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EC number: 480-880-4 | CAS number: 608-23-1
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Bioaccumulation: aquatic / sediment
Administrative data
Link to relevant study record(s)
- Endpoint:
- bioaccumulation in aquatic species: fish
- Type of information:
- (Q)SAR
- Adequacy of study:
- key study
- Study period:
- November 2017
- Reliability:
- 1 (reliable without restriction)
- 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:
- Results from two relevant supporting models corroborate key model result.
- Justification for type of information:
- See attached QPRF and QMRF section "Attached justification".
- Guideline:
- other: ECHA Guidance on Information Requirements and Chemical Safety Assessment. Chapter R.6: QSARs and grouping of chemicals
- Version / remarks:
- 2008
- Guideline:
- other: ECHA Practical guide How to use and report (Q)SARs
- Version / remarks:
- 2016
- Principles of method if other than guideline:
- Model selection for BCF calculation was based on a recent publication by Gissi et al. (2015), evaluating and comparing several relevant QSAR models for BCF prediction under REACH based on a validated experimental data set of 851 compounds containing a subset of ionisable compounds (at least 131). Considering the outcome of this work as well as the specific properties of the submission substance, the following models were selected:
Key model: US EPA T.E.S.T v. 4.2.1, Consensus Method (see attached QMRF and QPRF);
Supporting model (1): Arnot & Gobas (2003) bioconcentration model including predicted metabolism;
Supporting model (2): log Kow based equations - Equation according to Veith et al. (1979) recommended for compounds with log Kow values below 6.
For full details on a) rational for model selection; b) details on selected models with regard to comparative statistical evaluation by Gissi et al. (2015) and c) full literature references, see IUCLID section “Any other information on materials and methods incl. tables”! - GLP compliance:
- no
- Specific details on test material used for the study:
- • CAS number: 608-23-1
• EC number: 612-040-1
• IUPAC name / common name: 1-chloro-2,3-dimethylbenzene / 3-chloro-o-xylene
• Structural formula: C8-H9-Cl
• Structure codes: Canonical SMILES: CC1=C(C(=CC=C1)Cl)C
• Partition coefficient n-octanol water, log Kow: 4.1 (OECD 117; Wilbury Laboratories Inc., 2003) at 23°C - Details on sampling:
- Not applicabale
- Details on preparation of test solutions, spiked fish food or sediment:
- Not applicabale
- Test organisms (species):
- other: mostly lower trophic level fresh water fish species
- Details on test organisms:
- For the key model US EPA T.E.S.T. v. 4.2.1. the bioconcentration factor data set was compiled by researchers at the Mario Negri Istituto Di Ricerche Farmacologiche and based on Dimitrov et al. (2005). Fish experimental BCF values (two databases combined; experimental data obtained according to OECD 305 protocol; fish species: Cyprinus Carpio and salmonids) were obtained according to official protocols. Furthermore, as explained in the Literature (Zhao et al. 2008), all structures were checked one-by-one within the EC funded project CAESAR, by at least two scientists. Further high quality data were added from the Arnot & Gobas database as well as the EURAS Gold Standard Database.
The following relevant references are given in the User’s Guide on T.E.S.T. v. 4.2.:
- Dimitrov, S.; Dimitrova, N.; Parkerton, T.; Combers, M.; Bonnell, M.; Mekenyan, O. Base-line model for identifying the bioaccumulation potential of chemicals. SAR QSAR Environ. Res. 2005, 16, 531-554
- Arnot, J. A.; Gobas, F. A. P. C. A review of bioconcentration factor (BCF) and bioaccumulation factor (BAF) assessments for organic chemicals in aquatic organisms. Environ. Rev. 2006, 14, 257-297.
- EURAS. Establishing a bioconcentration factor (BCF) Gold Standard Database. http://www.euras.be/eng/project.asp?ProjectId=92 (accessed 5/20/09).
