2-(1-(3',3'-dimethyl-1'-cyclohexyl)ethoxy)-2-methyl propyl propanoate

Bioaccumulation: aquatic / sediment

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

bioaccumulation: aquatic / sediment

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

Study period:

Run on 2013-03

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

Remarks:

The bioconcentration factor (BCF) of the C6 isomers of the registered substance was evaluated with BCFBAF model v3.01 from EPI Suite v4.1, which fulfilled all OECD principles. The C6 isomer of the registered substance is within the domain of the BCFBAF model based on the molecular weight and fragments present in the BCFBAF database.

Justification for type of information:

1. SOFTWARE
EPISUITE v4.1

2. MODEL (incl. version number)
BCFBAF v3.01

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
C6 isomers of the registered substance: CC1(C)CCCC(C(OC(C)(C)COC(=O)(CC))C)C1
log Pow: 4.68 (experimental result)

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
See attached QMRF
- Defined endpoint: Bioconcentration Factor (BCF) and Bioaccumulation Factor (BAF).
- Unambiguous algorithm: BCFBAF v3.01 contains two methods for estimating BCFs. The first BCFBAF method is based on the original BCFWIN model and classifies a compound as either ionic or non-ionic. Ionic compounds include carboxylic acids, sulfonic acids and salts of sulfonic acids, and charged nitrogen compounds (nitrogen with a +5 valence such as quaternary ammonium compounds). All other compounds are classified as non-ionic. The second model for BCF estimation has been expanded to calculate both BCF as well as BAF for three general trophic levels of fish. This method is based on the multiple-linear regression-derived equation which is used by the BCFBAF program to estimate the kM Biotransformation Half-Life.
- Defined domain of applicability: The estimation domain for BCF is based on the number of instances given for each correction factor in any of the training set compounds, and the minimum and maximum values for molecular weight and log Kow.
- Appropriate measures of goodness-of-fit and robustness and predictivity: The following gives statistical information for the BCF training and validation datasets (includes ionic and non-ionic compounds). Number = 527 / r² = 0.833 / std deviation = 0.502 / avg deviation = 0.382. For the BCF validation dataset; Number = 158 / r² = 0.82 / std deviation = 0.59 / avg deviation = 0.46. Arnot-Gobas BCF and BAF statistics for the kM biotransformation half-life of the training dataset are; Number = 421 / r² = 0.821 / std deviation = 0.494 / avg deviation = 0.383. For the kM validation dataset; Number = 211 / r² = 0.734 / std deviation = 0.602 / avg deviation = 0.446.
- Mechanistic interpretation: no data

5. APPLICABILITY DOMAIN
See attached QPRF

Qualifier:

according to guideline

Guideline:

other: REACH guidance on QSARs R.6, May 2008

Deviations:

no

Principles of method if other than guideline:

See QMRF and QPRF in "Attached background material" and in "Any other information on materials and methods incl. tables" (the QMRF is only available for the former version of the QSAR model).

GLP compliance:

no

Specific details on test material used for the study:

- log Pow: 4.68 (experimental result)

Radiolabelling:

no

Details on sampling:

Not applicable

Details on preparation of test solutions, spiked fish food or sediment:

Not applicable

Details on test organisms:

Not applicable

Test type:

other: QSAR

Water / sediment media type:

not specified

Hardness:

Not applicable

Test temperature:

Not applicable

pH:

Not applicable

Dissolved oxygen:

Not applicable

TOC:

Not applicable

Salinity:

Not applicable

Details on test conditions:

Not applicable

Nominal and measured concentrations:

Not applicable

Reference substance (positive control):

no

Details on estimation of bioconcentration:

Not applicable

Key result

Type:

BCF

Value:

569 L/kg

Basis:

whole body w.w.

Remarks on result:

other: BCF model using log Kow value.

Key result

Type:

BCF

Value:

196 L/kg

Basis:

whole body w.w.

Remarks on result:

other: Arnot-Gobas Method, including a biotransformation rate estimates, lower trophic.

Details on kinetic parameters:

Not applicable

Metabolites:

Not applicable

Results with reference substance (positive control):

Not applicable

Details on results:

Arnot-Gobas Method: Based on the biodegradation potential of the test substance, it's more relevant to consider the result including biotransformation rate estimates instead of the result assuming a biotransformation rate of zero.

Reported statistics:

Not applicable

BCF model, for C6 isomer:

Log Kow (estimated) : 5.51

Log Kow (experimental): not available from database

Log Kow used by BCF estimates: 4.68 (user entered)

Equation Used to Make BCF estimate:

Log BCF = 0.6598 log Kow - 0.333 + Correction

Correction(s) value: no applicable correction factors

Estimated Log BCF = 2.755 (BCF = 568.7 L/kg wet-wt)

Arnot-Gobas BCF model (Whole body Primary Biotransformation Rate estimate for fish), for C6 isomer:

