Cyclohexanepropanol, 2,2,3,6-tetramethyl-.alpha.-propyl-

Toxicity to aquatic algae and cyanobacteria

Link to relevant study record(s)

Reference

Endpoint:

toxicity to aquatic algae and cyanobacteria

Type of information:

(Q)SAR

Adequacy of study:

key study

Study period:

2020

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

results derived from a valid (Q)SAR model and falling into its applicability domain, with adequate and reliable documentation / justification

Justification for type of information:

1. SOFTWARE
Software Package: iSafeRat® HA-QSAR toolbox v2.5,
Contact KREATIS
Dr. Paul Thomas
KREATiS SAS
23, rue du Creuzat
38080 L’ISLE D’ABEAU
FRANCE

2. MODEL (incl. version number)
a. iSafeRat® HA-QSAR toolbox v2.5 – Algal growth inhibition (72-hour ErC50) ; including the following specific sub-models:
(i) non-polar narcosis (MechoA 1.1)
01 February 2014 (model development); 13 March 2020 (current model version)

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
See attached: ‘Determination of toxicity to algae (72-hour ErL50) of Reaction mass of (3RS)-1-[(1RS,3SR,6SR)-2,2,3,6-tetramethylcyclohexyl]hexan-3-ol and (3RS)-1-[(1SR,3RS,6RS)-2,2,3,6-tetramethylcyclohexyl]hexan-3-ol tested as the Water Accommodated Fraction (WAF)’ version 1.0; dated August 2020.

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
Full details of the method are provided in the attached QMRF named 'iSafeRat® HA-QSAR based on a holistic approach for predicting physicochemical and ecotoxicological endpoints’ version 1.9 ; 13 March 2020

5. APPLICABILITY DOMAIN
See ‘any other information on results incl. tables’.
See attached: ‘Determination of toxicity to algae (72-hour ErL50) of Reaction mass of (3RS)-1-[(1RS,3SR,6SR)-2,2,3,6-tetramethylcyclohexyl]hexan-3-ol and (3RS)-1-[(1SR,3RS,6RS)-2,2,3,6-tetramethylcyclohexyl]hexan-3-ol tested as the Water Accommodated Fraction (WAF)’ version 1.0; dated August 2020.

6. ADEQUACY OF THE RESULT
1) QSAR model is scientifically valid. 2) The substance falls within the (general) applicability domain of the QSAR model and/or with interpretation by expert judgement. 3) The prediction is fit for regulatory purpose. The prediction is adequate for the Classification and Labelling or risk assessment of the substance as indicated in REACH Regulation (EC) 1907/2006: Annex XI Section 1.3. Specifically when combined with further information such as physico-chemistry and environmental fate testing and modelling.

Reason / purpose for cross-reference:

reference to other study

Guideline:

other: REACH Guidance on QSARs R.6, May/July 2008

Principles of method if other than guideline:

1. a. iSafeRat® HA-QSAR toolbox v2.5 – Algal growth inhibition 72h ErC50 ; including the following specific sub-models:
(i) non-polar narcosis (MechoA 1.1)
2. Aquatic Toxicity Assessment using the Additivity Approach or based on a constituent and worst-case approach
3. Assessment of degradability and/or n-octanol/water partitioning behaviour and/or bioaccumulation for the purpose of Classification and Labelling

Specific details on test material used for the study:

Detailed information on the 'test material identity' is provided in the attached QSAR Prediction Reporting Format (QPRF) document including information on individual constituents.

Duration:

72 h

Dose descriptor:

EL50

Effect conc.:

> 0.485 mg/L

Nominal / measured:

meas. (not specified)

Conc. based on:

test mat.

Basis for effect:

growth rate

Remarks on result:

other: 95% Confidence Interval: - mg/L ; Water Solubility of the test item was measured to be 0.485 mg/L or -5.695 in log10 (mol/L) at 20°C (reference study: EU Method A.6, 2020).

1. Defined Endpoint:

QMRF 3. Ecotoxic effects

QMRF 3.2. Short-term toxicity to algae (inhibition of the exponential growth rate)

Reference to type of model used and description of results:

1. a. iSafeRat® HA-QSAR toolbox v2.5 – Algal growth inhibition 72h ErC50 ; including the following specific sub-models:

(i) non-polar narcosis (MechoA 1.1)

01 February 2014 (model development); 13 March 2020 (current model version)

 

2. Description of results and assessment of reliability of the prediction:

See attachment QPRF: ‘Determination of toxicity to algae (72-hour ErL50) of Reaction mass of (3RS)-1-[(1RS,3SR,6SR)-2,2,3,6-tetramethylcyclohexyl]hexan-3-ol and (3RS)-1-[(1SR,3RS,6RS)-2,2,3,6-tetramethylcyclohexyl]hexan-3-ol tested as the Water Accommodated Fraction (WAF)’ version 1.0; dated August 2020.

