Nonanoic acid, mixed esters with heptanoic acid, pentaerythritol and valeric acid

Bioaccumulation: aquatic / sediment

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

bioaccumulation in aquatic species: fish

Type of information:

other: publication

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:

The activity of carboxylesterase (CaE), a class of nonspecific serine hydrolases, was evaluated in vitro in tissues and microsomes of rainbow trout. In the assays the formation of 4-nitrophenol from 4-nitrophenyl acetate was measured spectrophotometrically.

GLP compliance:

no

Test organisms (species):

Oncorhynchus mykiss (previous name: Salmo gairdneri)

Details on test organisms:

TEST ORGANISM
- Common name: rainbow trout
- Source: Trouts were obtained as eyed embryos from Mt. Lassen Trout Farms, Mt. Lassen CA, USA
- Age at study initiation: < 1 year
- Length at study initiation (lenght definition, mean, range and SD):
- Weight at study initiation: 1.64 ± 0.07 g wet weight
- Weight at termination (mean and range, SD):
- Method of holding: Trout were held in flow-through aerated raceways at 12 ± 1 °C. The laboratory water was softened Lake Huron water that had been sand-filtered, pH adjusted with CO 2, carbon-filtered, and ultraviolet irradiated. Laboratory water was monitored weekly for pH, alkalinity, conductivity, and hardness; and quarterly for selected inorganics, pesticides, and poly-chlorinated biphenyls. Typical water quality values were pH of 7.5, alkalinity of 43 mg/L, hardness of 70 mg/L (as CaCO3 ), and conductivity of 140 mhos/cm. Fish were killed by a blow to the head and placed immediately on ice before tissue preparation.

Route of exposure:

other: In vitro exposure

Test type:

other: In vitro study

Water / sediment media type:

natural water: freshwater

Remarks on result:

other: Precise results cannot be given, see explanation in any other information on results incl. tables.

The results of this study demonstrated that rainbow trout had high esterase activity over a broad range of temperatures, that carboxylesterase (CaE) activity significantly increased between the yolk-sac and juvenile life stages, and that variation between the CaE activity in trout and three other families of freshwater fish was limited.

Reference 2

Endpoint:

bioaccumulation in aquatic species: fish

Type of information:

other: publication

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Data from review article/book chapter.

Qualifier:

no guideline followed

Principles of method if other than guideline:

no data

GLP compliance:

no

Test organisms (species):

other: not applicable

Route of exposure:

other: not applicable

Remarks on result:

other: Precise results cannot be given, see explanation in any other information on results incl. tables.

Carboxylesterases are a class of enzymes responsible for the ester cleavage of carboxylic esters. Liver B-carboxylesterases are the most prominent group of all “nonspecific” ester-cleaving enzymes. The preferred substrates of B-esterases are aliphatic esters. B-type esterases have been characterized in human muscle, kidney, brain, liver and serum of mammals. The activity of B-esterase from pig and rat liver was shown for several carboxylesters (e.g. methyl octanoate, heptyl acetate).

Reference 3

Endpoint:

bioaccumulation in aquatic species: fish

Type of information:

other: publication

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

Remarks on result:

other: Precise results cannot be given, see explanation in any other information on results incl. tables.

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.

Reference 4

Endpoint:

bioaccumulation in aquatic species: fish

Type of information:

other: publication

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Qualifier:

no guideline followed

Principles of method if other than guideline:

The study was conducted to examine the effects and fate of a number of chemicals, including hydrocarbons and chlorinated hydrocarbons. The interactions between these chemicals in fish were studied using several approaches: examination of the uptake, metabolism and elimination of selected chemicals by fish; assessment of the effects of selected inducing agents on hepatic xenobiotic metabolizing enzymes (assayed in vitro); and studies of the effects of inducing agents on the metabolism and disposition of other chemicals in vitro.

GLP compliance:

no

Test organisms (species):

other: Salmo gairdneri, Lepomis macrochirus, Cyprinus carpio and Archosargus probatocephalus

Route of exposure:

other: intraperitoneal injection

Remarks on result:

other: Precise results cannot be given, see explanation in any other information on results incl. tables.

Esters do not readily bioaccumulate in fish. This might be caused by the wide carboxyesterase distribution, high tissue content, rapid substrate turnover and limited substrate specificity.

Reference 5

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, 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

Type:

BCF

Value:

0.901 L/kg

Basis:

whole body w.w.

Remarks on result:

other: including biotransformation, upper trophic

Type:

other: log BCF

Value:

-0.045 dimensionless

Basis:

whole body w.w.