- Zhao, C. B., E.; Chana, A.; Roncaglioni, A.; Benfenati, E. A new hybrid system of QSAR models for predicting bioconcentration factors (BCF). Chemosphere 2008, 73, 1701-1707. - Route of exposure:
- aqueous
- Justification for method:
- aqueous exposure method used for following reason: Recommended according to ECHA guidance R.7c (2017) if experimentally feasible
- Test type:
- other: Predominantly (94%) flow through according to Arnot and Gobas (2006) BCF database considering acceptable (category 1) data, only
- Water / sediment media type:
- other: Predominantly (80%) fresh water according to Arnot and Gobas (2006) BCF database considering acceptable (category 1) data, only
- Hardness:
- Not applicable
- Test temperature:
- Not applicable
- pH:
- Not applicable
- Dissolved oxygen:
- Not applicable
- TOC:
- Not applicable
- Salinity:
- Not applicable
- Conductivity:
- Not applicable
- Details on test conditions:
- Not applicable
- Nominal and measured concentrations:
- Not applicable
- Reference substance (positive control):
- not required
- Details on estimation of bioconcentration:
- For key model calculation via US EPA T.E.S.T. v.4.2.1. BCF Consensus Method, see attached QMRF and QPRF!
For supporting estimations via Arnot & Gobas (2003) bioconcentration model as well as BCF-calculation via the equation by Veith et al. (1979), see below section "Any other information on materials and methods including tables"! - Lipid content:
- >= 5 - <= 6 %
- Remarks on result:
- other: generally assumed lipid content for lower trophic fish
- Key result
- Type:
- BCF
- Value:
- >= 141 - <= 269 L/kg
- Basis:
- whole body w.w.
- Calculation basis:
- other: QSAR
- Remarks:
- Actual result of BCF Consensus Method: 141 L/kg (range of 5 single models: 83-208 L/kg); worst case BCF (implying maximum underestimation from 14 similar compounds): 269 L/kg whole body wet weight (externally calculated).
- Remarks on result:
- other: Key model: US EPA T.E.S.T. v. 4.2.1. BCF Consensus Method
- Type:
- BCF
- Value:
- 222 L/kg
- Basis:
- whole body w.w.
- Calculation basis:
- other: QSAR
- Remarks:
- BCF derived for lower trophic level fish, 5.98% lipid content at 12°C env. Temp., using a corrected (based on experimental data for similar compounds) normalized metabolic rate constant of 1.47 /d
- Remarks on result:
- other: Supporting model: Arnot & Gobas (2003) bioconcentration model
- Type:
- BCF
- Value:
- 474 L/kg
- Basis:
- whole body w.w.
- Calculation basis:
- other: QSAR
- Remarks:
- BCF derived for lower trophic level fish (standard experimental fish species), 5.98% lipid content at 12°C env. Temp., using metabolic rate constant as predicted: 0.353 /d
- Remarks on result:
- other: Supporting model: Arnot & Gobas (2003) bioconcentration model
- Type:
- BCF
- Value:
- 610 L/kg
- Basis:
- whole body w.w.
- Calculation basis:
- other: QSAR
- Remarks:
- BCF calculated based on experimentally determined log Kow of 4.1 (HPLC method according to OECD 117)
- Remarks on result:
- other: Supporting model: equation according to Veith et al. (1979)
- Details on kinetic parameters:
- Not applicable
- Metabolites:
- Not applicable
- Results with reference substance (positive control):
- Not applicable
- Details on results:
- KEY MODEL RESULT: US EPA T.E.S.T. (version 4.2.1) BCF-Calculation
The T.E.S.T. Consensus Method estimates BCF based on the results of 5 sub-models (single models), taking into account the applicability domain of each method. At least predictions of 2 sub-models are required, otherwise the predicted value is deemed unreliable and not used. Sub-model results are integrated in the Consensus Method for BCF by averaging. Details on US EPA T.E.S.T. BCF model is given in the available QSAR Model Reporting Format (QMRF_BCF_TEST_v4-2-1_2018).
The following results per sub-model were obtained and used within the T.E.S.T. Consensus method for BCF:
• Hierarchical Clustering: BCF 180.60 L/kg wet weight
• Single Model: BCF 181.87 L/kg wet weight
• Group Contribution: BCF 207.63 L/kg wet weight
• FDA: BCF 96.85 L/kg wet weight
• Nearest Neighbour: BCF 83.25 L/kg wet weight
Accordingly, the result for T.E.S.T. Consensus Method (arithmetic mean over single model log BCF results) is BCF 140.62 L/kg wet weight (log BCF= 2.15).
