Reaction mass of 3a,4,5,6,7,7a-hexahydro-4,7-methano-1H-inden-5-yl pivalate and 3a,4,5,6,7,7a-hexahydro-4,7-methano-1H-inden-6-yl pivalate

Short-term toxicity to aquatic invertebrates

Administrative data

Endpoint:

short-term toxicity to aquatic invertebrates

Type of information:

(Q)SAR

Adequacy of study:

key study

Study period:

July 2016

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
ECOSAR v.1.11, Programme freely available to download at https://www.epa.gov/tsca-screening-tools/ecological-structure-activity-relationships-ecosar-predictive-model

2. MODEL (incl. version number)
Ester Class 48-hr daphnid LC50

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
Constituent 1: O=C(C(C)(C)C)OC1CC2C3C(C1C2)CC=C3
Constituent 2: O=C(C(C)(C)C)OC1CC2C3C(C1C2)CC=C3

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
The ECOSAR Class Program and underlying methodology have been developed over a period of more than 25 years by EPA/OPPT. The current ECOSAR version (v1.11, May 2012) is programmed to identify 111 chemical classes and allows access to 704 QSARs for numerous endpoints and organisms. The model is valid according to the following five OECD priciples.
- Defined endpoint: Acute toxicity to invertebrates (Daphnid)
- Unambiguous algorithm: Log 48-h LC50 (mmol/L) = -0.6305 (log Kow) + 0.7049
- Defined domain of applicability: to esters with a Log Kow of < 5 and a molecular weight of < 1000.
- Appropriate measures of goodness-of-fit and robustness and predictivity: n = 40 (training set) + 21 (validation set), r2 = 0.7984
- Mechanistic interpretation: Within each ECOSAR class, aquatic toxicity has been shown to be positively correlated with lipophilicity (as modelled by log Kow) up to a log Kow limit of 5 (for acute effects on fish and daphnia) and 6.4 (for green algae).

Note: All ECOSAR QSARs have been derived using predicted log Kow values (KOWWIN version 1.67) for the training set chemicals to minimize potential measurement variability which may arise from inconsistent laboratory test conditions. In ECOSAR version 1.11, the log Kow values were predicted using the KOWWIN v1.68 program from U.S. EPA’s EPISuite model.

5. APPLICABILITY DOMAIN
- Descriptor domain: The Pivacyclene constituents have a log Kow of 4.046 (KOWWIN v1.68) and MW of 234, which fall within the applicability domain of the ECOSAR Ester SAR (maximum log Kow is 5.0, maximum molecular weight is 1000).
- Structural and mechanistic domains: Based on the chemical structure, ECOSAR v1.1 attributed the Pivacyclene constituents to the chemical class of “Esters”. Experimentally derived high quality green algae EC50 values exist for Pivacyclene (ErC50 > 0.53 mg/L; 2.1 mg/L estimated by extrapolation and EbC50/EyC50 = 0.41 mg/L). A comparison of these measured values with predicted EC50 value of 0.79 mg/L derived from the corresponding ECOSAR Ester SAR for GREEN ALGAE 96-h EC50 (Growth), confirms that the “Ester” class is appropriate for Pivacyclene.
- Similarity with analogues in the training set: The training set contains 40 daphnia LC50 values for 15 named esters and 8 confidential esters (see ECOSAR v1.11 on-line help).
- Other considerations (as appropriate): Two substances with existing aquatic toxicity data have been identified as close structural analogues of Pivacyclene. These are the corresponding propionate and acetate esters. A comparison of the predicted and experimental daphnia 48-hr E(L)C50 values indicates that the Ester ECOSAR provides a conservative estimate of the aquatic toxicity of the structural analogue substances:
Analogue 1 (EC 272-805-7): Measured 48h EC50 > 14 mg/L; Estimated 48h LC50 = 8.217 mg/L
Analogue 2 (EC 911-369-0): Measured 48h EC50 = 25 mg/L; Estimated 48h LC50 = 15.623 mg/L

More detailed information is provided in the attached QSAR Prediction Reporting Format (QPRF) document.

