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Short-term toxicity to fish

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Endpoint:
short-term toxicity to fish
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Study period:
1998
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
other: Read-across from an analogue substance for which there is available information (Klimish =4).
Justification for type of information:
REPORTING FORMAT FOR THE ANALOGUE APPROACH
See cross-reference to justification of read-across.
Reason / purpose:
read-across source
Reason / purpose:
read-across: supporting information
Key result
Duration:
96 h
Dose descriptor:
LC50
Effect conc.:
1.1 mg/L
Nominal / measured:
not specified
Conc. based on:
test mat.
Basis for effect:
mortality
Remarks on result:
other: Based on the read-across from the analogue substance d-limonene.
Conclusions:
Based on the read-across from an analogue substance, the 96 hour LC50 is estimated to be 1.1 mg/L.
Executive summary:

Based on the read-across from an analogue substance, the 96 hour LC50 is estimated to be 1.1 mg/L.

Endpoint:
short-term toxicity to fish
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Study period:
1989
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Read-across from an analogue substance for which there is available information (Klimish=2).
Justification for type of information:
REPORTING FORMAT FOR THE ANALOGUE APPROACH
See cross-reference to justification of read-across.
Reason / purpose:
read-across source
Reason / purpose:
read-across: supporting information
Key result
Duration:
96 h
Dose descriptor:
LC50
Effect conc.:
702 µg/L
Nominal / measured:
meas. (arithm. mean)
Conc. based on:
test mat.
Basis for effect:
mortality
Remarks on result:
other: 619-796 µg/L
Remarks:
Based on the read-acros from the analogue substance d-limonene.
Key result
Duration:
96 h
Dose descriptor:
EC50
Effect conc.:
702 µg/L
Nominal / measured:
meas. (arithm. mean)
Conc. based on:
test mat.
Basis for effect:
mobility
Remarks on result:
other: 619-796 µg/L
Remarks:
Based on the read-across from the analogue substance d-limonene.
Conclusions:
Based on the read-across from the analogue substance d-limonene. The 96h-LC50 was estimated to be 702 µg/L.
Executive summary:

Based on the read-across from the analogue substance d-limonene. The 96h-LC50 was estimated to be 702 µg/L.

Endpoint:
short-term toxicity to fish
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Study period:
1989
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study conducted similarly to OECD guideline 203 but without GLP compliance and with minor deviations (hardness of the dilution water not determined; no data on acclimation period). The report is sufficiently well documented.
Justification for type of information:
REPORTING FORMAT FOR THE ANALOGUE APPROACH
See cross-reference to justification of read-across.
Reason / purpose:
read-across source
Reason / purpose:
read-across: supporting information
Key result
Duration:
96 h
Dose descriptor:
LC50
Effect conc.:
720 µg/L
Nominal / measured:
meas. (arithm. mean)
Conc. based on:
test mat.
Basis for effect:
mortality
Remarks on result:
other: 618-839 µg/L
Remarks:
Based on the read-across from the analogue substance d-limonene.
Key result
Duration:
96 h
Dose descriptor:
EC50
Effect conc.:
688 µg/L
Nominal / measured:
meas. (arithm. mean)
Conc. based on:
test mat.
Basis for effect:
mobility
Remarks on result:
other: 606-782 µg/L
Remarks:
Based on the read-across from the analogue substance d-limonene.
Conclusions:
Based on the read-across from the analogue substance d-limonene, the 96 hour LC50 or EC50 of l-limonene to fathead minnow were estimated to be 720 µg/L or 688 µg/L, respectively.
Executive summary:

Based on the read-across from the analogue substance d-limonene, the 96 hour LC50 or EC50 of l-limonene to fathead minnow were estimated to be 720 µg/L or 688 µg/L, respectively.