TYPE	NUM	LOG BIOTRANSFORMATION FRAGMENT DESCRIPTION	COEFF	VALUE
Frag Frag Frag Frag Frag Frag Frag Frag L Kow MolWt Const	1 2 1 6 2 1 4 1 * * *	Ester [-C(=O)-O-C] Carbon with 4 single bonds & no hydrogens Aliphatic ether [C-O-C] Methyl [-CH3] -CH2- [linear] -CH- [linear] -CH2- [cyclic] -CH- [cyclic] Log Kow = 4.68 (user-entered) Molecular Weight Parameter Equation Constant	-0.7605 -0.2984 -0.0232 0.2451 0.0242 -0.1912 0.0963 0.0126 0.3073	-0.7605 -0.5969 -0.0232 1.4706 0.0484 -0.1912 0.3850 0.0126 1.4384 -0.7294 -1.5058
RESULT RESULT NOTE		Log Bio Half-life (days) Bio Half-life (days) Bio Half-life Normalized to 10 g fish at 15°C		-0.4834 0.3286

Biotransformation rate constant: kM (rate constant) = 2.11 / day (10 gram fish).

Arnot-Gobas BCFBAF Methods (including biotransformation rate estimates):

Estimated Log BCF (upper trophic) = 2.132 (BCF = 135.5 L/Kg wet-wt).

Estimated Log BCF (mid trophic) = 2.257 (BCF = 180.6 L/Kg wet-wt).

Estimated Log BCF (lower trophic) = 2.293 (BCF = 196.2 L/Kg wet-wt).

Arnot-Gobas BCFBAF Methods (assuming a biotransformation rate of zero):

Estimated Log BCF (upper trophic) = 3.641 (BCF = 4379 L/Kg wet-wt).

Validity criteria fulfilled:

yes

Conclusions:

The BCF for C6 isomers of the registered substance is estimated to be 569 L/Kg wet-wt based on the log Kow value and 196 L/kg wet-wt based on Arnot-Gobas method (lower trophic, including biotransformation rate estimates).

Executive summary:

The bioconcentration factor (BCF) of the C6 isomers of the registered substance was evaluated with BCFBAF model v3.01 from EPI Suite v4.1, which fulfilled all OECD principles. The substance is within the domain of the BCFBAF model based on the molecular weight and fragments present in the BCFBAF database.

It's more relevant to consider the result obtain with Arnot-Gobas Method, including biotransformation rate estimates instead of the result obtain with Arnot-Gobas Method, assuming a biotransformation rate of zero. The BCF is estimated to be 569 L/Kg wet-wt based on the log Kow value and 196 L/kg wet-wt based on Arnot-Gobas method (lower trophic, including biotransformation rate estimates).

Reference 2

Endpoint:

bioaccumulation: aquatic / sediment

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

Study period:

Run on 2013-03

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

Remarks:

The bioconcentration factor (BCF) of the C7 isomer of the registered substance was evaluated with BCFBAF model v3.01 from EPI Suite v4.1, which fulfilled all OECD principles. The C7 isomer of the registered substance is within the domain of the BCFBAF model based on the molecular weight and fragments present in the BCFBAF database.

Justification for type of information:

1. SOFTWARE
EPISUITE v4.1

2. MODEL (incl. version number)
BCFBAF v3.01

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
C7 isomer of the registered substance: CCC(=O)OCC(C)(C)OC1CC(C)(C)CCCC1C
log Pow: 4.68 (experimental result)

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
See attached QMRF
- Defined endpoint: Bioconcentration Factor (BCF) and Bioaccumulation Factor (BAF).
- Unambiguous algorithm: BCFBAF v3.01 contains two methods for estimating BCFs. The first BCFBAF method is based on the original BCFWIN model and classifies a compound as either ionic or non-ionic. Ionic compounds include carboxylic acids, sulfonic acids and salts of sulfonic acids, and charged nitrogen compounds (nitrogen with a +5 valence such as quaternary ammonium compounds). All other compounds are classified as non-ionic. The second model for BCF estimation has been expanded to calculate both BCF as well as BAF for three general trophic levels of fish. This method is based on the multiple-linear regression-derived equation which is used by the BCFBAF program to estimate the kM Biotransformation Half-Life.
- Defined domain of applicability: The estimation domain for BCF is based on the number of instances given for each correction factor in any of the training set compounds, and the minimum and maximum values for molecular weight and log Kow.
- Appropriate measures of goodness-of-fit and robustness and predictivity: The following gives statistical information for the BCF training and validation datasets (includes ionic and non-ionic compounds). Number = 527 / r² = 0.833 / std deviation = 0.502 / avg deviation = 0.382. For the BCF validation dataset; Number = 158 / r² = 0.82 / std deviation = 0.59 / avg deviation = 0.46. Arnot-Gobas BCF and BAF statistics for the kM biotransformation half-life of the training dataset are; Number = 421 / r² = 0.821 / std deviation = 0.494 / avg deviation = 0.383. For the kM validation dataset; Number = 211 / r² = 0.734 / std deviation = 0.602 / avg deviation = 0.446.
- Mechanistic interpretation: no data

5. APPLICABILITY DOMAIN
See attached QPRF

Qualifier:

according to guideline

Guideline:

other: REACH guidance on QSARs R.6, May 2008

Deviations:

no

Principles of method if other than guideline:

See QMRF and QPRF in "Attached background material" and in "Any other information on materials and methods incl. tables" (the QMRF is only available for the former version of the QSAR model).