Concluding based on details given in the QPRF attached to this document, the Consensus Method prediction is associated with a high reliability because
• all five T.E.S.T. BCF sub-models give very similar results, such that the prediction of the Consensus Method of 140.62 L/kg falls within the range 83.25 to 207.63 L/kg;
• for all 5 sub-models as well as the Consensus Method, the mean absolute error (MAE) for the similar compound fraction from test and training set is lower than the MAE for the respective total data set, which increases confidence in predicted values; and finally, because
• the maximum underestimation for 14 retained similar compounds with experimental data from test and training set is only 0.28 log units based on results of the Consensus Method (recommended by US EPA for BCF estimation due to highest prediction accuracy when compared to the 5 sub-models).
It can therefore be concluded with high certainty that BCF of the target compound is far below the regulatory threshold for B.
The BCF based on the estimate of the T.E.S.T. Consensus Method for the submission substance is given together with the results range from the 5 underlying sub-models. Further, some uncertainty in the estimate apparent from analysis of calculated and experimental values for similar compounds is considered manually:
the maximum underestimation of 0.28 log units found from assessment of 14 similar compounds with experimental data from test and training set was added to the predicted value for the submission substance (2.15 + 0.28) and thus yields a worst-case log value of 2.43, corresponding to a worst-case BCF of 269 L/kg.
FINAL RESULT relevant for PBT assessment and exposure and risk assessment:
BCF (US EPA T.E.S.T version 4.2.1; rounded): 141 L/kg whole body wet weight (range of 5 single models: 83-208 L/kg); worst case BCF (implying maximum underestimation from 14 similar compounds): 269 L/kg whole body wet weight.
For further information please see corresponding methodological background on the model given in relevant QMRF as well as QPRF attached to this document.
RESULTS SUPPORTING MODELS (1) ARNOT AND GOBAS (2003) BIOCONCENTRATION MODEL AND (2) EQUATION ACCORDING TO VEITH ET AL. (1979)
See sections "Any other information on results incl. tables" as well as "Overall remarks, attachments". - Validity criteria fulfilled:
- yes
- Remarks:
- with regard to OECD principles for (Q)SAR validation as well as ECHA guidance document R.6 (2008)
- Conclusions:
- The results of the key model (US EPA T.E.S.T. v. 4.2.1 BCF Consensus Method) and the supporting models (supporting model 1: Arnot & Gobas (2003) Bioconcentration Model; supporting model 2: equation according to Veith et al. (1979)) conclusively demonstrate that:
• The submission substance is not bioaccumulative (BCF clearly below 2000 L/kg);
• The worst case BCF (implying maximum underestimation from 14 similar compounds) of 269 L/kg wet weight based on T.E.S.T. Consensus Method results (key model) will be sufficiently conservative as the relevant figure for chemical risk assessment. - Executive summary:
To conclude on a bioconcentration potential (BCF), three different models have been applied:
Key model: US EPA T.E.S.T. version 4.2.1 Consensus Method on BCF
The estimate for BCF according to T.E.S.T. is adequate for PBT/vPvB assessment (first tier) and risk assessment (first tier) for the submission substance because: (a) the model fulfils the OECD principles for QSAR models (algorithm and experimental data used for model building and validation are freely available) and (b) the submission substance is in the applicability domain of the model and evaluation of sufficiently similar compounds with experimental data increases the confidence in the estimated value for the submission substance according to ECHA guidance chapter R.6 (ECHA, 2008), section R.6.1.5.3.
All single model results integrated within the Consensus Method are far below the regulatory threshold for B (BCF 2000):
• Hierarchical clustering: BCF 180.60 L/kg wet weight
• Single model: BCF 181.87 L/kg wet weight
• Group contribution: BCF 207.63 L/kg wet weight
• FDA: BCF 96.85 L/kg wet weight
• Nearest neighbour: BCF 83.25 L/kg wet weight
• Consensus method: BCF 140.62 L/kg wet weight (average over 5 single models); log BCF= 2.15
Further, some uncertainty in the estimate apparent from analysis of calculated and experimental values for similar compounds is considered manually: the maximum underestimation of 0.28 log units found from assessment of 14 similar compounds with experimental data from test and training set was added to the predicted value for the submission substance (2.15 + 0.28) and thus yields a worst-case log value of 2.43, corresponding to a worst-case BCF of 269 L/kg.