 

 

Endpoint:
short-term toxicity to fish
Type of information:
(Q)SAR
Adequacy of study:
weight of evidence
Study period:
2011-05-30
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Calculation with a valid QSAR (ECOSAR), l-limonene falls within the applicability domain of the (Q)SAR model, the prediction fits for the regulatory purpose, and the information is enough documented.
Justification for type of information:
1. Relevance of the model

ECOSAR v1.00 is reported as a usable valid model by ECHA (R6: QSARs and grouping of chemicals, May 2008).
ECOSAR contains a library of class-based QSARs for predicting aquatic toxicity, overlaid with an expert decision tree for selecting the appropriate chemical class. ECOSAR Version 1.00 is programmed to identify over 120 chemical classes and allows access to over 600 QSARs for numerous endpoints and organisms.
The structure-activity relationships (SARs) presented in ECOSAR v1.00 are used to predict the aquatic toxicity of chemicals based on their similarity of structure to chemicals for which the aquatic toxicity has been previously measured. SARs are developed for chemical classes based on measured test data that have been submitted by industry to the US-Environmental Protection Agency or collected from publicly available sources. To date, over 440 SARs have been developed for more than 120 chemical classes. The supporting data sets (training sets) used to derive SARs within a chemical class range from the very large, e.g., neutral organics, to the very small, e.g., aromatic diazoniums. The class with the greatest number of SARs based on measured data is the neutral organics class, which has SARs ranging from acute and chronic toxicity to fish to a 14-day LC50 SAR for earthworms in artificial soil.
The ECOSAR Class Program is a computerized version of the ecotoxicity analysis procedures as currently practiced by the Office of Pollution Prevention and Toxics (OPPT) when data are lacking for regulatory endpoints. It has been developed within the regulatory constraints of the Toxic Substances Control Act (TSCA). It is a pragmatic approach to SAR as opposed to a theoretical approach.

2. Validation of the model

- Endpoint (OECD Principle 1)
Acute toxicity to fish (lethality). 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).The studies collected for the training set chemicals in ECOSAR undergo an extensive data validation step to ensure appropriateness for inclusion in the model. 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.

- Algorithm (OECD Principle 2)
Neutral organics, FISH 96-h LC50 ESTIMATED TOXICITY:
The fish 96-h LC50 values used to develop this SAR were measured and the octanol water partition coefficients (Kow) were calculated using the computer program, KOWWIN (Version 1.67). The SAR equation used to estimate toxicity is: Log LC50 (mmol/L) = -0.8799 log Kow + 1.6467
The LC50 is in millimoles per liter (mM/L); N = 327 + 61; and the Coefficient of Determination (R2) = 0.8753. To convert the LC50 from mM/L to mg/L, multiply by the molecular weight of the compound.


-Applicability domain (OECD Principle 3)
Neutral organic chemicals are non ionizable and non reactive and act via simple nonpolar narcosis generally thought of as a reversible, drug-induced loss of conscience (general anesthesia). This general narcosis is often referred to as baseline toxicity (Franks and Lieb 1990, Veith and Broderius 1990). Application: Solvents, non-reactive, non-ionizable neutral organic compounds:
1. Alcohols
2. Acetals
3. Ketones
4. Ethers
5. Alkyl halides
6. Aryl halides
7. Aromatic hydrocarbons
8. Halogenated aromatic hydrocarbons
9. Halogenated aliphatic hydrocarbons
10. Sulfides and di-sulfides

ECOSAR v.1.00 SAR Limitations:
Maximum Kow: 5.0 (96h-LC50)
Maximum MW: 1000

- Uncertainty of the prediction (OECD Principle 4)
n=327 chemicals,
R2= 0.8753

4. Mechanistic interpretation: The QSAR for neutral organics is based on the assumption that all chemicals have a minimal toxicity based on the interference of the chemical with biological membranes, which can be modelled by the octanol-water partition coefficient (Kow).