Reaction mass of (3RS)-1-[(1RS,3SR,6SR)-2,2,3,6-tetramethylcyclohexyl]hexan-3-ol and (3RS)-1-[(1SR,3RS,6RS)-2,2,3,6-tetramethylcyclohexyl] hexan-3-ol:

Principle of calculation employed for the substance: the additivity principle based on constituents acting with the same MechoA

Step 1 : determination of the water solubility of each individual constituent

Step 2 : determination of the analytically measurable aqueous phase (AMAP)

Step 3 : determination of the bioavailable toxic fraction of each constituent

Step 4: calculation of the global activity of the WAF and determination of the toxic loading rate

Results:

72-h ErL50 = > water solubility limit [i.e. > 0.485 mg/L]

Water Solubility of the test item was measured to be 0.485 mg/L or -5.695 in log10 (mol/L) at 20°C (cited reference study: EU Method A.6, 2020).

i.e. the test item 72-h ErL50 is expected to be greater than the limit of solubility (according to the WAF method) of the substance

 

NOTE: Stereoisomerism is not taken into account by the calculation. By default, the reported prediction is applicable for all the stereoisomeric forms of this substance. i.e. 1-[2,2,3,6-tetramethylcyclohexyl]hexan-3-ol is considered equivalent to : all constituent possible stereoisomers including e.g. Reaction mass of (3RS)-1-[(1RS,3SR,6SR)-2,2,3,6-tetramethylcyclohexyl]hexan-3-ol and (3RS)-1-[(1SR,3RS,6RS)-2,2,3,6-tetramethylcyclohexyl] hexan-3-ol; this and stereoisomer predictions are fully documented in the QSAR Prediction Reporting Format (QPRF) documentation.

 

Inputs Used for Test Item: All modelling was based on input of SMILES notation for each constituent of the test item and the process relied on modelled or measured values for Kow and/or water solubility to define each constituent prediction. This approach is in line with the attached QMRF named ‘iSafeRat® HA-QSAR based on a holistic approach for predicting physicochemical and ecotoxicological endpoints’ version 1.9 ; 13 March 2020, and ECHA Guidance on Information Requirements and Chemical Safety Assessment Chapter R7.b for hazard assessment of substances and complex mixtures.

 

For the purpose of concluding on classification and labelling for this substance either (i) the additivity formula from Annex I, Section 4.1.3.5.2 of CLP Regulation (EC) 1272/2008 is applied or (ii) a worst case application of 72-h ErC50 or ErL50 effect levels is applied to known components of the substance. As applicable.

Substance rapidly degradable: No.

Log Kow: > 4.0 as surrogate to expected : BCF > 500 L/kg wet-wt.

Principle of calculation employed for the substance: the additivity principle based on constituents acting with the same MechoA

Step 1 : determination of the water solubility of each individual constituent

Step 2 : determination of the analytically measurable aqueous phase (AMAP)

Step 3 : determination of the bioavailable toxic fraction of each constituent

Step 4: calculation of the global activity of the WAF and determination of the toxic loading rate

 

Assessment of the substance within the applicability domain as documented within the corresponding QMRF named ‘iSafeRat® HA-QSAR based on a holistic approach for predicting physicochemical and ecotoxicological endpoints’ version 1.9 ; 13 March 2020 – section 5; indicates the substance:

(i) Falls within the Log Kow and Water Solubilities intermediate domain : (e.g. outside the descriptor regression domain log WSOL (mol/L) -4.38 to 0.49 but is within Subcooled Liquid Water Solubility of -9.34 to -4.38 in log10 (mol/L) intermediate descriptor domain, where results cannot be accurately measured). The result is therefore is considered an extrapolation. The result can be considered reliable with limitations placed on the estimate and additional assessment based on expert judgment. More information is provided below.

Comments: The Subcooled Liquid Water Solubility value given as the input to the iSafeRat® alg ErC50 model falls within the intermediate domain of the model between a Subcooled Liquid Water Solubility of -9.34 to -4.38 in log10 (mol/L) where baseline toxicity cannot be experimentally measured accurately. For confirmation, a statistical k-NN approach (k = 3) is performed on the data of substances found to be in the intermediate domain of the model. The toxicity of the three closest neighbours based on the solubility are considered. Based on these data, either the toxicity of the test item is expected to be greater than the limit of solubility, or the toxicity is estimated by the geometric mean between the toxicity value predicted using the regression line and the solubility cut-off line (with the confidence intervals being placed at these limits, as applicable). According to this analysis, the toxicity of the test item is estimated as greater than the water solubility limit.

