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 K_OW
• 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
 

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
 

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 K_OW 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

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 K_OW 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

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 K_OW 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.

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 K_OW 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

CHRONIC DAPHNID TOXICITY

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 K_OW 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

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 K_OW 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)

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 K_OW 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

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

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)

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)

Endocrine Disruption potential

iSafeRat®

- 2D SARs for EATS and positive and negative alerts

- Off-the-shelf models

Environmental properties

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 (October 2020)

- 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 (October 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 (October 2020)

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

- updates on MechoA dedicated to pesticides (October 2020)

Human Health Endpoints

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

- Acute Inhalation Toxicity

- Sensitisation MIE key event 1, with or without metabolic activation

- Dermal absorption

Endocrine Disruption Potential

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

- 3D modelling (docking) – expected Q4 2020

- Molecular Dynamics – expected early 2021