Ethoxyquin

Long-term toxicity to fish

Link to relevant study record(s)

Reference

Endpoint:

long-term toxicity to fish, other

Remarks:

Chronic toxicity

Type of information:

(Q)SAR

Adequacy of study:

key study

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
EPIWIN software by US-EPA

2. MODEL (incl. version number)
ECOSAR v1.11

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
O(c(ccc(NC(C=C1C)(C)C)c12)c2)CC
CAS 91-53-2

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
- The model and the training and validation sets are published by US Environmental Protection Agency (USA). Details in addition to the summary provided here can be found in the program.
- Defined endpoint:
ECOSAR study criteria articulate that the toxicity should be measured at pH 7 (replicating environmental conditions), the total organic carbon content should not exceed 2 mg/L, the water hardness should be approximately 150 mg/L CaCO3, results should be adjusted to, or measured at, 100% active ingredient, and flow-through measured is preferred over static nominal, etc. Data received or identified in the open literature which is not accompanied with full study details to confirm conditions are often not considered appropriate for model development. Therefore, many measured ecotoxicity data points can be found in the open literature which are not considered suitable for inclusion in the ECOSAR model.
When collecting studies for inclusion in the training sets, standard test species were preferred as identified in OPPTS guidelines for aquatic toxicity testing. For freshwater fish data, species frequently include bluegill sunfish (Lepomis macrochirus), common carp (Cyprinus carpio), fathead minnow (Pimephales promelas), guppy (Poecilia reticulate), rainbow trout (Oncorhynchus mykiss), red killifish (Oryzias latipes), or zebrafish (Brachydanio rerio). For freshwater invertebrates, species frequently include Daphnia magna or Daphnia pulex. For freshwater algae, species frequently include Desmodesmus subspicatus or Pseudokirchneriella subcapitata. Therefore, the equations in ECOSAR are derived from surrogate species of fish, zooplankton, and phytoplankton.
- Unambiguous algorithm: After collecting the training set information for each chemical including estimated log Kow and valid toxicity results, regression techniques are applied to the class-specific data sets to derive mathematical relationships between log Kow and toxicity (often called the resulting algorithm). These resulting class-specific equations typically take the form of y = mx + b, where “y” represents the toxic effect concentration (i.e. log LC50 in mmol/L) and “x” represents the log Kow value. Using these resulting linear equations, toxicity values (mmol/L) for untested chemicals may then be calculated in a three-step process: (1) select the appropriate class using the ECOSAR class definitions, (2) input the measured or estimated log Kow value of the molecule into the mathematical regression equation to estimate the toxic effect concentration (mmol/L), (3) use molecular weight of the subject chemical to convert the estimated effect concentration from mmol/L to mg/L for use in aquatic toxicity hazard profiles. The computerized ECOSAR program is designed to automatically complete all three steps when providing estimates based on the users chemical input.
- Defined domain of applicability: EPI Suite cannot be used for all chemical substances. The intended application domain is organic chemicals. Inorganic and organometallic chemicals generally are outside the domain. To estimate the toxicity to aquatic organisms of neutral organics and organic classes with excess toxicity, the log Kow and molecular weight are required. In general, when the log Kow is less than or equal to 5.0 for fish and daphnid, or 6.4 for green algae, ECOSAR provides reliable quantitative (numeric) toxicity estimates for acute effects. For chronic exposures, the applicable log Kow range to derive reliable quantitative (numeric) values is extended up to log Kow 8.0. In the development of the ECOSAR equations for neutral organics and classes with excess toxicity, the training sets generally include chemicals with log Kow values in the range of -3 to 8 and molecular weights less than 1000. However, the domain of the model is considered to be larger than the descriptor range of the training set of chemicals.

