2-Cyclopentene-1-acetic acid, ethyl ester

Endpoint summary

Description of key information

Acute Oral Toxicity: LD50 = 2510 mg/kg bw

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

migrated information: read-across based on grouping of substances (category approach)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: The QSAR analysis has been performed according to the REACh Guidance on QSARs R.6, May/July 2008.

Qualifier:

according to guideline

Guideline:

other: REACh Guidance on QSARs R.6, May/July 2008

Principles of method if other than guideline:

OECD Q(S)AR Toolbox prediction

GLP compliance:

not specified

Test type:

other: QSAR prediction

Limit test:

no

Species:

other: Rat;Mouse;rat, Wistar (SPF);rabbit

Strain:

other: Sprague-Dawley;New Zealand White;Wistar

Route of administration:

oral: gavage

Sex:

male/female

Dose descriptor:

LD50

Effect level:

2 510 mg/kg bw

The prediction was based on dataset comprised from the following descriptors: LD50
Estimation method: Linear approximation
Model equation:
LD50 = -424 (±1429) +962 (±363) * log Kow, mg/kg bw
Domain logical expression:Result: In Domain

(("a" and "b" ) and ("c" and "d" ) )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Allyl AND Carboxylic acid ester AND Cycloalkene by Organic functional groups

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as High (Class III) by Toxic hazard classification by Cramer (with extensions)

Domain logical expression index: "c"

Parametric boundary:The target chemical should have a value of log Kow which is >= -1.09

Domain logical expression index: "d"

Parametric boundary:The target chemical should have a value of log Kow which is <= 6.43

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Based on the predicted oral LD50 of 2510 mg/kg bw, the substance is not classified (NC) according to the criteria of the Directive 67/548/EEC or EU CLP Regulation (EC) 1272/2008 for acute lethality.

Executive summary:

The categorization for the grouping of analogues has been based on Functional Groups similarity, and only molecules contanining allyl, carboxylic acid ester and cycloalkene feature were included.

After applying a trend analysis of the analogues, the categorization is refined by Cramer class category. The only chemicals removed being of lower toxicity class, this refinement is considered conservative.

In order to follow a worst case approach, the clear outliers to the curve are then manually discarded, which increases the slope.

Those refinements do not, however, have any dramatic impact on the predicted LD50, which always stays above 2500mg/kg bw.

Any attempt of further refinement (by test conditions or other profilers) of the category only leads to an increase of the value of the LD50.

Based on the predicted oral LD50 of 2510 mg/kg bw, the substance is not classified (NC) according to the criteria of the Directive 67/548/EEC or EU CLP Regulation (EC) 1272/2008 for acute lethality.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 510 mg/kg bw

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Acute Oral Toxicity:

No experimental study on Sultanene is available, but a Q(S)AR study has been performed to calculate the oral LD50 of Sultanene based on experimental data available on analogue molecules, using an OECD QSAR Toolbox trend analysis.

Category definition:

The categorization for the grouping of analogues has been based on Functional Groups similarity, and only molecules contanining allyl, carboxylic acid ester AND cycloalkene features were included.

After applying a trend analysis of the analogues, the categorization is refined by Cramer class category. The only chemicals removed being of lower toxicity class, this refinement is considered conservative.

In order to follow a worst case approach, the clear outliers to the curve are then manually discarded, which increases the slope.

Those refinements do not, however, have any dramatic impact on the predicted LD50, which always stays above 2500mg/kg bw.

Any attempt of further refinement (by test conditions or other profilers) of the category only leads to an increase of the value of the LD50.

Thus, in order to stay conservative we validate the worst case prediction of LD50 oral rodent = 2510 mg/kg bw.

Further not reported arguments:

In a separate QSAR analysis, it has been tried to take into account the metabolism of Sultanene, seeing that the endpoint Acute Oral Toxicity is based on a systemic response and bound to create metabolites.

Using the Rat liver S9 simulator of the OECD Toolbox that is recognised to mimic in vivo metabolisation, we generated 4 metabolites of Sultanene:

- cyclopent-1-ene-1-acetic acid (CAS: 21622-08-2; SMILES: C1(CC(=O)OCC)=CCCC1 )

- ethanol (CAS: 64-17-5; SMILES: C(C)O )

- ethanal (CAS: 75-07-0; SMILES: C(C)=O )

- acetic acid (CAS: 64-19-7; SMILES: C(C)(=O)O )

All metabolites are expected to show less toxicity than Sultanene itself, as they are classified Cramer class I, instead of Cramer class III. It is then reasonable to believe that any Sultanene reaching the blood stream, will undergo a detoxification process by oxidative metabolism.

The categorization strategy followed the one described above, but included the profiler categories of both Sultanene and its metabolites.

The category is based on analogues containing at least one of the functional groups: Acetoxy, Alcohol, Aldehyde, Allyl, Carboxylic acid or Cycloalkene. This category beeing a wide one, 1939 analogues were found.

A first refinement by Cramer class, discarding the class II analogues, did not help lower down the amount of candidate analogues significantly enough.

No other criteria was found to refine the category, seeing that none of them put in light clear outliers or changed significantly the value of the predicted LD50.

Even though the build category of analogues was wide, a clear LD50-Log Kow tendency curve is shown by the experimental data on analogues. All species tested seemed to have the same sensitivity according to the LogKow of the analogues and showed the same repartition of data points on the curve.

The predicted LD50 oral was 3810 mg/kg bw, which confirm our hypothesis of a detoxification of Sultanene via metabolism.

Unfortunately, the OECD Toolbox program was not able to generate a full report of this analysis, seeing the too many analogues and data points it was based on. Thus, no Endpoint Study Summary was included here, but only this brief summary.

Still, this argument confort us in the assumption of following a very conservative approach by validating the earlier prediction of 2510 mg/kg bw.

Overall Conclusion:

Following intensive analysis of Sultanene via the OECD Q(S)AR Toolbox, it has been assumed safe and conservative to assign the predicted value of LD50 oral rodent = 2510 mg/kg bw.

Justification for selection of acute toxicity – oral endpoint
The QSAR prediction is adequate and considered to be reliable enough to give an accurate estimation of the acute oral toxicity potential of Sultanene.

Justification for classification or non-classification

Based on the predicted oral LD50 of 2510 mg/kg bw, the substance is not classified (NC) according to the criteria of the Directive 67/548/EEC or EU CLP Regulation (EC) 1272/2008 for acute lethality.