GLP compliance:

no

Specific details on test material used for the study:

- log Pow: 4.68 (experimental result)

Radiolabelling:

no

Details on sampling:

Not applicable

Details on preparation of test solutions, spiked fish food or sediment:

Not applicable

Details on test organisms:

Not applicable

Test type:

other: QSAR

Water / sediment media type:

not specified

Hardness:

Not applicable

Test temperature:

Not applicable

pH:

Not applicable

Dissolved oxygen:

Not applicable

TOC:

Not applicable

Salinity:

Not applicable

Details on test conditions:

Not applicable

Nominal and measured concentrations:

Not applicable

Reference substance (positive control):

no

Details on estimation of bioconcentration:

Not applicable

Key result

Type:

BCF

Value:

569 L/kg

Basis:

whole body w.w.

Remarks on result:

other: BCF model using log Kow value.

Key result

Type:

BCF

Value:

300 L/kg

Basis:

whole body w.w.

Remarks on result:

other: Arnot-Gobas Method, including a biotransformation rate estimates, lower trophic.

Details on kinetic parameters:

Not applicable

Metabolites:

Not applicable

Results with reference substance (positive control):

Not applicable

Details on results:

Arnot-Gobas Method: Based on the biodegradation potential of the test substance, it's more relevant to consider the result including biotransformation rate estimates instead of the result assuming a biotransformation rate of zero.

Reported statistics:

Not applicable

BCF model, for C7 isomer:

Log Kow (estimated) : 5.51

Log Kow (experimental): not available from database

Log Kow used by BCF estimates: 4.68 (user entered)

Equation Used to Make BCF estimate:

Log BCF = 0.6598 log Kow - 0.333 + Correction

Correction(s) value: no applicable correction factors

Estimated Log BCF = 2.755 (BCF = 568.7 L/kg wet-wt)

Arnot-Gobas BCF model (Whole body Primary Biotransformation Rate estimate for fish), for C7 isomer:

TYPE	NUM	LOG BIOTRANSFORMATION FRAGMENT DESCRIPTION	COEFF	VALUE
Frag Frag Frag Frag Frag Frag Frag L Kow MolWt Const	1 2 1 6 2 4 2 * * *	Ester [-C(=O)-O-C] Carbon with 4 single bonds & no hydrogens Aliphatic ether [C-O-C] Methyl [-CH3] -CH2- [linear] -CH2- [cyclic] -CH- [cyclic] Log Kow = 4.68 (user-entered) Molecular Weight Parameter Equation Constant	-0.7605 -0.2984 -0.0232 0.2451 0.0242 0.0963 0.0126 0.3073	-0.7605 -0.5969 -0.0232 1.4706 0.0484 0.3850 0.0252 1.4384 -0.7294 -1.5058
RESULT RESULT NOTE		Log Bio Half-life (days) Bio Half-life (days) Bio Half-life Normalized to 10 g fish at 15°C		-0.2795 0.5254

Biotransformation rate constant: kM (rate constant) = 1.319 / day (10 gram fish).

Arnot-Gobas BCFBAF Methods (including biotransformation rate estimates):

Estimated Log BCF (upper trophic) = 2.327 (BCF = 212.3 L/Kg wet-wt).

Estimated Log BCF (mid trophic) = 2.445 (BCF = 278.4 L/Kg wet-wt).

Estimated Log BCF (lower trophic) = 2.477 (BCF = 300.3 L/Kg wet-wt).

Arnot-Gobas BCFBAF Methods (assuming a biotransformation rate of zero):

Estimated Log BCF (upper trophic) = 3.641 (BCF = 4379 L/Kg wet-wt).

Validity criteria fulfilled:

yes

Conclusions:

The BCF for the C7 isomer of the registered substance is estimated to be 569 L/Kg wet-wt based on the log Kow value and 300 L/kg wet-wt based on Arnot-Gobas method (lower trophic, including biotransformation rate estimates).

Executive summary:

The bioconcentration factor (BCF) of the C7 isomer of the registered substance was evaluated with BCFBAF model v3.01 from EPI Suite v4.1, which fulfilled all OECD principles. The substance is within the domain of the BCFBAF model based on the molecular weight and fragments present in the BCFBAF database.

It's more relevant to consider the result obtain with Arnot-Gobas Method, including biotransformation rate estimates instead of the result obtain with Arnot-Gobas Method, assuming a biotransformation rate of zero. The BCF is estimated to be 569 L/Kg wet-wt based on the log Kow value and 300 L/kg wet-wt based on Arnot-Gobas method (lower trophic, including biotransformation rate estimates).

Reference 3

Endpoint:

bioaccumulation in aquatic species: fish

Type of information:

experimental study

Remarks:

Experimental study performed on the C6 isomers of the transformation product of the registered substance.

Adequacy of study:

weight of evidence

Study period:

31 Oct 2013 to 29 Nov 2013

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Remarks:

The test substance is not the registered substance, it's the C6 isomers of the transformation product of the registered substance. Study following the latest OECD guideline methodology performed under GLP. Moreover the substance properties (e.g. solubility) are well within thresholds allowing a fully valid BCF study to be performed without significant deviations from the Guideline recommendations.