5. APPLICABILITY DOMAIN
- Descriptor domain: Ethoxyquin is an organic chemical with a molecular weight of 217.31 g/mol, its logPow is 3.39 at pH 7, and hence falls into the applicability domain of the model providing accurate results.
- Structural and mechanistic domains: The substance is neutral organic chemical and falls hence in the structural domain of the model
- Similarity with analogues in the training set: There are currently 130 chemical classes programmed into ECOSAR: Acid Chlorides/Halides, Acrylamides, Acrylates, Aldehydes - Mono, Aldehydes - Poly, Aliphatic Amines, Allyl / Vinyl Aldehydes, Allyl / Vinyl Alcohols, Allyl / Vinyl Ethers, Allyl / Vinyl Halides, Allyl / Vinyl Ketones, Allyl / Vinyl Nitriles, Allyl / Vinyl Sulfones, Allyl / Vinyl Thiocarbamates, Alkoxysilanes, Amides , Anilines - Aromatic Amines, Anilines, Amino (meta), Anilines, Amino (ortho) , Anilines, Amino (para) , Azides, Aziridines, Azonitriles, Baseline Toxicity Equations, Benzodioxoles, Benzothiazoles, Benzotriazoles, Benzoylcyclohexanediones, Benzyl Alcohols, Benzyl Amines, Benzyl Halides, Benzyl Imides, Benzyl Ketones, Benzyl Nitriles, Benzyl Thiols, , Bromoalkanes, Caprolactams, Carbamate Esters, Carbamate Esters, Oximes, Diazoniums, Diazoniums, Aromatic, Diketones, Dinitroanilines - Dinitroaromatic Amines, Dinitrobenzenes, Dinitrophenols, Dyes, Cationic, Epoxides, Mono, Epoxides, Mono Acid Substituted, Epoxides, Poly, Epoxides, Halo, Esters, Esters, Dithiophosphates, Esters, Monothiophosphates, Esters, Phosphate, Esters, Phosphinate, Esters, Halo, Esters, Nitriles, Esters, Peroxy, Esters x 10, Haloacetamides, Haloalcohols, Haloamines, Halo Benzamides, Halo Epoxides, Halo Esters, Halo Ethers, Halo Hydantoins, Halo Ketones, Halo Nitriles, Halo Pyridines, Hydrazines, Hydrazines, Semicarbazide, Alkyl Substituted, Hydrazines, Semicarbazide, Aryl, Meta/Para Substituted, Hydrazines, Semicarbazide, Aryl, Ortho Substituted, Hydroquinones / Quinones, Imidazoles, Imides, Imide Acids, Isocyanates, Isothiazolones, Ketone Alcohols, Malononitriles, Melamines, Mercaptans, Methacrylates, Neutral Organics, Nitriles, alpha OH, Nitriles, Esters, Nitriles, Polyaliphatic, Nitro alcohols, Nitro-/Nitrosobenzamides, Oxetanes, Peroxy Acids / Peroxides, Peroxy esters, Phenols, Phenols, Amines, Phenols, Poly, Phosphine Oxide, Phthalonitriles, Propargyl Alcohols, Propargyl Alcohols (Hindered) , Propargyl Amines, Propargyl Carbamates, Propargyl Ethers, Propargyl Halides, Pyrazoles, Pyrroles, Pyrethroids, Pyridines, alpha-Acid, Pyridine Thiones, Quinones / Hydroquinones, Rosins, Salicylates, Salicylic Acid, Schiff Bases, Silamines, Silanes (alkoxy) , Sulfonyl Ureas, Thiazolidinones, Thiazolidinones, Acid, Thiocarbamates, Di (Free Acid), Thiocarbamates, Di (Substituted), Thiocarbamates, Di (Fe salts), Thiocarbamates, Di (Mn salts), Thiocarbamates, Di (Na salts), Thiocarbamates, Di (Zn salts), Thiocarbamates, Mono, Thiocyanates, Thiols, Thiomethacrylates, Thiophenes, Thiotetrazoles, Thioureas, Triazines, Triazole Pyrimidines, Triazoles, Ureas, Substituted, Vinyl / Allyl Alcohols, Vinyl / Allyl Aldehyes, Vinyl / Allyl Amines, Vinyl / Allyl Esters, Vinyl / Allyl Ethers, Vinyl / Allyl Ether Amines, Vinyl / Allyl Halides, Vinyl / Allyl Ketones, Vinyl / Allyl Nitriles, Vinyl / Allyl Sulfones, Vinyl / Allyl Thiocarbamates. All chemical structures and functional groups of the substance are hence contained in the available chemical groups of the model.

6. ADEQUACY OF THE RESULT
The training set consist of data gained from testing under OPPTS guidelines for aquatic toxicity testing, which are equivalent to the respective OECD guidelines or EU methods, which are recommended as testing guidelines for testing with the purpose for classification and labelling, or risk assesment under REACH. Ethoxyquin falls into the applicability domain of the model providing accurate results. Hence, the present prediction fits the purpose of classification and labelling and/or risk assessment.