Remarks on result:

other: including biotransformation, upper trophic

Type:

BAF

Value:

0.901

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.

Reference 6

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, 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

Type:

BCF

Value:

6.322 L/kg

Basis:

whole body w.w.

Remarks on result:

other: including biotransformation, upper trophic

Type:

other: log BCF

Value:

0.801 dimensionless

Basis:

whole body w.w.

Remarks on result:

other: including biotransformation, upper trophic

Type:

BAF

Value:

6.323

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.

Reference 7

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, 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

Type:

BCF

Value:

0.893 L/kg

Basis:

whole body w.w.

Remarks on result:

other: including biotransformation, upper trophic

Type:

other: log BCF

Value:

-0.049 dimensionless

Basis:

whole body w.w.

Remarks on result:

other: including biotransformation, upper trophic

Type:

BAF

Value:

0.893

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.

Description of key information

The potential for bioaccumulation of Monopentaerythritol tetraesters and dipentaerythritol hexaesters of valeric, heptanoic and nonanoic acids is assumed to be low based on all available data.

Additional information

Experimental bioaccumulation data are not available for Monopentaerythritol tetraesters and dipentaerythritol hexaesters of valeric, heptanoic and nonanoic acids. The high log Kow (> 10) for most components, as an intrinsic chemical property of the substance, indicates a potential for bioaccumulation. However, the information gathered on environmental behaviour and metabolism, in combination with QSAR-estimated values, provide enough evidence (in accordance to the 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 and to state that the substance is likely to show negligible bioaccumulation potential.

Due to ready biodegradability and high potential of adsorption, the substance can be effectively removed in conventional sewage treatment plants (STPs) by biodegradation and by sorption to organic matter. An assessment of bioaccumulation for possible degradation products is not considered to be necessary. Due to the ready biodegradability rapid and ultimate biodegradation under most environmental conditions is assumed. Thus, according to ECHA Guidance R.7b, no further investigation of the bioaccumulation of transformation products is required (ECHA, 2017b). The low water solubility (< 2.01 mg/L at 20 °C) and high estimated log Kow (> 10) for most of the components indicate that the substance is highly lipophilic. If released into the aquatic environment, the substance undergoes extensive biodegradation and sorption on organic matter. Thus, the bioavailability in the water column is reduced rapidly. The relevant route of uptake of Monopentaerythritol tetraesters and dipentaerythritol hexaesters of valeric, heptanoic and nonanoic acids in aquatic organisms is expected to be predominantly by ingestion of particle bound substance.

The smaller the molecule, the more easily it will be taken up. In general, molecular weights below 500 g/mol are favorable for oral absorption (ECHA, 2017d). As the molecular weight of Monopentaerythritol tetraesters and dipentaerythritol hexaesters of valeric, heptanoic and nonanoic acids ranges from 472.61 – 1095.61 g/mol absorption of the molecule is considered to be limited. Absorption after oral administration is also unexpected when the “Lipinski Rule of Five” (Lipinski et al. (2001), Ghose et al. (1999)) is applied to the substance Monopentaerythritol tetraesters and dipentaerythritol hexaesters of valeric, heptanoic and nonanoic acids, as the substance fails two rules for good bioavailability (molecular weight is >500 and the log Pow is >5). Thus, oral absorption is expected to be limited. Please refer to the toxicokinetic statement in IUCLID section 7.1 for further information.

However, should the substance be taken up by fish during the process of digestion and absorption in the intestinal tissue, aliphatic esters like Monopentaerythritol tetraesters and dipentaerythritol hexaesters of valeric, heptanoic and nonanoic acids are expected to be initially metabolized via enzymatic hydrolysis to the corresponding free fatty acid. The hydrolysis is catalyzed by classes of enzymes known as carboxylesterases or esterases (Heymann, 1980). The most important of which are the B-esterases in the hepatocytes of mammals (Heymann, 1980; Anders, 1989). Carboxylesterase activity has been noted in a wide variety of tissues in invertebrates as well as in fish (Leinweber, 1987; Soldano et al., 1992; Barron et al., 1999, Wheelock et al., 2008). The catalytic activity of this enzyme family leads to a rapid biotransformation/metabolism of xenobiotics which reduces the bioaccumulation or bioconcentration potential (Lech & Bend, 1980). It is known for esters that they are readily susceptible to metabolism in fish (Barron et al., 1999) and reliable literature data have clearly shown that esters do not readily bioaccumulate in fish (Rodger & Stalling, 1972; Barron et al., 1990). In fish species, this might be caused by the wide distribution of carboxylesterase, high tissue content, rapid substrate turnover and limited substrate specificity (Lech & Melancon, 1980; Heymann, 1980). The metabolism of the enzymatic hydrolysis products is presented in the following chapter.