Qualifier:

according to guideline

Guideline:

other: OECD Guideline No 305 Bioaccumulation in fish: aqueous and dietary exposure (2012)

Deviations:

no

Qualifier:

according to guideline

Guideline:

other: Test methods concerning new chemical substances < Bioconcentration test of chemical substances in the bodies of fish ans shellfish> NITE 2011

Deviations:

no

Principles of method if other than guideline:

Not applicable

GLP compliance:

yes

Radiolabelling:

no

Details on sampling:

No data

Vehicle:

no

Details on preparation of test solutions, spiked fish food or sediment:

80.43 mg of test substance was weighed into a 100 mL sample tube and dissolved in water at 50°C while stirring. The solution was transferred into a 5L reagent bottle, heated to 50°C to dissolve the substance and this was repeated 10 times and allowed to cool. The total soltion was made up to 4L to achieve a final stock solution concentration of approximately 20 mg/L.
Two secondary stock solutions were prepared by dilutin of the primary stock to obtain concentrations of 7 and 0.7 mg/L.

Test solutions were prepared by dilution of the 2ndary stocks using a flow-through system to obtain final nominal test concentrations of 0.07 and 0.007 mg/L.

Test organisms (species):

Cyprinus carpio

Details on test organisms:

Fish from Kitamura carp breeding farm (Kumamoto Prefecture, Japan) of 8 ± 4 cm were seleected, treated with Elevage (4-[2-5nitro-2-furanyl]ethenyl]benzoic acid, sodium salt) a,d rock salt afte rwhich they were acclimated at 25°C for 7 days. Mortality was <5% before use in the test.
Mean body wt = 3.84± 0.27 g
Mean total length = 7.0± 0.3 cm
Lipid content before exp = 4.5% (n=2)
after exp.= 4.9% (n=2)
Food: feed for carp (37% crude protein; 2.5% crude lipids)
Fish were fed daily approx 1.5% bodyweight per day but no food provided on sampling days

Route of exposure:

aqueous

Test type:

flow-through

Water / sediment media type:

natural water: freshwater

Total exposure / uptake duration:

28 d

Total depuration duration:

0 d

Hardness:

55 mg/L not specified but presumed "as Ca CO3"

Test temperature:

24.9-25.5°C

pH:

7.7-7.8

Dissolved oxygen:

7.20-7.35

TOC:

<2 mg/L DOC

Salinity:

no data

Details on test conditions:

10 fish were sampled per concentration over the study period, with 5 sampling times and 2 fish per sampling time.

Nominal and measured concentrations:

Test solutions were prepared by dilution of the 2ndary stocks using a flow-through system to obtain final nominal test concentrations of 0.07 (level 1) and 0.007 (level 2) mg/L.
The measured values were as follows:
For level 1: 0.0655 (± 0.00726) + 0.000167 ± (0.0000105) = 0.007427 mg/L combined isomers
For level 2: 0.00649± (0.000567) + 0.000220 ± (0.0000105) = 0.00671 mg/L combined isomers

Reference substance (positive control):

no

Details on estimation of bioconcentration:

Samples of water and whole fish were taken on days 7, 14, 21, 26 and 28 for the two test concentrations and water, fish and lipid content was determined on days 0 and 28 for the control.
BCFs were termined at each time point. Max BCFs were 25 (on day 7) for Level 1 and <35 at Level 2 (35 was the LOQ for this concentration)

Key result

Type:

BCF

Value:

15 L/kg

Basis:

whole body w.w.

Time of plateau:

7 d

Calculation basis:

steady state

Remarks on result:

other: (R,S)-isomer

Remarks:

Conc.in environment / dose:0.0655 mg/L

Key result

Type:

BCF

Value:

17 L/kg

Basis:

whole body w.w.

Time of plateau:

7 d

Calculation basis:

steady state

Remarks on result:

other: (S,R)-isomer

Remarks:

Conc.in environment / dose:0.00206 mg/L

Key result

Type:

BCF

Value:

< 30 L/kg

Basis:

whole body w.w.

Time of plateau:

7 d

Calculation basis:

steady state

Remarks on result:

other: (R,S)-isomer

Remarks:

Conc.in environment / dose:0.00649

Key result

Type:

BCF

Value:

< 35 L/kg

Basis:

whole body w.w.

Time of plateau:

7 d

Calculation basis:

steady state

Remarks on result:

other: (S,R)-isomer

Remarks:

Conc.in environment / dose:0.000220

Details on kinetic parameters:

BCFs were determned at steady state as tissue concentration divided by water concentration

Metabolites:

no data

Results with reference substance (positive control):

No positive control performed

Details on results:

In a BCF study on a mixture of 2 isomers (at 96 and 3%) of the test substance, perforemd at two concentrations (nominal 0.07 and 0.007 mg/L) measured at approximately 0.065 and 0.0065 mg/L, the BCFs were found to be between 15 and 17 and

Reported statistics:

mean values of test solutions and BCFs were accompanied by standard deviations

In a preliminary test using two fish and 8 days of exposure, BCFs were found to be <32 and <46 respectively.

