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Bioaccumulation: aquatic / sediment

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Endpoint:
bioaccumulation in aquatic species: fish
Type of information:
(Q)SAR
Adequacy of study:
weight of evidence
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
EPI Suite v4.11 Estimation Programs Interface Suite™ for Microsoft® Windows v 4.11. US EPA, United States Environmental Protection Agency, Washington, DC, USA.

2. MODEL (incl. version number)
BCFBAF v3.01, regression-based method

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
See “Test material information”

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
See attached information on the model provided by the developer. Further information on the OECD criteria as outlined by the applicant is provided below under "Any other information of materials and methods incl. tables"

5. APPLICABILITY DOMAIN
See attached information and information as provided in "Any other information on results incl. tables".

6. ADEQUACY OF THE RESULT
See assessment of adequacy as outlined in the "Overall remarks, attachments" section.
Principles of method if other than guideline:
- Software tool(s) used including version: EPI Suite v4.11
- Model(s) used: BCFBAF v3.01
Full reference and details of the used formulas can be found in:
1. Meylan, W.M., Howard, P.H, Aronson, D., Printup, H. and S. Gouchie.  1997.  "Improved Method for Estimating Bioconcentration Factor (BCF) from Octanol-Water Partition Coefficient", SRC TR-97-006 (2nd Update), July 22, 1997; prepared for: Robert S. Boethling, EPA-OPPT, Washington, DC; Contract No. 68-D5-0012; prepared by: ; Syracuse Research Corp., Environmental Science Center, 6225 Running Ridge Road, North Syracuse, NY 13212.
2. Meylan,WM, Howard,PH, Boethling, RS et al. 1999.  Improved Method for Estimating Bioconcentration / Bioaccumulation Factor from Octanol/Water Partition Coefficient.Environ. Toxicol. Chem. 18(4): 664-672 (1999).
- Model description: see field 'Justification for non-standard information', 'Attached justification' and 'any other information on Material and methods'
- Justification of QSAR prediction: see field 'Justific ation for type of information', 'Attached justification' and/or 'overall remarks'
GLP compliance:
no
Test organisms (species):
other: Fish
Route of exposure:
aqueous
Test type:
other: calculation
Water / sediment media type:
natural water: freshwater
Details on estimation of bioconcentration:
BASIS FOR CALCULATION OF BCF
- Estimation software: BCFBAF v3.01
- Result based on calculated log Kow of: 8.98 (estimated, KOWWIN v.1.68)
Type:
BCF
Value:
359.9 L/kg
Basis:
whole body w.w.
Type:
other: Log BCF
Value:
2.556 dimensionless
Basis:
whole body w.w.

For detailed information on the results please refer to the attached report.

Endpoint:
bioaccumulation: aquatic / sediment
Type of information:
(Q)SAR
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
results derived from a valid (Q)SAR model, but not (completely) falling into its applicability domain, with adequate and reliable documentation / justification
Remarks:
The substance is not fully compliant with the applicability domain of the model. However, this calculation is used in a weight of evidence approach, in accordance to the REACh Regulation (EC) No 1907/2006, Annex XI General rules for adaptation of the standard testing regime set out in Annexes VII to X, 1.2. It is adequately documented and justified: the prediction is evaluated on the basis of the model performance on similar substances. For more details see section `overall remarks, attachments´.
Justification for type of information:
1. SOFTWARE
EPI Suite v4.11 Estimation Programs Interface Suite™ for Microsoft® Windows v 4.11. US EPA, United States Environmental Protection Agency, Washington, DC, USA.

2. MODEL (incl. version number)
BCFBAF v3.01, Arnot-Gobas method

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
See “Test material information”

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
See attached information on the model provided by the developer. Further information on the OECD criteria as outlined by the applicant is provided below under "Any other information of materials and methods incl. tables"

5. APPLICABILITY DOMAIN
See attached information and information as provided in "Any other information on results incl. tables".