6. ADEQUACY OF THE RESULT
The QSAR result is considered reliable according to OECD principles. The QSAR model is scientifically valid and Pivacyclene falls within its applicability domain. Furthermore, taking into consideration the information on structural analogues, the predicted Daphnia 48-h LC50 value for Pivacyclene of 2.635 mg/L can be considered conserative and worst-case. Thus the value is suitable for the purpose of classification and labelling and/or risk assessment.

Data source

Reference

Reference Type:

review article or handbook

Title:

Methodology Document for the Ecological Structure-Activity Relationship Model (ECOSAR) Class Program v1.11

Author:

Kelly Mayo-Bean, Kendra Moran, Bill Meylan, Peter Ranslow

Year:

2012

Bibliographic source:

http://www.epa.gov/oppt/newchems/tools/21ecosar.htm

Materials and methods

Test guideline

Guideline:

other:

Version / remarks:

REACH Guidance; Chapter R.6: QSARs and grouping of chemicals, May 2008

Principles of method if other than guideline:

ECOSAR v1.11, ESTER class, 48-hr Daphnid LC50 QSAR.

Test material

Test material information

Constituent 1

Reference substance name:

3a,4,5,6,7,7a-hexahydro-4,7-methano-1H-inden-6-yl pivalate

EC Number:

268-259-4

EC Name:

3a,4,5,6,7,7a-hexahydro-4,7-methano-1H-inden-6-yl pivalate

Cas Number:

68039-44-1

Molecular formula:

C15H22O2

IUPAC Name:

3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-6-yl pivalate

Constituent 2

Reference substance name:

3a,4,5,6,7,7a-hexahydro-4,7-methano-1H-inden-5-yl pivalate

EC Number:

268-261-5

EC Name:

3a,4,5,6,7,7a-hexahydro-4,7-methano-1H-inden-5-yl pivalate

Cas Number:

68039-45-2

Molecular formula:

C15H22O2

IUPAC Name:

3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-5-yl pivalate

impurity 1

Reference substance name:

rel-(1R,2S,3aR,4S,5R,6aS,7R)-octahydro-1,5:2,4-dimethanopentalen-7-yl pivalate

Molecular formula:

C15H22)2

IUPAC Name:

rel-(1R,2S,3aR,4S,5R,6aS,7R)-octahydro-1,5:2,4-dimethanopentalen-7-yl pivalate

Test material form:

other: liquid, may crystalize to white solid

Specific details on test material used for the study:

SMILES USED AS INPUT FOR THE MODEL
Constituent 1: O=C(C(C)(C)C)OC1CC2C3C(C1C2)CC=C3
Constituent 2: O=C(C(C)(C)C)OC1CC2C3C(C1C2)CC=C3

Results and discussion

Effect concentrations

Effect concentrations 1

Key result

Duration:

48 h

Dose descriptor:

LC50

Effect conc.:

2.635 mg/L

Remarks on result:

other:

Remarks:

QSAR prediction for Constituent 1

Effect concentrations 2

Key result

Duration:

48 h

Dose descriptor:

LC50

Effect conc.:

2.634 mg/L

Remarks on result:

other:

Remarks:

QSAR prediction for Constituent 2

Details on results:

Pivacyclene is a mixture of two structural isomers, which are double bond positional isomers. It consists of approximately:

55-70% w/w 3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-5-yl pivalate (Constituent 1)

30-45 % w/w 3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-6-yl pivalate (Constituent 2)

The stereochemical/isomeric features do not affect the reliability of the prediction. A separate prediction was performed using the SMILES for each constituent. Both gave the same results. This is explained by the fact that both isomers are assigned to the Ester ECOSAR class and have the same log Kow (see QPRF document for further details).

The ECOSAR v1.11 results files are attached (see section "Attached Background Material").

Applicant's summary and conclusion

Validity criteria fulfilled:

yes

Remarks:

The QSAR model is scientifically valid and Pivacyclene falls within its applicability domain (See attached QPRF for details).

Conclusions:

The substance, Pivacyclene, was predicted to have a daphnid 48-hr LC50 of 2.635 mg/L.

The QSAR result is considered reliable according to OECD principles. The QSAR model is scientifically valid and Pivacyclene falls within its applicability domain. Furthermore, taking into consideration the information on structural analogues, the predicted Daphnia 48-h LC50 value for Pivacyclene of 2.635 mg/L can be considered conservative and worst-case. Thus the value is suitable for the purpose of classification and labelling and/or risk assessment.