Lipid change was confirmed to be less than or equal to 25% between the start and end of the study (4.5% at the start of the experiment and 4.9% at the end).

Validity criteria fulfilled:

yes

Conclusions:

A study was performed on the major transformation product (C6 isomers: one at 96% and the second at 3%) of the registered substance, by the Institute of Ecotoxicology, Japan in 2013. The study followed the latest OECD 305 Guideline (2012) and was conducted using the test substance dissolved in water at two sub-lethal concentrations for a period of 28 days. The authors considered that steady date was reached on day 28 although there was evidence that steady-state had already occurred by day 7 of the study. In both concentrations extremely low BCFs were determined (11 -25 with a mean of 15 at the highest water concentration of approximately 0.07 mg/L based on the major isomer and <21 -<35 [LOD] at the lowest water concentration of approximately 0.007 mg/L based on the major isomer). Results from the second isomer was almost identical. This study conclusively demonstrated that the major breakdown product of the registered substance will not bioaccumulate to any significant degree in aquatic organisms.

Executive summary:

A study was performed on the major transformation product (C6 isomers: one at 96% and the second at 3%) of the registered substance, by the Institute of Ecotoxicology, Japan in 2013. The study followed the latest OECD 305 Guideline (2012) using carp (Cyprinus carpio) of approximately 7 -8 cm in length. and was conducted using the test substance Dissolved in water at two sub-lethal concentrations for a period of 28 days in a flow-through system. Physicochemical paramenters (oxygen concentration, pH and temperature) were measured throughout the study at each sampling date and found to be well within acceptable limits and extrememly stable throughout the study. The authors considered that the fish reached steady date on day 28 although there was evidence that steady-state had already occurred by day 7 of the study thus no depuration phase was necessary. In both concentrations extremely low BCFs were determined (11 -25 with a mean of 15 at the highest water concentration of approximately 0.07 mg/L based on the major isomer and <21 -<35 [LOD] at the lowest water concentration of approximately 0.007 mg/L based on the major isomer). Results from the second isomer was almost identical. This study conclusively demonstrated that the major breakdown product of the registered substance will not bioaccumulate to any significant degree in aquatic organisms.

Reference 4

Endpoint:

bioaccumulation: aquatic / sediment

Type of information:

(Q)SAR

Remarks:

QSAR result on the C6 isomers of the transformation product of the registered substance

Adequacy of study:

weight of evidence

Study period:

Run on 2013-03

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 limited documentation / justification

Remarks:

The bioconcentration factor (BCF) of the C6 isomers of the transformation product of the registered substance was evaluated with BCFBAF model v3.01 from EPI Suite v4.1, which fulfilled all OECD principles. This substance is within the domain of the BCFBAF model based on the molecular weight and fragments present in the BCFBAF database.

Justification for type of information:

1. SOFTWARE
EPISUITE v4.1

2. MODEL (incl. version number)
BCFBAF v3.01

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
C6 isomers of the transformation product of the registered substance: C1C(C)(C)CCCC1C(C)OC(C)(C)COH
log Pow: 4.33 (experimental result)

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
See attached QMRF
- Defined endpoint: Bioconcentration Factor (BCF) and Bioaccumulation Factor (BAF).
- Unambiguous algorithm: BCFBAF v3.01 contains two methods for estimating BCFs. The first BCFBAF method is based on the original BCFWIN model and classifies a compound as either ionic or non-ionic. Ionic compounds include carboxylic acids, sulfonic acids and salts of sulfonic acids, and charged nitrogen compounds (nitrogen with a +5 valence such as quaternary ammonium compounds). All other compounds are classified as non-ionic. The second model for BCF estimation has been expanded to calculate both BCF as well as BAF for three general trophic levels of fish. This method is based on the multiple-linear regression-derived equation which is used by the BCFBAF program to estimate the kM Biotransformation Half-Life.
- Defined domain of applicability: The estimation domain for BCF is based on the number of instances given for each correction factor in any of the training set compounds, and the minimum and maximum values for molecular weight and log Kow.
- Appropriate measures of goodness-of-fit and robustness and predictivity: The following gives statistical information for the BCF training and validation datasets (includes ionic and non-ionic compounds). Number = 527 / r² = 0.833 / std deviation = 0.502 / avg deviation = 0.382. For the BCF validation dataset; Number = 158 / r² = 0.82 / std deviation = 0.59 / avg deviation = 0.46. Arnot-Gobas BCF and BAF statistics for the kM biotransformation half-life of the training dataset are; Number = 421 / r² = 0.821 / std deviation = 0.494 / avg deviation = 0.383. For the kM validation dataset; Number = 211 / r² = 0.734 / std deviation = 0.602 / avg deviation = 0.446.
- Mechanistic interpretation: no data

5. APPLICABILITY DOMAIN
See attached QPRF

Qualifier:

according to guideline

Guideline:

other: REACH guidance on QSARs R.6, May 2008

Deviations:

no

Principles of method if other than guideline:

See QMRF and QPRF in "Attached background material" and in "Any other information on materials and methods incl. tables" (the QMRF is only available for the former version of the QSAR model).