Result Key model:
BCF (US EPA T.E.S.T version 4.2.1; rounded): 141 L/kg whole body wet weight (range of 5 single models: 83-208 L/kg); worst case BCF (implying maximum underestimation from 14 similar compounds): 269 L/kg whole body wet weight.
Supporting model results corroborate the result obtained from the key model:
Supporting model 1:
Arnot & Gobas (2003) bioconcentration model – result: BCF 222 L/kg wet weight (using corrected metabolic rate constant based on similar compounds).
This result is only slightly above to the key model prediction of BCF 141 L/kg wet weight by T.E.S.T. Consensus Method and still below the worst case BCF of 269 L/kg derived from T.E.S.T. prediction under manual consideration of results for similar compounds. The result from the mechanistically based Arnot & Gobas (2003) bioconcentration model therefore clearly supports the result of the key model. But even the BCF of 474 L/kg resulting from using the less probable non-corrected metabolic rate constant is still far below the regulatory threshold for B (2000).
Supporting model 2:
BCF estimated according to the equation by Veith et al. (1979) based on experimentally determined log Kow – result: BCF 610 L/kg wet weight.
Sensitivity and conservatism (no biotransformation assumed) of this method render it appropriate to give additional confidence that the submission substance 3-chloro-o-xylene definitely is not bioaccumulative according to REACH. As such, it qualitatively corroborates the outcome of the key model US EPA T.E.S.T. Consensus Method even if the result for BCF is higher. It thus reinforces reliability of the key study.
Taken together, it is safe to conclude that
· The submission substance is not bioaccumulative (BCF clearly below 2000 L/kg);
· The worst case BCF (implying maximum underestimation from 14 similar compounds) of 269 L/kg wet weight based on T.E.S.T. Consensus Method results (key model) will be sufficiently conservative as the relevant figure for chemical risk assessment.
Reference
Supporting Model 1: Arnot & Gobas (2003) Bioconcentration Model – results
Calculation and Results Tables for Upper and Lower Trophic Level Fish:
Table1: The Arnot & Gobas (2003) model on bioconcentration for lower trophic level fish with 5.98% lipid content non-corrected metabolic rate constant. Calculation was performed in MS Excel spreadsheet according to Arnot and Gobas (2003) with correction according to Arnot and Gobas (2006) where annotated. Formulas for calculation of the different kinetic constants and other parameters dependent from the input parameters are given together with their results. Details are given in the text section.
Weights and lipid fraction of upper, mid and lower trophic fish |
|||||||||
T= |
12 |
°C |
Temperature |
Wup [kg] |
1.53 |
LB_upper |
0.107 |
||
W= |
0.096 |
kg |
Weight of Organism |
Wmid [kg] |
0.184 |
LB_mid |
0.0685 |
||
LB= |
0.0598 |
Lipid content of oranism |
Wlow [kg] |
0.096 |
LB_lower |
0.0598 |
|||
KM_N= |
0.3526 |
metabolic transformation rate constant normalized to 10 g fish at 15°C - input from BCFBAF v. 3.01 |
|||||||
KM= |
0.19439526 |
dayE(-1) |
kM,X = kM,N x (WX/WN)^(-0.25) x e^(0.01(TX–TN)) |
||||||
K1= |
1/((0.01+1/Kow)*W^(0.4)= |
255.304901 |
Uptake rate constant |
||||||
k2= |
k1/(LB*Kow)= |
0.33912356 |
Elimination rate constant (via respiratory surface) |
||||||
KD= |
0.02*W^(-0.15)*e^(0.06*T)/(5.1*10^(-8)*Kow+2)= |
0.02918851 |
Dietary uptake rate constant |
||||||
KE= |
0.125*kD= |
0.00364856 |
Fecal egestion rate constant |
||||||
KG= |
0.0005*W^(-0,2)= |
0.00079894 |
Growth rate constant (growth dilution) |
||||||
λPOC= |
Concentration of particulate organic carbon= |
0.0000005 |
g/ml |
default |
|||||
λDOC= |
Concentration of dissolved organic carbon= |
0.0000005 |
g/ml |
default |
|||||
ɸ= |
Fraction of freely dissolved chemical in water= |
1/(1+λPOC*0.35*Kow+λDOC*0.08*Kow)= |
0.99730062 |
||||||
(second term corrected to "λDOC*0.08*Kow" according to Arnot & Gobas, 2006) |
|||||||||
log Kow= |
4.1 |
Kow= |
12589.2541 |
||||||
BCF= |
(1-LB)+(k1*ɸ/(k2+kE+KG+kM))= |
474.233271 |
log BCF= |
2.67599202 |
Table 2: The Arnot & Gobas (2003) model on bioconcentration for upper trophic level fish with 10.7% lipid content – non-corrected metabolic rate constant. Calculation was performed in MS Excel spreadsheet according to Arnot and Gobas (2003) with correction according to Arnot and Gobas (2006) where annotated. Formulas for calculation of the different kinetic constants and other parameters dependent from the input parameters are given together with their results. Details are given in the text section.