6. ADEQUACY OF THE RESULT
See assessment of adequacy as outlined in the "Overall remarks, attachments" section.
Qualifier:
according to guideline
Guideline:
other: REACH Guidance on QSARs R.6
Principles of method if other than guideline:
- Software tool(s) used including version: EPI Suite v4.11
- Model(s) used: BCFBAF v3.01

Full reference and details of the used formulas can be found in:

1. Arnot JA, Gobas FAPC. 2003. A generic QSAR for assessing the bioaccumulation potential of organic chemicals in aquatic food webs. QSAR and Combinatorial Science 22: 337-345.
- Model description: see field 'Justification for non-standard information', 'Attached justification' and 'any other information on Material and methods'
- Justification of QSAR prediction: see field 'Justific ation for type of information', 'Attached justification' and/or 'overall remarks'
GLP compliance:
no
Vehicle:
no
Test organisms (species):
other: Fish
Route of exposure:
other: aqueous and dietary
Test type:
other: calculation
Water / sediment media type:
natural water: freshwater
Details on estimation of bioconcentration:
BASIS FOR CALCULATION OF BCF
- Estimation software: EPI Suite v4.11, BCFBAF v3.01
- Result based on calculated log Pow of: 8.98
Type:
BCF
Value:
1.05 L/kg
Basis:
whole body w.w.
Remarks on result:
other: including biotransformation, upper trophic
Type:
other: log BCF
Value:
0.021 dimensionless
Basis:
whole body w.w.
Remarks on result:
other: including biotransformation, upper trophic

For detailed information on the results please refer to the attached report.

Endpoint:
bioaccumulation: aquatic / sediment
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Data from review article.
Qualifier:
no guideline followed
Principles of method if other than guideline:
Review article, describing biotransformation reactions and their effect on toxicity and bioaccumulation of certain chemicals in fish.
GLP compliance:
no
Test organisms (species):
other: not applicable
Route of exposure:
other: not applicable
Test type:
other: not applicable
Type:
other:
Remarks on result:
other: Not applicable, review article.

The catalytic activity of the carboxylesterase family leads to a rapid biotransformation/metabolism of xenobiotics which reduces the bioaccumulation or bioconcentration potential. Several in-vivo and in-vitro experiments showed the biotransformation of xenobiotics in fish. The biotransformation reactions have been shown to occur in fish at rates which have siginificant effects on toxicity and residue dynamics of selected chemicals. Inhibition of these reactions can lead to increased toxicity and bioaccumulation factors. Thus, it was shown that the carboxylesterase activity has an influence on the bioaccumulation of xenobiotics.

Endpoint:
bioaccumulation: aquatic / sediment
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable, well documented publication which meets basic scientific principles.
Qualifier:
no guideline followed
Principles of method if other than guideline:
In vitro enzyme study with liver microsomal and cytosolic fractions from different fish species recommended as test species in OECD guidelines.
GLP compliance:
no
Test organisms (species):
other: Poecilia reticulata, Cyprinus carpio, Danio rerio, Leuciscus idus, Salmo gairdneri
Details on test organisms:
TEST ORGANISM
- Common name: Guppy, common carp, zebra fish, golden orfe, rainbow trout
- Source: Guppy, common carp and zebra fish were purchased from Euraquarium, Bologna, Italy. Rainbow trout was kindly supplied by Istituto Ittiogenico, Rome, Italy.
- Length at study initiation: see Tab. 1
- Weight at study initiation: see Tab. 1
- Method of breeding: The guppy stocks were made up of adult females only, whereas all other fish stocks included individuals of both sexes. Fish sizes and rearing conditions were chosen to meet EEC test guidelines as closely as possible.

ACCLIMATION
- Acclimation period: Fish were acclimatised for at least one week.
- Type and amount of food: Fish were fed a semisynthetic diet purchased from Piccioni, Brescia, Italy.
- Health during acclimation (any mortality observed): Less than 2% mortality per week was observed in all the stocks used.
Route of exposure:
other: not applicable, in vitro study
Test type:
other: in vitro
Water / sediment media type:
natural water: freshwater
Type:
other:
Remarks on result:
other: Not applicable, review article.

The metabolic efficiency of the liver in the enzymatic hydrolysis of exogenous substrates is dependent on both the substrate type and the fish species. Indeed, the fish studied metabolise much more readily phenyl acetate, the typical substrate of A-esterases, and the phosphate monoester, than the B-esterase substrates. The inter-species differences in activities (referred to unit body weight) vary within a factor of 7 – 17 for esterases (with p-nitrophenyl phosphate, phenyl acetate or ethyl-butyrate as substrate), while reaching a factor of variation of even 60 for acetanilide amidase.

In line with previous evidence on hepatic mono-oxygenase and glutathione S-transferases, guppy is the most active fish species, also with reference to non-specific hydrolases. At variance with results on the other enzyme families, carp also is endowed with the highest levels of hydrolases.