GLP compliance:

no

Specific details on test material used for the study:

- log Pow: 4.33 (experimental result)

Radiolabelling:

no

Details on sampling:

Not applicable

Details on preparation of test solutions, spiked fish food or sediment:

Not applicable

Details on test organisms:

Not applicable

Test type:

other: QSAR

Water / sediment media type:

not specified

Hardness:

Not applicable

Test temperature:

Not applicable

pH:

Not applicable

Dissolved oxygen:

Not applicable

TOC:

Not applicable

Salinity:

Not applicable

Details on test conditions:

Not applicable

Nominal and measured concentrations:

Not applicable

Reference substance (positive control):

no

Details on estimation of bioconcentration:

Not applicable

Key result

Type:

BCF

Value:

334 L/kg

Basis:

whole body w.w.

Remarks on result:

other: BCF model using log Kow value.

Key result

Type:

BCF

Value:

414 L/kg

Basis:

whole body w.w.

Remarks on result:

other: Arnot-Gobas Method, including a biotransformation rate estimates, lower trophic.

Details on kinetic parameters:

Not applicable

Metabolites:

Not applicable

Results with reference substance (positive control):

Not applicable

Details on results:

Arnot-Gobas Method: It's more relevant to consider the result including biotransformation rate estimates instead of the result assuming a biotransformation rate of zero.

Reported statistics:

Not applicable

BCF model, for C6 isomer:

Log Kow (estimated) : 4.01

Log Kow (experimental): not available from database

Log Kow used by BCF estimates: 4.33 (user entered)

Equation Used to Make BCF estimate:

Log BCF = 0.6598 log Kow - 0.333 + Correction

Correction(s) value: no applicable correction factors

Estimated Log BCF = 2.524 (BCF = 334.1 L/kg wet-wt)

Arnot-Gobas BCF model (Whole body Primary Biotransformation Rate estimate for fish), for C6 isomer:

TYPE	NUM	LOG BIOTRANSFORMATION FRAGMENT DESCRIPTION	COEFF	VALUE
Frag Frag Frag Frag Frag Frag Frag Frag L Kow MolWt Const	1 2 1 5 1 1 4 1 * * *	Aliphatic alcohol [-OH] Carbon with 4 single bonds & no hydrogens Aliphatic ether [C-O-C] Methyl [-CH3] -CH2- [linear] -CH- [linear] -CH2- [cyclic] -CH- [cyclic] Log Kow = 4.33 (user-entered) Molecular Weight Parameter Equation Constant	-0.0616 -0.2984 -0.0232 0.2451 0.0242 -0.1912 0.0963 0.0126 0.3073	-0.0616 -0.5969 -0.0232 1.2255 0.0242 -0.1912 0.3850 0.0126 1.3308 -0.5856 -1.5058
RESULT RESULT NOTE		Log Bio Half-life (days) Bio Half-life (days) Bio Half-life Normalized to 10 g fish at 15°C		-0.0175 0.9606

Biotransformation rate constant: kM (rate constant) = 0.7216 / day (10 gram fish).

Arnot-Gobas BCFBAF Methods (including biotransformation rate estimates):

Estimated Log BCF (upper trophic) = 2.535 (BCF = 342.8 L/Kg wet-wt).

Estimated Log BCF (mid trophic) = 2.605 (BCF = 402.3 L/Kg wet-wt).

Estimated Log BCF (lower trophic) = 2.617 (BCF = 413.8 L/Kg wet-wt).

Arnot-Gobas BCFBAF Methods (assuming a biotransformation rate of zero):

Estimated Log BCF (upper trophic) = 3.328 (BCF = 2128 L/Kg wet-wt).

Validity criteria fulfilled:

yes

Conclusions:

The BCF for the major isomers of the transformation product (C6) of the registered substance is estimated to be 334 L/Kg wet-wt based on the log Kow value and 414 L/kg wet-wt based on Arnot-Gobas method (lower trophic, including biotransformation rate estimates).

Executive summary:

The bioconcentration factor (BCF) of the major isomers of the transformation product (C6) of the registered substance was evaluated with BCFBAF model v3.01 from EPI Suite v4.1, which fulfilled all OECD principles. This substance is within the domain of the BCFBAF model based on the molecular weight and fragments present in the BCFBAF database.

It's more relevant to consider the result obtain with Arnot-Gobas Method, including biotransformation rate estimates instead of the result obtain with Arnot-Gobas Method, assuming a biotransformation rate of zero. The BCF is estimated to be 334 L/Kg wet-wt based on the log Kow value and 414 L/kg wet-wt based on Arnot-Gobas method (lower trophic, including biotransformation rate estimates).

Reference 5

Endpoint:

bioaccumulation: aquatic / sediment

Type of information:

(Q)SAR

Remarks:

QSAR result on the C7 isomer of the transformation product of the registered substance

Adequacy of study:

weight of evidence

Study period:

Run on 2013-03

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 limited documentation / justification

Remarks:

The bioconcentration factor (BCF) of isomer C7 of the transformation product of the registered substance was evaluated with BCFBAF model v3.01 from EPI Suite v4.1, which fulfilled all OECD principles. This substance is within the domain of the BCFBAF model based on the molecular weight and fragments present in the BCFBAF database.