5. Adequacy of result for classification & labelling an/or risk assessment
According to the main criteria used by Hulzebos and Posthumus, ECOSAR is a reliable QSAR to predict 96h-LC50 for fish. The ECOSAR prediction of toxicity of l-limonene on fish is adequate for the purpose of risk assessment and classification and labelling.
Qualifier:
according to
Guideline:
other: REACH Guidance document on the validation of the (Q)SAR models R.6
Deviations:
no
Principles of method if other than guideline:
ECOSAR model for neutral organics.
GLP compliance:
no
Remarks:
The data were calculated by a computer model
Analytical monitoring:
not required
Details on sampling:
Not applicable (calculated data)
Vehicle:
no
Details on test solutions:
Not applicable (calculated data)
Test organisms (species):
other: For freshwater 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)
Details on test organisms:
No data
Test type:
other: QSAR modeled data
Water media type:
freshwater
Limit test:
no
Total exposure duration:
96 h
Post exposure observation period:
Not applicable (calculated data)
Hardness:
ECOSAR study criteria articulate that the water hardness should be approximately 150 mg/L CaCO3
Test temperature:
Not applicable (calculated data)
pH:
ECOSAR study criteria articulate that the toxicity should be measured at pH 7 (replicating environmental conditions)
Dissolved oxygen:
Not applicable (calculate data)
Salinity:
Not applicable
Nominal and measured concentrations:
Not applicable (calculated data)
Details on test conditions:
Not applicable (calculated data)
Reference substance (positive control):
not required
Key result
Duration:
96 h
Dose descriptor:
LC50
Effect conc.:
0.845 mg/L
Nominal / measured:
estimated
Conc. based on:
test mat.
Basis for effect:
mortality
Details on results:
1. Relevance of the model

ECOSAR v1.00 is reported as a usable valid model by ECHA (R6: QSARs and grouping of chemicals, May 2008).
ECOSAR contains a library of class-based QSARs for predicting aquatic toxicity, overlaid with an expert decision tree for selecting the appropriate chemical class. ECOSAR Version 1.00 is programmed to identify over 120 chemical classes and allows access to over 600 QSARs for numerous endpoints and organisms.
The structure-activity relationships (SARs) presented in ECOSAR v1.00 are used to predict the aquatic toxicity of chemicals based on their similarity of structure to chemicals for which the aquatic toxicity has been previously measured. SARs are developed for chemical classes based on measured test data that have been submitted by industry to the US-Environmental Protection Agency or collected from publicly available sources. To date, over 440 SARs have been developed for more than 120 chemical classes. The supporting data sets (training sets) used to derive SARs within a chemical class range from the very large, e.g., neutral organics, to the very small, e.g., aromatic diazoniums. The class with the greatest number of SARs based on measured data is the neutral organics class, which has SARs ranging from acute and chronic toxicity to fish to a 14-day LC50 SAR for earthworms in artificial soil.
The ECOSAR Class Program is a computerized version of the ecotoxicity analysis procedures as currently practiced by the Office of Pollution Prevention and Toxics (OPPT) when data are lacking for regulatory endpoints. It has been developed within the regulatory constraints of the Toxic Substances Control Act (TSCA). It is a pragmatic approach to SAR as opposed to a theoretical approach.

2. Validation of the model

- Endpoint (OECD Principle 1)
Acute toxicity to fish (lethality). 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).The studies collected for the training set chemicals in ECOSAR undergo an extensive data validation step to ensure appropriateness for inclusion in the model. 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.

- Algorithm (OECD Principle 2)
Neutral organics, FISH 96-h LC50 ESTIMATED TOXICITY:
The fish 96-h LC50 values used to develop this SAR were measured and the octanol water partition coefficients (Kow) were calculated using the computer program, KOWWIN (Version 1.67). The SAR equation used to estimate toxicity is: Log LC50 (mmol/L) = -0.8799 log Kow + 1.6467
The LC50 is in millimoles per liter (mM/L); N = 327 + 61; and the Coefficient of Determination (R2) = 0.8753. To convert the LC50 from mM/L to mg/L, multiply by the molecular weight of the compound.


