monoesters of C16 and C18 (branched and linear) fatty acids with decan-1-ol

Endpoint summary

Description of key information

Oral: LD50 (QSAR) = 4280 mg/kg bw

Oral: LD50 (female, mouse) > 2000 mg/kg bw (read-across)

Dermal: LD50 (male/female, rat) > 2000 mg/kg bw (read-across)

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Remarks:

Summary of available data used for the endpoint assessment of the target substance

Adequacy of study:

weight of evidence

Justification for type of information:

refer to analogue justification provided in IUCLID section 13

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: Source: 3687-46-5

The acute oral toxicity study performed with the source substance decyl oleate (CAS 3687-46-5) was selected as key study for reasons of structural similarity and data availability. Besides this, further acute oral toxicity studies with the source substances 2-octododecyl myristate (CAS 22766-83-2) in rats and with Fatty acids, C8-10, C12-18-alkyl esters (CAS 95912-86-0) in mice were taken into account as supporting information. In both studies the LD50 was > 2000 mg/kg bw, the recommended limit value in the current OECD guideline.

Interpretation of results:

other: CLP/EU GHS criteria not met, no classification required according to Regulation (EC) No. 1272/2008

Conclusions:

In the acute oral toxicity studies with the source substances no adverse effects were observed and the determined LD50 were higher than 2000 mg/kg bw, the recommended limit value in the current OECD guideline. As explained in the analogue justification, this result is considered to be valid also for the target substance.

Reference 2

Endpoint:

acute toxicity: oral

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 and falling into its applicability domain, with adequate and reliable documentation / justification

Justification for type of information:

Acute Oral Toxicity of Decyl isostearate – DEREK
1 Substance
1.1 CAS number 84605-08-3
1.2 EC number 306-448-6
1.3 Chemical name
IUPAC Decyl 16-methylheptadecanoate
Other Heptadecanoic acid, 16-methyl-, decyl ester
Other Decyl isostearate
1.4 Structural formula

1.5 Structure codes
SMILES CCCCCCCCCCOC(=O)CCCCCCCCCCCCCCC(C)C
InChI InChI=1S/C28H56O2/c1-4-5-6-7-8-17-20-23-26-30-28(29)25-22-19-16-14-12-10-9-11-13-15-18-21-24-27(2)3/h27H,4-26H2,1-3H3
Other
Stereochemical features N/A

2 General Information
2.1 Date of QPRF 09 March 2018
2.2 Author and contact details Envigo, Shardlow Business Park, London Road, Shardlow, Derbyshire, DE72 2GD

3 Prediction
3.1 Endpoint (OECD Principle 1)
Endpoint Oral toxicity
Dependent variable Not applicable
3.2 Algorithm (OECD Principle 2)
Model or submodel name Adrenal gland toxicity, High acute toxicity, alpha-2-mu-Globulin nephropathy, Kidney disorders, Bladder disorders, Kidney function-related toxicity, Bladder urothelial hyperplasia, Nephrotoxicity, Bone marrow toxicity, Ocular toxicity, Bradycardia, Pulmonary toxicity, Cardiotoxicity, Splenotoxicity, Cumulative effect on white cell count and immunology, Thyroid toxicity, Hepatotoxicity, Urolithiasis, HERG channel inhibition in vitro
Model version Knowledge Base: Derek KB 2018 1.1, Version 1.1 from 23/11/2017
Reference to QMRF There is no QMRF available. Further information can be obtained from Lhasa Ltd.
Predicted values (model result) No alerts matched
Predicted values (comments) No alerts fired for the listed targeted endpoints:
Adrenal gland toxicity, High acute toxicity, alpha-2-mu-Globulin nephropathy, Kidney disorders, Bladder disorders, Kidney function-related toxicity, Bladder urothelial hyperplasia, Nephrotoxicity, Bone marrow toxicity, Ocular toxicity, Bradycardia, Pulmonary toxicity, Cardiotoxicity, Splenotoxicity, Cumulative effect on white cell count and immunology, Thyroid toxicity, Hepatotoxicity, Urolithiasis, HERG channel inhibition in vitro
Input for prediction Smiles
Descriptor values Not applicable
3.3 Applicability domain (OECD Principle 3)
Domains Alert description image:
as no alerts were fired, there are no identified structural alerts to provide a domain.


Structural analogues as no alerts were fired, there are no structural analogues to report
Consideration on structural analogues n/a.
3.4 The uncertainty of the prediction (OECD principle 4)
As no alerts were fired no conclusion is made on the toxicity of the compound.
3.5 The chemical and biological mechanisms according to the model underpinning the predicted result (OECD principle 5)
No mechanism to report as no alerts were identified.