Description of key information

Propane-1,2,3-triyl 2-ethylhexanoate (CAS No. 7360-38-5) exhibits a low potential for bioaccumulation, based on QSAR calculations and rapid metabolisation as expected for this substance.

Key value for chemical safety assessment

Additional information

No experimental data evaluating the bioaccumulation potential of Propane-1,2,3-triyl 2-ethylhexanoate (CAS No. 7360-38-5) is available. The substance exhibits a high log Kow (log Kow = 8.98), suggesting potential to bioaccumulate in biota. However, the information gathered on environmental behaviour and metabolism in combination with QSAR-estimated values provide enough evidence (in accordance to the REACh Regulation (EC) No 1907/2006, Annex XI General rules for adaptation of the standard testing regime set out in Annexes VII to X, 1.2, to cover the data requirements of Regulation (EC) No. 1907/2006, Annex IX) to state that this substance is likely to show no bioaccumulation potential.

Intrinsic properties and fate

Propane-1,2,3-triyl 2-ethylhexanoate (CAS No. 7360-38-5) is readily biodegradable.According to the Guidance on information requirements and chemical safety assessment, Chapter R.7b, readily biodegradable substances can be expected to undergo rapid and ultimate degradation in most environments, including biological Sewage Treatment Plants (STPs) (ECHA, 2017b).Therefore, after passing through conventional STPs, only low concentrations of these substances are likely to be (if at all) released into the environment.

Propane-1,2,3-triyl 2-ethylhexanoate (CAS No. 7360-38-5) exhibits a high log Kow (log Kow = 8.98) and a water solubility < 0.05 mg/L. The Guidance on information requirements and chemical safety assessment, Chapter R7.B (ECHA, 2017b) states that once insoluble chemicals enter a standard STP, they will be extensively removed in the primary settling tank and fat trap and thus, only limited amounts will get in contact with activated sludge organisms. Nevertheless, once this contact takes place, these substances are expected to be removed from the water column to a significant degree by adsorption to sewage sludge (Guidance on information requirements and chemical safety assessment, Chapter R.7a, ECHA, 2017a) and the rest will be extensively biodegraded (due to ready biodegradability).Thus, discharged concentrations of these substances into the aqueous compartment are likely to be very low.Should the substances be released into the water phase, due to their hydrophobicity and expected high adsorption potential, they will tend to bind to sediment and other particulate organic matter, and therefore, the actual dissolved fraction available to fish via water will be reduced. Thus, the main route of exposure for aquatic organisms such as fish will be via food ingestion or contact with suspended solids.

QSAR data

Additional information on the bioaccumulation Propane-1,2,3-triyl 2-ethylhexanoate (CAS No. 7360-38-5) in fish species is available. Estimated bioconcentration (BCF) and bioaccumulation (BAF) values were calculated for this substance using the BCFBAF v3.01 program (Estimation Programs Interface Suite™ for Microsoft® Windows v 4.11., US EPA), including biotransformation rates (Arnot-Gobas method). Even though the substance is outside the applicability domain of the used model (model training set is constituted of substances with log Kow values in the range of 0.31 to 8.70), the calculations (especially the low BCF values calculated using the Arnot-Gobas method) reflect the rapid biotransformation assumed for Propane-1,2,3-triyl 2-ethylhexanoate (CAS No. 7360-38-5). The calculated BCF and BAF values are 360 L/kg (BCF, regression based estimate) and 1.05 (Arnot-Gobas method, BCF and BAF, respectively). BCF calculations reflect the bioaccumulation potential after uptake via water, whereas the BAF gives an indication of the bioaccumulation when all exposure routes (water, food, etc.) are taken into account.

The obtained results indicate that Propane-1,2,3-triyl 2-ethylhexanoate is likely to show no bioaccumulation potential.According to Regulation (EC) No. 1907/2006, Annex XIII, 1.1.2, a substance only fulfills the bioaccumulation criterion (B) when BCF values are > 2000. Even though this condition is preferred to be confirmed with experimental data, in this case the estimated QSAR-based BCFs provide sufficient reliable evidence which suggests that the substance will not be bioaccumulative.