-Applicability domain (OECD Principle 3)
Neutral organic chemicals are non ionizable and non reactive and act via simple nonpolar narcosis generally thought of as a reversible, drug-induced loss of conscience (general anesthesia). This general narcosis is often referred to as baseline toxicity (Franks and Lieb 1990, Veith and Broderius 1990). Application: Solvents, non-reactive, non-ionizable neutral organic compounds:
1. Alcohols
2. Acetals
3. Ketones
4. Ethers
5. Alkyl halides
6. Aryl halides
7. Aromatic hydrocarbons
8. Halogenated aromatic hydrocarbons
9. Halogenated aliphatic hydrocarbons
10. Sulfides and di-sulfides

ECOSAR v.1.00 SAR Limitations:
Maximum Kow: 5.0 (96h-LC50)
Maximum MW: 1000

- Uncertainty of the prediction (OECD Principle 4)
n=327 chemicals,
R2= 0.8753

4. Mechanistic interpretation: The QSAR for neutral organics is based on the assumption that all chemicals have a minimal toxicity based on the interference of the chemical with biological membranes, which can be modelled by the octanol-water partition coefficient (Kow).

5. Adequacy of result for classification & labelling an/or risk assessment
According to the main criteria used by Hulzebos and Posthumus, ECOSAR is a reliable QSAR to predict 96h-LC50 for fish. The ECOSAR prediction of toxicity of l-limonene on fish is adequate for the purpose of risk assessment and classification and labelling.
Results with reference substance (positive control):
Not applicable (calculated data)
Reported statistics and error estimates:
Not applicable (calculated data)

No other information

Validity criteria fulfilled:
yes
Remarks:
Log Kow < 5 at 25°C, MW = 136g/mol
Conclusions:
Based on a measured log Kow of 4.38, results of computer modelling to estimate acute toxicity in a 96-hour freshwater fish study show that the LC50 was 0.845 mg/L.
Executive summary:

The acute toxicity of l-limonene to fish was estimated using the ECOSAR model from EPISUITE 4.1 reported as a valid model by ECHA (R6: QSAR and grouping of chemicals, May 2008). ECOSAR computes toxicity based on a linear mathematical relationship between the predicted log Kow values and the corresponding log of the measured toxicity values (mmol/L) . l-limonene feld in the applicability domain of this QSAR model and the calculation was ran using its measured log Kow value of 4.38.

Results of computer modelling to estimate acute toxicity in a 96-hour freshwater fish study show that the LC50 was 0.845 mg/L.

This ECOSAR prediction of acute toxicity of l-limonene on fish is adequate for the purpose of risk assessment and classification and labelling.

Description of key information

Weight of evidence: Two reliable studies performed with d-limonene on Pimephales promelas similary to OECD guideline 203 but without GLP compliance gave comparable results leading to a calculated (geometric mean) 96 hour-LC50 of 711 µg/L. A non assignable study from a reliable source (MITI) performed on Oryzias latipes with dipentene, the racemic dl-limonene, giving a 96h-LC50 of 1.1 mg/L suggested that both enantiomers have a similar acute toxicity on fish. This hypothesis is confirmed by the similar value of toxicity estimated by a valid QSAR model on l-limonene.

Key value for chemical safety assessment

LC50 for freshwater fish:
0.71 mg/L

Additional information

Two reliable studies performed similary to OECD guideline 203 but without GLP compliance were carried out with two samples of d-limonene from different sources on the freshwater fish Fathead minnows (Pimephales promelas) under flow-through conditions. Mortality, behaviour and morphological aberrations were observed at 24, 48, 72 and 96 hours. The 96h-LC50 were calculated to be 702 (619 -796) µg/L and 720 (618 -839) µg/L. As no differences in test conditions or test reliability could be determined and because the results are less than one order of magnitude apart, they can be harmonised by a geometric mean. Therefore the 96h-LC50 for fish with d-limonene is calculated to be 0.71 mg/L.

A similar result was found in a study from the Japan Ministry (formerly MITI) on red killifish (Oryzias latipes) with dipentene, the dl-limonene racemic form, establishing a 96h-LC50 of 1.1 mg/L. This study is not well documented but its source is reliable and the result suggest that the two enantiomers have the same level of toxicity on fish. A valid computer modelling (ECOSAR) was used to assess the toxicity of l-limonene and its result freshwater fish 96-hour LC50 of 0.845 mg/L supported the similar acute toxicity of both enantiomers on fish.

Among these studies, the geometric mean of the results from the two standard studies on d-limonene giving a 96h-LC50 of 0,71 mg/L is considered as the relevant value to be used for the purpose of risk assessment and classification and labelling.