4 Adequacy (Optional)
4.1 Regulatory purpose Oral toxicity endpoint for REACh registration.

4.2 Approach for regulatory interpretation of the model result
Result may support prediction of toxicity/non-toxicity.

4.3 Outcome The report indicates that no alerts were identified for the target substance from the list of endpoints assessed.


4.4 Conclusion The reliability of the prediction is not possible to assess since no alerts were identified and thus no criteria are available to assess. The lack of identified alerts does not equate to an identified lack of toxicity, thus the report cannot be considered to conclude anything in isolation. However, it could provide supporting information in a weight of evidence.

Qualifier:

no guideline followed

Principles of method if other than guideline:

- Principle of test: QSAR
- Short description of test conditions: n/a
- Parameters analysed / observed: Adrenal gland toxicity, High acute toxicity, alpha-2-mu-Globulin nephropathy, Kidney disorders, Bladder disorders, Kidney function-related toxicity, Bladder urothelial hyperplasia, Nephrotoxicity, Bone marrow toxicity, Ocular toxicity, Bradycardia, Pulmonary toxicity, Cardiotoxicity, Splenotoxicity, Cumulative effect on white cell count and immunology, Thyroid toxicity, Hepatotoxicity, Urolithiasis, HERG channel inhibition in vitro

Remarks on result:

other: The listed series of profilers which are related to oral toxicity were assessed. In each case no alerts were highlighted, supporting the predictions made by the other software.

Acute Oral Toxicity of Decyl isostearate – DEREK
1	Substance
	1.1	CAS number			84605-08-3
	1.2	EC number			306-448-6
	1.3	Chemical name
			IUPAC		Decyl 16-methylheptadecanoate
			Other		Heptadecanoic acid, 16-methyl-, decyl ester
			Other		Decyl isostearate
	1.4	Structural formula
	1.5	Structure codes
			SMILES		CCCCCCCCCCOC(=O)CCCCCCCCCCCCCCC(C)C
			InChI		InChI=1S/C28H56O2/c1-4-5-6-7-8-17-20-23-26-30-28(29)25-22-19-16-14-12-10-9-11-13-15-18-21-24-27(2)3/h27H,4-26H2,1-3H3
			Other
			Stereochemical features		N/A
2	General Information
	2.1	Date of QPRF			09 March 2018
	2.2	Author and contact details			Envigo, Shardlow Business Park, London Road, Shardlow, Derbyshire, DE72 2GD
3	Prediction
	3.1	Endpoint (OECD Principle 1)
			Endpoint		Oral toxicity
			Dependent variable		Not applicable
	3.2	Algorithm (OECD Principle 2)
			Model or submodel name		Adrenal gland toxicity, High acute toxicity, alpha-2-mu-Globulin nephropathy, Kidney disorders, Bladder disorders, Kidney function-related toxicity, Bladder urothelial hyperplasia, Nephrotoxicity, Bone marrow toxicity, Ocular toxicity, Bradycardia, Pulmonary toxicity, Cardiotoxicity, Splenotoxicity, Cumulative effect on white cell count and immunology, Thyroid toxicity, Hepatotoxicity, Urolithiasis, HERG channel inhibition in vitro
			Model version		Knowledge Base: Derek KB 2018 1.1, Version 1.1 from 23/11/2017
			Reference to QMRF		There is no QMRF available. Further information can be obtained from Lhasa Ltd.
			Predicted values (model result)		No alerts matched
			Predicted values (comments)		No alerts fired for the listed targeted endpoints: Adrenal gland toxicity, High acute toxicity, alpha-2-mu-Globulin nephropathy, Kidney disorders, Bladder disorders, Kidney function-related toxicity, Bladder urothelial hyperplasia, Nephrotoxicity, Bone marrow toxicity, Ocular toxicity, Bradycardia, Pulmonary toxicity, Cardiotoxicity, Splenotoxicity, Cumulative effect on white cell count and immunology, Thyroid toxicity, Hepatotoxicity, Urolithiasis, HERG channel inhibition in vitro
			Input for prediction		Smiles
			Descriptor values		Not applicable
	3.3	Applicability domain (OECD Principle 3)
			Domains		Alert description image: as no alerts were fired, there are no identified structural alerts to provide a domain.
			Structural analogues		as no alerts were fired, there are no structural analogues to report
			Consideration on structural analogues		n/a.
	3.4	The uncertainty of the prediction (OECD principle 4)
					As no alerts were fired no conclusion is made on the toxicity of the compound.
	3.5	The chemical and biological mechanisms according to the model underpinning the predicted result (OECD principle 5)
					No mechanism to report as no alerts were identified.
4	Adequacy (Optional)
	4.1	Regulatory purpose			Oral toxicity endpoint for REACh registration.
	4.2	Approach for regulatory interpretation of the model result
					Result may support prediction of toxicity/non-toxicity.
	4.3	Outcome			The report indicates that no alerts were identified for the target substance from the list of endpoints assessed.
	4.4	Conclusion			The reliability of the prediction is not possible to assess since no alerts were identified and thus no criteria are available to assess. The lack of identified alerts does not equate to an identified lack of toxicity, thus the report cannot be considered to conclude anything in isolation. However, it could provide supporting information in a weight of evidence.