Weights and lipid fraction of upper, mid and lower trophic fish |
|||||||||
T= |
12 |
°C |
Temperature |
Wup [kg] |
1.53 |
LB_upper |
0.107 |
||
W= |
1.53 |
kg |
Weight of Organism |
Wmid [kg] |
0.184 |
LB_mid |
0.0685 |
||
LB= |
0.107 |
Lipid content of oranism |
Wlow [kg] |
0.096 |
LB_lower |
0.0598 |
|||
KM_N= |
0.3526 |
metabolic transformation rate constant normalized to 10 g fish at 15°C - input from BCFBAF v. 3.01 |
|||||||
KM= |
0.09729278 |
dayE(-1) |
kM,X = kM,N x (WX/WN)^(-0.25) x e^(0.01(TX–TN)) |
||||||
K1= |
1/((0.01+1/Kow)*W^(0.4)= |
84.3511627 |
Uptake rate constant |
||||||
k2= |
k1/(LB*Kow)= |
0.06261917 |
Elimination rate constant (via respiratory surface) |
||||||
KD= |
0.02*W^(-0.15)*e^(0.06*T)/(5.1*10^(-8)*Kow+2)= |
0.01926854 |
Dietary uptake rate constant |
||||||
KE= |
0.125*kD= |
0.00240857 |
Fecal egestion rate constant |
||||||
KG= |
0.0005*W^(-0,2)= |
0.00045923 |
Growth rate constant (growth dilution) |
||||||
λPOC= |
Concentration of particulate organic carbon= |
0.0000005 |
g/ml |
default |
|||||
λDOC= |
Concentration of dissolved organic carbon= |
0.0000005 |
g/ml |
default |
|||||
ɸ= |
Fraction of freely dissolved chemical in water= |
1/(1+λPOC*0.35*Kow+λDOC*0.08*Kow)= |
0.99730062 |
||||||
(second term corrected to "λDOC*0.08*Kow" according to Arnot & Gobas, 2006) |
|||||||||
log Kow= |
4.1 |
Kow= |
12589.2541 |
||||||
BCF= |
(1-LB)+(k1*ɸ/(k2+kE+KG+kM))= |
517.686196 |
log BCF= |
2.71406659 |
Table 3: The Arnot & Gobas (2003) model on bioconcentration for lower trophic level fish with 5.98% lipid content – corrected metabolic rate constant. Calculation was performed in MS Excel spreadsheet according to Arnot and Gobas (2003) with correction according to Arnot and Gobas (2006) where annotated. Formulas for calculation of the different kinetic constants and other parameters dependent from the input parameters are given together with their results. Details are given in the text section.