Justification for type of information:

1. SOFTWARE
EPISUITE v4.1

2. MODEL (incl. version number)
BCFBAF v3.01

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
C7 isomer of the transformation product of the registered substance: OCC(C)(C)OC1CC(C)(C)CCCC1C
log Pow: 4.40 (KREATIS QSAR - iSafeRat v1.5, 2016)

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
See attached QMRF
- Defined endpoint: Bioconcentration Factor (BCF) and Bioaccumulation Factor (BAF).
- Unambiguous algorithm: BCFBAF v3.01 contains two methods for estimating BCFs. The first BCFBAF method is based on the original BCFWIN model and classifies a compound as either ionic or non-ionic. Ionic compounds include carboxylic acids, sulfonic acids and salts of sulfonic acids, and charged nitrogen compounds (nitrogen with a +5 valence such as quaternary ammonium compounds). All other compounds are classified as non-ionic. The second model for BCF estimation has been expanded to calculate both BCF as well as BAF for three general trophic levels of fish. This method is based on the multiple-linear regression-derived equation which is used by the BCFBAF program to estimate the kM Biotransformation Half-Life.
- Defined domain of applicability: The estimation domain for BCF is based on the number of instances given for each correction factor in any of the training set compounds, and the minimum and maximum values for molecular weight and log Kow.
- Appropriate measures of goodness-of-fit and robustness and predictivity: The following gives statistical information for the BCF training and validation datasets (includes ionic and non-ionic compounds). Number = 527 / r² = 0.833 / std deviation = 0.502 / avg deviation = 0.382. For the BCF validation dataset; Number = 158 / r² = 0.82 / std deviation = 0.59 / avg deviation = 0.46. Arnot-Gobas BCF and BAF statistics for the kM biotransformation half-life of the training dataset are; Number = 421 / r² = 0.821 / std deviation = 0.494 / avg deviation = 0.383. For the kM validation dataset; Number = 211 / r² = 0.734 / std deviation = 0.602 / avg deviation = 0.446.
- Mechanistic interpretation: no data

5. APPLICABILITY DOMAIN
See attached QPRF

Qualifier:

according to guideline

Guideline:

other: REACH guidance on QSARs R.6, May 2008

Deviations:

no

Principles of method if other than guideline:

See QMRF and QPRF in "Attached background material" and in "Any other information on materials and methods incl. tables" (the QMRF is only available for the former version of the QSAR model).

GLP compliance:

no

Specific details on test material used for the study:

- log Pow: 4.40 (KREATIS QSAR - iSafeRat v1.5, 2016)

Radiolabelling:

no

Details on sampling:

Not applicable

Details on preparation of test solutions, spiked fish food or sediment:

Not applicable

Details on test organisms:

Not applicable

Test type:

other: QSAR

Water / sediment media type:

not specified

Hardness:

Not applicable

Test temperature:

Not applicable

pH:

Not applicable

Dissolved oxygen:

Not applicable

TOC:

Not applicable

Salinity:

Not applicable

Details on test conditions:

Not applicable

Nominal and measured concentrations:

Not applicable

Reference substance (positive control):

no

Details on estimation of bioconcentration:

Not applicable

Key result

Type:

BCF

Value:

372 L/kg

Basis:

whole body w.w.

Remarks on result:

other: BCF model using log Kow value.

Key result

Type:

BCF

Value:

607 L/kg

Basis:

whole body w.w.

Remarks on result:

other: Arnot-Gobas Method, including a biotransformation rate estimates, lower trophic.

Details on kinetic parameters:

Not applicable

Metabolites:

Not applicable

Results with reference substance (positive control):

Not applicable

Details on results:

Arnot-Gobas Method: It's more relevant to consider the result including biotransformation rate estimates instead of the result assuming a biotransformation rate of zero.

Reported statistics:

Not applicable

BCF model, for C7 isomer:

Log Kow (estimated) : 4.01

Log Kow (experimental): not available from database

Log Kow used by BCF estimates: 4.40 (user entered)

Equation Used to Make BCF estimate:

Log BCF = 0.6598 log Kow - 0.333 + Correction

Correction(s) value: no applicable correction factors

Estimated Log BCF = 2.570 (BCF = 371.6 L/kg wet-wt)

Arnot-Gobas BCF model (Whole body Primary Biotransformation Rate estimate for fish), for C7 isomer:

TYPE	NUM	LOG BIOTRANSFORMATION FRAGMENT DESCRIPTION	COEFF	VALUE
Frag Frag Frag Frag Frag Frag Frag L Kow MolWt Const	1 2 1 5 1 4 2 * * *	Aliphatic alcohol [-OH] Carbon with 4 single bonds & no hydrogens Aliphatic ether [C-O-C] Methyl [-CH3] -CH2- [linear] -CH2- [cyclic] -CH- [cyclic] Log Kow = 4.40 (user-entered) Molecular Weight Parameter Equation Constant	-0.0616 -0.2984 -0.0232 0.2451 0.0242 0.0963 0.0126 0.3073	-0.0616 -0.5969 -0.0232 1.2255 0.0242 0.3850 0.0252 1.3523 -0.5856 -1.5371
RESULT RESULT NOTE		Log Bio Half-life (days) Bio Half-life (days) Bio Half-life Normalized to 10 g fish at 15°C		0.2079 1.614

Biotransformation rate constant: kM (rate constant) = 0.4295 / day (10 gram fish).