Metabolism of Propane-1,2,3-triyl 2-ethylhexanoate

If Propane-1,2,3-triyl 2-ethylhexanoate is uptaken by living organisms, aliphatic esters such as the substance will be initially metabolized via enzymatic hydrolysis to the respective fatty acid and alcohol components as would other dietary fats (e.g., Linfield, 1984). The hydrolysis is catalyzed by carboxylesterases and esterases, with B-esterases located in hepatocytes of mammals being the most important (Heymann, 1980; Anders, 1989). However, carboxylesterase activity has also been reported from a wide variety of tissues in invertebrates and fishes (e.g., Leinweber, 1987; Suldano et al., 1992; Barron et al., 1999; Wheelock et al., 2008). In fish, the high catalytic activity, low substrate specificity and wide distribution of the enzymes in conjunction with a high tissue content lead to a rapid biotransformation of aliphatic esters, which significantly reduces its bioaccumulation potential (Lech & Melancon, 1980; Lech & Bend, 1980).

Metabolites

Glycerol and 2-ethylhexanoic acid are the expected hydrolysis products from the enzymatic reaction catalyzed by carboxylesterase. The metabolism of fatty alcohols has been intensively reviewed in the literature (e.g., see Rizzo et al., 1987; Hargrove et al., 2004). The free alcohols can either be esterified to form wax esters (which are similar to triglycerides) or they can be transformed to fatty acids in a two-step enzymatic process catalyzed by alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH). The responsible enzymes ADH and ALDH are present in a large number of animals including plants, microorganisms and fish (e.g., Sund & Theorell, 1963; Nilson, 1990; Yoshida et al., 1997; Reimers et al., 2004; Lassen et al., 2005). 

The metabolism of alcohols in fish was intensively studied by Reimers et al. (2004).They isolated and characterized two cDNAs from the zebra fish, Danio rerio, encoding ADHs, which showed specific metabolic activity in in-vitro assays with various alcohol components ranging from C4 to C8. The emerging aldehydes were shown to be further oxidized to the corresponding fatty acid by ALDH enzymes. The most effective ALDH2, which is mainly located in the mitochondria of liver cells showed a similarity of 75% to mammalian ALDH2 enzymes and a similar catalytic activity (also see Nilsson, 1988). The same metabolic pathway was shown for longer chain alcohols, such as stearyl and oleyl alcohol in the intestines of rats (Sieber et al., 1974).

The further metabolism of the fatty acids in general is also well investigated in various organisms, such as plants (e.g., Harwood 1988), fish (e.g., Henderson, 1996; Turchini, 2006) or algae (e.g., Nichols, 1968).The free fatty acids can either be stored as triglycerides or be oxidized via mitochondrial ß-oxidation removing C2-units, in order to store usable energy in form of ATP (Masoro, 1977). Acetyl-CoA, the final product of the ß-oxidation process, can further be mineralized in the tricarboxylic acid cycle via different enzymatically catalyzed processes to carbon dioxide.

Both hydrolysis products, 2-ethylhexanoic acid and glycerol, were assessed as safe by authorities regarding their bioaccumulation potential (Environment Canada, 2011; OECD, 2002).This is also underlined by their low log Kow values (-1.65 and 2.96, for Glycerol and 2-ethylhexanoic acid, respectively; values calculated using KOWWIN v1.68).

Summarizing, Propane-1,2,3-triyl 2-ethylhexanoate is expected to be rapidly hydrolyzed to 2-ethylhexanoic acid and glycerol.Both hydrolysis products are supposed to be satisfactory metabolized in aquatic organisms and are not bioaccumulative. Therefore, for Propane-1,2,3-triyl 2-ethylhexanoate no potential for bioaccumulation is to be expected.

Conclusion

Propane-1,2,3-triyl 2-ethylhexanoate is not expected to be bioaccumulative. Due to it´s readily biodegradable nature, extensive degradation of this substances in conventional STPs will take place and only low concentrations are expected to be released (if at all) into the environment. Once present in the aquatic compartment, further biodegradation will occur and, due the high log Kow will be bioavailable to aquatic organisms such as fish mainly via feed and contact with suspended organic particles. After uptake by fish species, extensive and fast biotransformation of the substance into Glycerol and 2-ethylhexanoic acid is expected. The supporting BCF/BAF values estimated with the BCFBAF v3.01 program also indicate that this substance will not be bioaccumulative (all well below 2000 L/kg).

The information above provides strong evidence supporting the statement that rapid metabolism and low bioaccumulation potential can be expected for this substance.

A detailed reference list is provided in the technical dossier (see IUCLID, section 13) and within the CSR.