay et al. 2009, Thomas et al. 2013) (see tutorial).
Accuracy:

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

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Acute toxicity for fish, daphnids or algae 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 15 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® fishEC50 WAF, daphEC50 WAF or algEC50 WAF study can test acute toxicity on fish, daphnid or agae (in mg/L) of Water Accommodated Fraction (WAF) of a substance (expressed as the lethal loading rate, LL50, in mg/L)

Study/studies replaced and value reported:
  • OECD 203 (Fish Acute Toxicity Test)
  • OECD 236 (Fish Embryo Acute Toxicity (FET) Test)
  • OECD 202 (Daphnia sp., Acute Immobilisation 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 have to falls within non-polar narcotics compounds (MOA 1 according to Verhaar et al., 2000): this mode of action covers non-ionic organic chemicals (e.g. alkanes, alcohols, ketones, ethers, macrocyclics...)
  • 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:
  • regression with sub-cooled liquid solubility (Mackay et al. 2009, Thomas et al. 2013)
  • phase equilibrium thermodynamic concentration reprocessing (Berlusconi et al. 2013)
  • removal of non-bioavailable mixture phase (see video tutorial)
Accuracy:

As accurate as a WAF experimental study following the specific guideline
(confidence limits on develoment
)

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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:
  • non-polar narcotics (MOA 1 according to Verhaar et al., 2000): this mode of action covers non-ionic organic chemicals (e.g. alkanes, alcohols, ketones, aldehydes, macrocyclics...)

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

Methodology:
  • regression with sub-cooled liquid solubility (Mackay et al., 2009; Thomas et al., 2013) (for tutorial click here)
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

Physico-chemical properties

  • Melting Point
  • Boiling Point
  • Relative density
  • Surface tension
  • Flash Point
  • Flammability
  • Explosive Properties
  • Self-ignition temperature
  • OxidisingProperties
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Environmental properties

Adsorption of non-polar compounds

In complement with an in vitro study:

  • Quantified Metabolic profile
  • BCF of parent substance
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Ecotoxicity endpoints

KREATiS is currently working on development of new in silico models to predict these following endpoints in ecotoxicology to facilitate registrations under REACH 2018:

- update of the Activated sludge respiration inhibition for esters (expected early 2017)

- update of the acute toxicity to fish, daphnids and algae for polar narcotic compounds (i.e. MOA 2 according to Verhaar et al., 2000) like nitrogenous and ionic compounds (expected mid-2017)

- update of the chronic toxicity to fish, daphnids and algae for polar narcotic compounds (i.e. MOA 2 according to Verhaar et al., 2000) like nitrogenous and ionic compounds (expected December 2017)

- update of the chronic toxicity to fish, daphnids and algae for reactive substances (acrylates, aldehydes, epoxydes, etc.) (expected December 2017)

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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 to facilitate registrations under REACH 2018:

- Acute Oral Toxicity (expected early 2018)

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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