(ii) Falls within the structural fragment domain

(iii) Falls within the mechanistic domain of MechoA 1.1

 

3. Uncertainty of the prediction and mechanistic domain:

An external validation set is available for the chemical class used in this prediction (Algae 72h-ErC50) however is not publicly available. Interested parties are invited to contact the model author. The QMRF has been peer reviewed by Joint Research Centre, ISPRA, Italy. The related QMRF (Algae 72h-NOEC) was submitted to the Joint Research Centre, ISPRA, Italy QMRF inventory (citation available in the attached document).

Full details on the training set, internal and external validations, as applicable are included in the attached QMRF named ‘iSafeRat® HA-QSAR based on a holistic approach for predicting physicochemical and ecotoxicological endpoints’ version 1.9 ; 13 March 2020.

 

Uncertainty in the prediction relates to:

Statistical characteristics are provided (i) for the prediction: in the attached QPRF and (ii) for the model: in the attached QMRF, respectively.

Validity criteria fulfilled:

yes

Conclusions:

The results are adequate for the for the regulatory purpose.

Executive summary:

iSafeRat® HA-QSAR toolbox v2.5 – Algal growth inhibition 72h ErC50 ; including the following specific sub-models:

(i) non-polar narcosis (MechoA 1.1)

Endpoint values: Algae growth inhibition

Principle of calculation employed for the substance: the additivity principle based on constituents acting with the same MechoA

Step 1 : determination of the water solubility of each individual constituent

Step 2 : determination of the analytically measurable aqueous phase (AMAP)

Step 3 : determination of the bioavailable toxic fraction of each constituent

Step 4: calculation of the global activity of the WAF and determination of the toxic loading rate

Results:

72-h ErL50 = > water solubility limit [i.e. > 0.485 mg/L]

Water Solubility of the test item was measured to be 0.485 mg/L or -5.695 in log10 (mol/L) at 20°C (cited reference study: EU Method A.6, 2020).

i.e. the test item 72-h ErL50 is expected to be greater than the limit of solubility (according to the WAF method) of the substance

 

Adequacy of the QSAR:

1) QSAR model is scientifically valid. 2) The substance falls within the (general) applicability domain of the QSAR model and/or with interpretation by expert judgement. 3) The prediction is fit for regulatory purpose.

The prediction is adequate for the Classification and Labelling or risk assessment of the substance as indicated in REACH Regulation (EC) 1907/2006: Annex XI Section 1.3. The assessment indicates that the prediction is suitable for the regulatory conclusion in accordance with the tonnage driven information requirements. Specifically when combined with further information such as physico-chemistry and environmental fate testing and modelling.

Description of key information

QSAR: 72h-ErL50 (aquatic algae) = > water solubility limit [i.e. > 0.485 mg/L], iSafeRat® HA-QSAR toolbox v2.5, KREATIS SAS, 2020

Additional information

Key data : QSAR, iSafeRat® HA-QSAR toolbox v2.5, KREATIS SAS, 2020

iSafeRat® HA-QSAR toolbox v2.5 – Algal growth inhibition 72h ErC50 ; including the following specific sub-models:

(i) non-polar narcosis (MechoA 1.1)

Endpoint values: Algae growth inhibition

72-hr ErL50: > water solubility limit [i.e. > 0.485 mg/L]

 

Adequacy of the QSAR:

1) QSAR model is scientifically valid. 2) The substance falls within the (general) applicability domain of the QSAR model and/or with interpretation by expert judgement. 3) The prediction is fit for regulatory purpose.

The prediction is adequate for the Classification and Labelling or risk assessment of the substance as indicated in REACH Regulation (EC) 1907/2006: Annex XI Section 1.3. The assessment indicates that the prediction is suitable for the regulatory conclusion in accordance with the tonnage driven information requirements. Specifically when combined with further information such as physico-chemistry and environmental fate testing and modelling.

 

References for further information:

1. QMRF Title: ‘iSafeRat® HA-QSAR based on a holistic approach for predicting physicochemical and ecotoxicological endpoints’ version 1.9 ; 13 March 2020

2. QPRF Title: ‘Determination of toxicity to algae (72-hour ErL50) of Reaction mass of (3RS)-1-[(1RS,3SR,6SR)-2,2,3,6-tetramethylcyclohexyl]hexan-3-ol and (3RS)-1-[(1SR,3RS,6RS)-2,2,3,6-tetramethylcyclohexyl]hexan-3-ol tested as the Water Accommodated Fraction (WAF)’ version 1.0; dated August 2020.