Interpretation of results:

GHS criteria not met

Conclusions:

With the DEREK model, the following series of profilers were assessed which are related to oral toxicity:
Adrenal gland toxicity, High acute toxicity, alpha-2-mu-Globulin nephropathy, Kidney disorders, Bladder disorders, Kidney function-related toxicity, Bladder urothelial hyperplasia, Nephrotoxicity, Bone marrow toxicity, Ocular toxicity, Bradycardia, Pulmonary toxicity, Cardiotoxicity, Splenotoxicity, Cumulative effect on white cell count and immunology, Thyroid toxicity, Hepatotoxicity, Urolithiasis, HERG channel inhibition in vitro.
In each case no alerts were highlighted, supporting the predictions made by the other software.
Prediction to be used as part of a weight of evidence.

Reference 3

Endpoint:

acute toxicity: oral

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 and falling into its applicability domain, with adequate and reliable documentation / justification

Justification for type of information:

Acute Oral Toxicity of Decyl isostearate – T.E.S.T.
1 Substance
1.1 CAS number 84605-08-3
1.2 EC number 306-448-6
1.3 Chemical name
IUPAC Decyl 16-methylheptadecanoate
CAS Heptadecanoic acid, 16-methyl-, decyl ester
Other Decyl isostearate
1.4 Structural formula

1.5 Structure codes
SMILES CCCCCCCCCCOC(=O)CCCCCCCCCCCCCCC(C)C
InChI InChI=1S/C28H56O2/c1-4-5-6-7-8-17-20-23-26-30-28(29)25-22-19-16-14-12-10-9-11-13-15-18-21-24-27(2)3/h27H,4-26H2,1-3H3
Other
Stereochemical features N/A

2 General Information
2.1 Date of QPRF 09 March 2018
2.2 Author and contact details , Envigo, Shardlow Business Park, London Road, Shardlow, Derbyshire, DE72 2GD

3 Prediction
3.1 Endpoint (OECD Principle 1)
Endpoint Acute oral toxicity
Dependent variable Oral rat LD50 -log10(mol/kg)
3.2 Algorithm (OECD Principle 2)
Model or submodel name US EPA T.E.S.T Oral Rat LD50; Consensus method
Model version 4.2
Reference to QMRF Not available
Predicted values (model result) LD50 = 11522.05 mg/kg
Predicted values (comments) Unit conversion provided by the software. All single methods, hierarchical clustering, FDA, and nearest neighbour predicted values greater than the classification limit for CLP.
Input for prediction Smiles
Descriptor values Due to the large number of descriptors used all information are attached in the software printout section.
3.3 Applicability domain (OECD Principle 3)
Domains i. Query structure is within the domain of the model
ii. All descriptors of the query structure are within ranges
iii. Considerations on the mechanism domain are not applicable since statistical model
Structural analogues i Butyl stearate
ii Bis(2-ethylhexyl) dodecanedioate
iii. N,N-Didecyl-1-decanamine
iv. bis(2-ethylhexyl) nonanedioate


Consideration on structural analogues With 95.5% the average similarity of the four most similar structures in the training set to the query structure is considered to be high. Predicted and experimental values of similar structures vary by a factor of up to 2.00 which is well below a default factor of 10 often used in traditional risk assessment of environmental chemicals to compensate for uncertainties*. Hence concordance between predicted and actual value is high.
3.4 The uncertainty of the prediction (OECD principle 4)
The mean absolute error (MAE) for the prediction with the training set (0.15) is less than the MAE for the entire set (0.34) which provides confidence. The MAE for the prediction with external test set (0.29) is also less than the MAE of the entire set (0.43) supporting the conclusion from the training set. Additionally, high similarity of structural analogues, and high accuracy in the prediction of similar structures further supports the prediction
3.5 The chemical and biological mechanisms according to the model underpinning the predicted result (OECD principle 5)
Not applicable since statistical model

4 Adequacy (Optional)
4.1 Regulatory purpose Acute toxicity endpoint for REACh registration

4.2 Approach for regulatory interpretation of the model result
Result is directly applicable since no conversion of the result is required. Unit conversion is provided by the model.