Weights and lipid fraction of upper, mid and lower trophic fish |
|||||||||
T= |
12 |
°C |
Temperature |
Wup [kg] |
1.53 |
LB_upper |
0.107 |
||
W= |
0.096 |
kg |
Weight of Organism |
Wmid [kg] |
0.184 |
LB_mid |
0.0685 |
||
LB= |
0.0598 |
Lipid content of oranism |
Wlow [kg] |
0.096 |
LB_lower |
0.0598 |
|||
KM_N= |
1.47 |
metabolic transformation rate constant normalized to 10 g fish at 15°C - input from BCFBAF v. 3.01, corrected based on experimental values for similar compounds |
|||||||
KM= |
0.81043967 |
dayE(-1) |
kM,X = kM,N x (WX/WN)^(-0.25) x e^(0.01(TX–TN)) |
||||||
K1= |
1/((0.01+1/Kow)*W^(0.4)= |
255.304901 |
Uptake rate constant |
||||||
k2= |
k1/(LB*Kow)= |
0.33912356 |
Elimination rate constant (via respiratory surface) |
||||||
KD= |
0.02*W^(-0.15)*e^(0.06*T)/(5.1*10^(-8)*Kow+2)= |
0.02918851 |
Dietary uptake rate constant |
||||||
KE= |
0.125*kD= |
0.00364856 |
Fecal egestion rate constant |
||||||
KG= |
0.0005*W^(-0,2)= |
0.00079894 |
Growth rate constant (growth dilution) |
||||||
λPOC= |
Concentration of particulate organic carbon= |
0.0000005 |
g/ml |
default |
|||||
λDOC= |
Concentration of dissolved organic carbon= |
0.0000005 |
g/ml |
default |
|||||
ɸ= |
Fraction of freely dissolved chemical in water= |
1/(1+λPOC*0.35*Kow+λDOC*0.08*Kow)= |
0.99730062 |
||||||
(second term corrected to "λDOC*0.08*Kow" according to Arnot & Gobas, 2006) |
|||||||||
log Kow= |
4.1 |
Kow= |
12589.2541 |
||||||
BCF= |
(1-LB)+(k1*ɸ/(k2+kE+KG+kM))= |
221.575699 |
log BCF= |
2.34552213 |
Table 4: The Arnot & Gobas (2003) model on bioconcentration for upper trophic level fish with 10.7% lipid content – corrected metabolic rate constant. Calculation was performed in MS Excel spreadsheet according to Arnot and Gobas (2003) with correction according to Arnot and Gobas (2006) where annotated. Formulas for calculation of the different kinetic constants and other parameters dependent from the input parameters are given together with their results. Details are given in the text section.
Weights and lipid fraction of upper, mid and lower trophic fish |
|||||||||
T= |
12 |
°C |
Temperature |
Wup [kg] |
1.53 |
LB_upper |
0.107 |
||
W= |
1.53 |
kg |
Weight of Organism |
Wmid [kg] |
0.184 |
LB_mid |
0.0685 |
||
LB= |
0.107 |
Lipid content of oranism |
Wlow [kg] |
0.096 |
LB_lower |
0.0598 |
|||
KM_N= |
1.47 |
metabolic transformation rate constant normalized to 10 g fish at 15°C - input from BCFBAF v. 3.01, corrected based on experimental values for similar compounds |
|||||||
KM= |
0.40561653 |
dayE(-1) |
kM,X = kM,N x (WX/WN)^(-0.25) x e^(0.01(TX–TN)) |
||||||
K1= |
1/((0.01+1/Kow)*W^(0.4)= |
84.3511627 |
Uptake rate constant |
||||||
k2= |
k1/(LB*Kow)= |
0.06261917 |
Elimination rate constant (via respiratory surface) |
||||||
KD= |
0.02*W^(-0.15)*e^(0.06*T)/(5.1*10^(-8)*Kow+2)= |
0.01926854 |
Dietary uptake rate constant |
||||||
KE= |
0.125*kD= |
0.00240857 |
Fecal egestion rate constant |
||||||
KG= |
0.0005*W^(-0,2)= |
0.00045923 |
Growth rate constant (growth dilution) |
||||||
λPOC= |
Concentration of particulate organic carbon= |
0.0000005 |
g/ml |
default |
|||||
λDOC= |
Concentration of dissolved organic carbon= |
0.0000005 |
g/ml |
default |
|||||
ɸ= |
Fraction of freely dissolved chemical in water= |
1/(1+λPOC*0.35*Kow+λDOC*0.08*Kow)= |
0.99730062 |
||||||
(second term corrected to "λDOC*0.08*Kow" according to Arnot & Gobas, 2006) |
|||||||||
log Kow= |
4.1 |
Kow= |
12589.2541 |
||||||
BCF= |
(1-LB)+(k1*ɸ/(k2+kE+KG+kM))= |
179.459849 |
log BCF= |
2.2539673 |
Results
The results of the calculation of bioconcentration for the submission substance according to the Arnot and Gobas (2003) Bioconcentration Model are:
Upper trophic level fish, 10.7% lipid content:
a) non-corrected metabolic biotransformation rate constant (Table 2):
· BCF = 517.69 L/kg wet-weight
· log BCF = 2.71
b) corrected metabolic biotransformation rate constant (Table 4):
· BCF = 179.46 L/kg wet-weight
· log BCF = 2.25
Mid trophic level fish, 6.85% lipid content:
a) non-corrected metabolic biotransformation rate constant (not shown in tables):