Guideline:

other: REACH guidance on QSARs Chapter R.6

Version / remarks:

May 2008

GLP compliance:

no

Remarks:

not applicable

Analytical monitoring:

not required

Remarks:

QSAR estimation

Details on test solutions:

not applicable

Test organisms (species):

other: Frequent species: bluegill sunfish (Lepomis macrochirus), common carp (Cyprinus carpio), fathead minnow (Pimephales promelas), guppy (Poecilia reticulate), rainbow trout (Oncorhynchus mykiss), red killifish (Oryzias latipes), zebrafish (Brachydanio rerio)

Details on test organisms:

no further data regarding the training set are available

Test type:

other: ECOSAR study criteria (training set) articulate i.a. that flow-through measured is preferred over static nominal

Remarks on exposure duration:

The ChV, is defined as the geometric mean of the no observed effect concentration (NOEC) and the lowest observed effect concentration (LOEC). This can be mathematically represented as: ChV = 10^([log (LOEC x NOEC)]/2); no further information is given

Key result

Dose descriptor:

other: ChV

Effect conc.:

1.14 mg/L

Remarks on result:

ChV (chronic value, QSAR)

Remarks:

freshwater fish

Dose descriptor:

other: ChV

Effect conc.:

3.245 mg/L

Remarks on result:

ChV (chronic value, QSAR)

Remarks:

saltwater fish

ECOSAR Class Organism Duration End Pt mg/L (ppm)

Neutral Organics : Fish 96-hr LC50 10.077

Neutral Organics : Fish ChV 1.146

Neutral Organics : Fish (SW) 96-hr LC50 12.792

Neutral Organics : Fish (SW) ChV 3.245

Validity criteria fulfilled:

yes

Conclusions:

The study report describes a scientifically accepted calculation method for the ready biodegradability using the US-EPA software ECOSAR Version 1.11. No GLP criteria are applicable for the usage of this tool and the QSAR estimation is easily repeatable. The substance falls within the applicability domain of the QSAR model, hence, the result can be considered as reliable. The result is adequate for the regulatory purpose.

Executive summary:

The Chronic toxicity value (ChV) for fish of the substance ethoxyquin was determined by the QSAR program ECOSAR Version 1.11 (EPIWIN software) by US-EPA.The ECOSAR Class Program is a computerized version of the ECOSAR analysis procedures as currently practiced by the Office of Pollution Prevention and Toxics (OPPT), and estimates log Kow values using the US EPA's KOWWIN Program.The ChV, or Chronic Value, is defined as the geometric mean of the no observed effect concentration (NOEC) and the lowest observed effect concentration (LOEC).

When collecting studies for inclusion in the training sets, standard test species were preferred as identified in OPPTS guidelines for aquatic toxicity testing. Species frequently include bluegill sunfish (Lepomis macrochirus), common carp (Cyprinus carpio), fathead minnow (Pimephales promelas), guppy (Poecilia reticulate), rainbow trout (Oncorhynchus mykiss), red killifish (Oryzias latipes), or zebrafish (Brachydanio rerio).

The Chronic values were determined to be 1.146 mg/l for freshwater fish, and 3.245 mg/l for saltwater fish.

Adequacy of the QSAR:

- QSAR model is scientifically valid.

- The substance falls within the applicability domain of the QSAR model.

- The prediction is fit for regulatory purpose.

Description of key information

ChV = 1.146 mg/l (freshwater fish), 3.245 mg/l (saltwater fish) (ECOSAR estimation)

Additional information

The Chronic values were determined to be 1.146 mg/l for freshwater fish, and 3.245 mg/l for saltwater fish. The ChV, or Chronic Value, is defined as the geometric mean of the no observed effect concentration (NOEC) and the lowest observed effect concentration (LOEC). This can be mathematically represented as: ChV = 10^([log (LOEC x NOEC)]/2). As a result, the NOEC cannot be adequately determined to select the required key value for safety assessment.

According to REACH Annex IX column 2, Long-term toxicity testing shall be proposed by the registrant if the chemical safety assessment according to Annex I indicates the need to investigate further the effects on aquatic organisms. The choice of the appropriate test(s) depends on the results of the chemical safety assessment. Based on the available short-term information on fish, the LC50(96h) = 18 mg/L for rainbow trout (Oncorhynchus mykiss) (OECD TG 203, flow-through) does not trigger classification as acute toxic to the environment. Taking however into account the fact that ethoxyquin is not readily biodegradable, and the BCF is not available, the logPow however was determined to be 3.39 at pH 7 (i.e. < 4), this value would trigger classification as hazardous to the aquatic environment Category Chronic 3. In consequence, QSAR estimation was performed to determine the absolute necessity for classification. The ChV was determined as 1.146 mg/l (freshwater fish) resp. 3.245 mg/l (saltwater fish), but a NOEC could not be determined by the ECOSAR program. According to Regulation 1272/2008 as amended, non-rapidly degradable substances must be classified as chronic 2 if the NOEC is <= 1 mg/l, the necessity for classification as chronic 3 is not demanded by the regulation for values above 1 mg/kg. Based on the available information, no conclusion on the actually required classification can be drawn. The necessity for further testing is however not given, as alternatively (non)-classification as hazardous to the environment can be done via testing data on invertebrates or algae.