Arnot-Gobas BCFBAF Methods (including biotransformation rate estimates):

Estimated Log BCF (upper trophic) = 2.730 (BCF = 536.7 L/Kg wet-wt).

Estimated Log BCF (mid trophic) = 2.779 (BCF = 601 L/Kg wet-wt).

Estimated Log BCF (lower trophic) = 2.783 (BCF = 607 L/Kg wet-wt).

Arnot-Gobas BCFBAF Methods (assuming a biotransformation rate of zero):

Estimated Log BCF (upper trophic) = 3.393 (BCF = 2469 L/Kg wet-wt).

Validity criteria fulfilled:

yes

Conclusions:

The BCF for the C7 isomer of the transformation product of the registered substance is estimated to be 372 L/Kg wet-wt based on the log Kow value and 607 L/kg wet-wt based on Arnot-Gobas method (lower trophic, including biotransformation rate estimates).

Executive summary:

The bioconcentration factor (BCF) of the C7 isomer of the transformation product of the registered substance was evaluated with BCFBAF model v3.01 from EPI Suite v4.1, which fulfilled all OECD principles. This substance is within the domain of the BCFBAF model based on the molecular weight and fragments present in the BCFBAF database.

It's more relevant to consider the result obtain with Arnot-Gobas Method, including biotransformation rate estimates instead of the result obtain with Arnot-Gobas Method, assuming a biotransformation rate of zero. The BCF is estimated to be 372 L/Kg wet-wt based on the log Kow value and 607 L/kg wet-wt based on Arnot-Gobas method (lower trophic, including biotransformation rate estimates).

Description of key information

Constituent approach:

- Registered substance (parent): QSAR predictions, BCF comprised between 382 and 435 L/kg.

- Transformation product: Experimental GLP-OECD Guideline 305 study on C6 isomers and QSAR predictions on C6 and C7 isomers. BCF lower than 500 L/kg. The breakdown product of the registered substance will not bioaccumulate to any significant degree in aquatic organisms.

Key value for chemical safety assessment

BCF (aquatic species):

435 L/kg ww

Additional information

One experimental study was performed on the major isomers of the transformation product of the registered substance, by the Institute of Ecotoxicology in Japan in 2013. This study was performed in the context of the notification of the registered substance in Japan in 2014, under the New Chemical Substances Control Law. This study followed the latest OECD 305 Guideline (2012) and was conducted using C6 isomers of the transformation product dissolved in water at two sub-lethal concentrations for a period of 28 days. The authors considered that steady state was reached on day 28 although there was evidence that steady-state may have already occurred by day 7 of the study. In both concentrations extremely low BCFs were determined (11 -25 with a mean of 15 at the highest water concentration of approximately 0.07 mg/L based on the major isomer and <21 -<35 [LOD] at the lowest water concentration of approximately 0.007 mg/L based on the major isomer). Results from the second isomer was almost identical. This study conclusively demonstrated that the major breakdown product of the registered substance will not bioaccumulate to any significant degree in aquatic organisms.

This result was supported by QSAR predictions. The bioconcentration factors (BCF) of the registered substance and its transformation product (C6 and C7 isomers) were evaluated with BCFBAF model v3.01 from EPI Suite v4.1, which fulfilled all OECD principles. These substances are within the domain of the BCFBAF model based on the molecular weights and fragments present in the BCFBAF database.

For Arnot-Gobas Method, it's more relevant to consider the result obtain including biotransformation rate estimates instead of the result assuming a biotransformation rate of zero.

For the C6 isomers of the registered substance, the BCF is estimated at 382 L/kg wet-wt, corresponding to the mean of the BCF based on the log Kow value (568.7 L/kg wet-wt) and the BCF based on Arnot-Gobas method (196.2 L/kg wet-wt, lower trophic including biotransformation rate estimates).

For the C7 isomer of the registered substance, the BCF is estimated at 435 L/kg wet-wt, corresponding to the mean of the BCF based on the log Kow value (568.7 L/kg wet-wt) and the BCF based on Arnot-Gobas method (300.3 L/kg wet-wt, lower trophic including biotransformation rate estimates).

For the C6 isomers of the transformation product, the BCF is estimated at 374 L/kg wet-wt, corresponding to the mean of the BCF based on the log Kow value (334.1 L/kg wet-wt) and the BCF based on Arnot-Gobas method (413.8 L/kg wet-wt, lower trophic including biotransformation rate estimates).

For the C7 isomer of the transformation product, the BCF is estimated at 490 L/kg wet-wt, corresponding to the mean of the BCF based on the log Kow value (372 L/kg wet-wt) and the BCF based on Arnot-Gobas method (607 L/kg wet-wt, lower trophic including biotransformation rate estimates).

As the QSAR estimate for the C6 isomer of the transformation product is higher than the experimental value, the QSARs can considered to be a conservative estimate of the BCF for the registered substance and its degradation products.