Pentaerythritol is the product from the enzymatic reaction Monopentaerythritol tetraesters and dipentaerythritol hexaesters of valeric, heptanoic and nonanoic acids catalyzed by carboxylesterases. Pentaerythritol is absorbed rapidly but mainly excreted unchanged. DiCarlo et al. (1965) reported that 10 mg/kg C14-labled PE orally administered to mice was absorbed and excreted rapidly from the gastrointestinal tract. Almost half of the administered dose left the gastrointestinal tract within 15 min and 68% of the dose appeared as unchanged PE in the urine and feces after 4 hours already.

In addition the cleavage product has a very low potential for bioaccumulation based on the very low log Kow of -1.767 (estimated by KOWWIN v1.68).

The metabolism of fatty acids in mammals is well known and has been investigated intensively in the past (Stryer, 1994). The free fatty acids can either be stored as triglycerides or oxidized via mitochondrial ß-oxidation removing C2-units to provide energy in the form of ATP (Masoro, 1977). Acetyl-CoA, the product of the ß-oxidation, can further be oxidized in the tricarboxylic acid cycle to produce energy in the form of ATP. As fatty acids are naturally stored as trigylcerides in fat tissue and re-mobilized for energy production it can be concluded that even if they bioaccumulate, bioaccumulation will not pose a risk to living organisms. Fatty acids (typically C14 to C24 chain lengths) are also a major component of biological membranes as part of the phospholipid bilayer and therefore part of an essential biological component for the integrity of cells in every living organism (Stryer, 1994). Saturated fatty acids (SFA; C12 - C24) as well as mono-unsaturated (MUFA; C14 - C24) and poly-unsaturated fatty acids (PUFA; C18 - C22) were naturally found in muscle tissue of the rainbow trout (Danabas, 2011) and in the liver (SFA: C14 - C20; MUFA: C16 - C20; PUFA: C18 - C22) of the rainbow trout (Dernekbasi, 2012).

Additional information on bioaccumulation could be gathered using the (Q)SAR model BCFBAF v3.01. The estimated BCF values for Monopentaerythritol tetraesters and dipentaerythritol hexaesters of valeric, heptanoic and nonanoic acids indicate negligible bioaccumulation in organisms. When including biotransformation, low BCF/BAF values of 0.8931 - 0.8947 resulted (Arnot-Gobas estimate, including biotransformation, upper trophic). The applicability domain of the QSAR model (BCFBAF v3.01) consists of a descriptive domain and a structural domain. The representative components of the UVCB substance are not completely in the applicability domain of the model. The biotransformation rate in fish is estimated using structural fragments of the representative components to estimate the half-life. In this particular case all structural fragments necessary for the prediction of the half-life were included in the training set of the model. However, some of the fragments slightly exceeded the maximum number of instances in the training set which is not expected to have a significant impact on the final result. Even though the applicability domain of the model is not completely met, the (Q)SAR calculations can be used as supporting indication that the potential of bioaccumulation is low. Moreover, the results support the tendency that substances with high log Kow values (> 10) have a lower potential for bioconcentration as summarized in the ECHA Guidance R.11 and they are not expected to meet the B/vB criterion (ECHA, 2017d).

Conclusion

The biochemical process metabolizing aliphatic esters is ubiquitous in the animal kingdom. Based on the enzymatic hydrolysis of aliphatic esters and the subsequent metabolism of the corresponding carboxylic acid and alcohol, it can be concluded that the high log Kow, which indicates a potential for bioaccumulation, overestimates the true bioaccumulation potential of Monopentaerythritol tetraesters and dipentaerythritol hexaesters of valeric, heptanoic and nonanoic acids since it does not reflect the metabolism of substances in living organisms. BCF/BAF values estimated with the BCFBAF v3.01 program also indicate that Monopentaerythritol tetraesters and dipentaerythritol hexaesters of valeric, heptanoic and nonanoic acids will not be bioaccumulative (all well below 2000 L/kg). The cleavage product pentaerythritol has a low potential for bioaccumulation based on the low log Kow (< 3) and fatty acids are metabolised by common physiological processes.

Moreover, the bioavailability of the substance in the environment is limited due to its high lipophilicity and adsorption to organic matter.

Taking all these information into account, it can be concluded that the bioaccumulation potential of Monopentaerythritol tetraesters and dipentaerythritol hexaesters of valeric, heptanoic and nonanoic acids acid is low.