· BCF = 494.78 L/kg wet-weight
· log BCF = 2.69
b) corrected metabolic biotransformation rate constant (not shown in tables):
· BCF = 214.04 L/kg wet-weight
· log BCF = 2.33
Lower trophic level fish (standard experimental fish species), 5.98% lipid content:
a) non-corrected metabolic biotransformation rate constant (Table 1)::
· BCF = 474.23 L/kg wet-weight
· log BCF = 2.68
b) corrected metabolic biotransformation rate constant (Table 3):
· BCF = 221.58 L/kg wet-weight
· log BCF = 2.35
Conclusion on results
As outlined above, results according to the Arnot and Gobas BCF-model proved to be of high sensitivity and accuracy (MCC) with regard to discrimination between bioaccumulative (B, BCF >2000) and not bioaccumulative (not B, BCF <2000) substances (Gissiet al., 2015). The actual bioconcentration model is independent from a “training”-data set and the data quality thereof, as it is based on several relatively simple mechanistically based assumptions relating on few environmental and organism specific parameters and the K_{OW }of the compound in question. It is therefore completely different from regression based models dependent on the empirical database used for the regression. Furthermore as outlined by Arnot and Gobas (2003), regression based models tend to “arrive at an ‘average’ BCF value, allowing for a relatively large number of occurrences where the actual BCF is greater than the BCF predicted values”.
Taken into account the very different methodological approach and the results of the comparative evaluation of QSAR BCF models by Gissi et al. (2015), BCF values derived via the Arnot and Gobas model are an important complementation of the key model used for BCF estimation (US EPA T.E.S.T.).
The results obtained depending on the fish trophic level are given in the table below.
Table 5: Results for BCF [L/kg whole body wet weight] according to Arnot & Gobas (2003) model on bioconcentration dependent on a) trophic level of fish and b) the applied metabolic rate constant (as predicted; corrected based on experimental data for similar compounds):
Trophic level |
non-corrected normalized metabolic rate constant (0.353 /d) |
corrected normalized metabolic rate constant (1.47 /d) |
Upper trophic level fish |
517.69 |
179.46 |
Mid trophic level fish |
494.78 |
214.04 |
Lower trophic level fish |
474.23 |
221.58 |
Interestingly, for the non-corrected lower metabolic rate constant, BCF for upper trophic level fish is highest, while for the corrected higher metabolic rate constant BCF for lower trophic level fish is highest.
Because experimental fish species normally are lower trophic level fish, the result for lower trophic level fish is deemed to be most relevant for the submission substance.
The BCF of (rounded) 222 L/kg wet weight based on the corrected metabolic rate constant is only slightly above to the key model prediction of BCF 141 L/kg wet weight by T.E.S.T. Consensus Method and still below the worst case BCF of 269 L/kg derived from T.E.S.T. prediction under manual consideration of results for similar compounds. Based on the fundamentally different methodological approach this is an important and strong support for the result of the key model.
Based on deviations of experimental versus predicted results for the two most similar compounds to the submission substance (similarity coefficient 0.95 and 0.79 according to US EPA T.E.S.T. model), a higher than predicted metabolic rate constant is probable: experimental half-life values for these two compounds were lower than predicted by more than a factor of 10 (i.e. more than 1 log unit). Because of an arithmetic mean deviation of 0.62 log units (factor of 4.2) over a total of 4 similar compounds, the predicted rate constant for the target compound was increased by a moderate factor of 4.2. But even for the rather improbable case that the originally predicted value is closest to the truth, the resulting BCF of 474 L/kg is still far below the regulatory threshold of BCF 2000 for B.
References:
Arnot, J.A.; Gobas, F.A.P.C. (2003)
A generic QSAR for assessing the bioaccumulation potential of organic chemicals in aquatic food webs
QSAR & Combinatorial Science, 22, 337-345
Arnot, J.A.; Gobas, F.A.P.C. (2006)
A review of bioconcentration factor (BCF) and bioaccumulation factor (BAF) assessments for organic chemicals in aquatic organisms
Environmental Reviews, 14, 257-297
Description of key information
BCF was estimated by reliable QSAR: the results of the key model (US EPA T.E.S.T. v. 4.2.1 BCF Consensus Method) and the supporting models (supporting model 1: Arnot & Gobas (2003) Bioconcentration Model; supporting model 2: Equation according to Veith et al. (1979)) conclusively demonstrate that:
• The submission substance is not bioaccumulative (BCF clearly below 2000 L/kg);
• The worst case BCF (implying maximum underestimation from 14 similar compounds) of 269 L/kg wet weight based on T.E.S.T. Consensus Method results (key model) will be sufficiently conservative as the relevant figure for chemical risk assessment.
Key value for chemical safety assessment
- BCF (aquatic species):
- 269 L/kg ww
Additional information
No experimental data on bioaccumulation of the submission substance in fish are available. Considering ECHA guidance document R.7c (ECHA, 2017), section R.7.10.2 encouraging the use of alternative information at all supply levels, BCF was estimated by QSAR. To conclude on a bioconcentration potential (BCF), three different models have been applied:
Key model: US EPA T.E.S.T. version 4.2.1 Consensus Method on BCF
The estimate for BCF according to T.E.S.T. is adequate for PBT/vPvB assessment (first tier) and risk assessment (first tier) for the submission substance because: (a) the model fulfils the OECD principles for QSAR models (algorithm and experimental data used for model building and validation are freely available) and (b) the submission substance is in the applicability domain of the model and evaluation of sufficiently similar compounds with experimental data increases the confidence in the estimated value for the submission substance according to ECHA guidance chapter R.6 (ECHA, 2008), section R.6.1.5.3.
All single model results integrated within the Consensus Method are far below the regulatory threshold for B (BCF 2000):
• Hierarchical clustering: BCF 180.60 L/kg wet weight
• Single model: BCF 181.87 L/kg wet weight
• Group contribution: BCF 207.63 L/kg wet weight
• FDA: BCF 96.85 L/kg wet weight
• Nearest neighbour: BCF 83.25 L/kg wet weight
• Consensus method: BCF 140.62 L/kg wet weight (average over 5 single models); log BCF= 2.15
Further, some uncertainty in the estimate apparent from analysis of calculated and experimental values for similar compounds is considered manually: the maximum underestimation of 0.28 log units found from assessment of 14 similar compounds with experimental data from test and training set was added to the predicted value for the submission substance (2.15 + 0.28) and thus yields a worst-case log value of 2.43, corresponding to a worst-case BCF of 269 L/kg.
Result Key model:
BCF (US EPA T.E.S.T version 4.2.1; rounded): 141 L/kg whole body wet weight (range of 5 single models: 83-208 L/kg); worst case BCF (implying maximum underestimation from 14 similar compounds): 269 L/kg whole body wet weight.
Supporting model results corroborate the result obtained from the key model:
Supporting model 1:
Arnot & Gobas (2003) bioconcentration model – result: BCF 222 L/kg wet weight (using corrected metabolic rate constant based on similar compounds).
This result is only slightly above to the key model prediction of BCF 141 L/kg wet weight by T.E.S.T. Consensus Method and still below the worst case BCF of 269 L/kg derived from T.E.S.T. prediction under manual consideration of results for similar compounds. The result from the mechanistically based Arnot & Gobas (2003) bioconcentration model therefore clearly supports the result of the key model. But even the BCF of 474 L/kg resulting from using the less probable non-corrected metabolic rate constant is still far below the regulatory threshold for B (2000).
Supporting model 2:
BCF estimated according to the equation by Veith et al. (1979) based on experimentally determined log Kow – result: BCF 610 L/kg wet weight.
Sensitivity and conservatism (no biotransformation assumed) of this method render it appropriate to give additional confidence that the submission substance 3-chloro-o-xylene definitely is not bioaccumulative according to REACH. As such, it qualitatively corroborates the outcome of the key model US EPA T.E.S.T. Consensus Method even if the result for BCF is higher. It thus reinforces reliability of the key study.
Taken together, it is safe to conclude that
· The submission substance is not bioaccumulative (BCF clearly below 2000 L/kg);
· The worst case BCF (implying maximum underestimation from 14 similar compounds) of 269 L/kg wet weight based on T.E.S.T. Consensus Method results (key model) will be sufficiently conservative as the relevant figure for chemical risk assessment.
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