4.3 Outcome Not classified : LD50 11522.05 mg/kg bw.

4.4 Conclusion The predicted LD50 of 11522.05 mg/kg is higher than the CLP classification threshold (2000 mg/kg bw). Furthermore, the results from the three individual models are each above the CLP classification value, further supporting this result.
The positive prediction statistics suggest reliability in the results.
*Stedeford, T.; Zhao, Q.J.; Dourson, M.L.; Banasik, M.; Hsu, C.H. The application of non-default uncertainty factors in the US EPA’s Integrated Risk Information System (IRIS). Part I: UFL, UFS, and “Other uncertainty factors”. J. Environ. Sci. Heal. C 2007, 25, 245–279.

Qualifier:

no guideline followed

Principles of method if other than guideline:

- Principle of test: QSAR - US EPA TEST
- Short description of test conditions: n/a
- Parameters analysed / observed: 3 methods of LD50 prediction, with a 4th consensus model.

Key result

Sex:

not specified

Dose descriptor:

LD50

Effect level:

11 522 mg/kg bw

Based on:

test mat.

Remarks on result:

other: Consensus Model

Sex:

not specified

Dose descriptor:

LD50

Effect level:

4 280 mg/kg bw

Based on:

test mat.

Remarks on result:

other: Hierarchical clustering model

Sex:

not specified

Dose descriptor:

LD50

Effect level:

26 996 mg/kg bw

Based on:

test mat.

Remarks on result:

other: FDA model

Sex:

not specified

Dose descriptor:

LD50

Effect level:

13 240 mg/kg bw

Based on:

test mat.

Remarks on result:

other: nearest neighbour model

Acute Oral Toxicity of Decyl isostearate – T.E.S.T.
1	Substance
	1.1	CAS number			84605-08-3
	1.2	EC number			306-448-6
	1.3	Chemical name
			IUPAC		Decyl 16-methylheptadecanoate
			CAS		Heptadecanoic acid, 16-methyl-, decyl ester
			Other		Decyl isostearate
	1.4	Structural formula
	1.5	Structure codes
			SMILES		CCCCCCCCCCOC(=O)CCCCCCCCCCCCCCC(C)C
			InChI		InChI=1S/C28H56O2/c1-4-5-6-7-8-17-20-23-26-30-28(29)25-22-19-16-14-12-10-9-11-13-15-18-21-24-27(2)3/h27H,4-26H2,1-3H3
			Other
			Stereochemical features		N/A
2	General Information
	2.1	Date of QPRF			09 March 2018
	2.2	Author and contact details			Envigo, Shardlow Business Park, London Road, Shardlow, Derbyshire, DE72 2GD
3	Prediction
	3.1	Endpoint (OECD Principle 1)
			Endpoint		Acute oral toxicity
			Dependent variable		Oral rat LD50 -log10(mol/kg)
	3.2	Algorithm (OECD Principle 2)
			Model or submodel name		US EPA T.E.S.T Oral Rat LD50; Consensus method
			Model version		4.2
			Reference to QMRF		Not available
			Predicted values (model result)		LD50= 11522.05 mg/kg
			Predicted values (comments)		Unit conversion provided by the software. All single methods, hierarchical clustering, FDA, and nearest neighbour predicted values greater than the classification limit for CLP.
			Input for prediction		Smiles
			Descriptor values		Due to the large number of descriptors used all information are attached in the software printout section.
	3.3	Applicability domain (OECD Principle 3)
			Domains		i.	Query structure is within the domain of the model
					ii.	All descriptors of the query structure are within ranges
					iii.	Considerations on the mechanism domain are not applicable since statistical model
			Structural analogues		i Butyl stearate ii Bis(2-ethylhexyl) dodecanedioate iii. N,N-Didecyl-1-decanamine iv. bis(2-ethylhexyl) nonanedioate
			Consideration on structural analogues		With 95.5% the average similarity of the four most similar structures in the training set to the query structure is considered to be high. Predicted and experimental values of similar structures vary by a factor of up to 2.00 which is well below a default factor of 10 often used in traditional risk assessment of environmental chemicals to compensate for uncertainties*. Hence concordance between predicted and actual value is high.
	3.4	The uncertainty of the prediction (OECD principle 4)
					The mean absolute error (MAE) for the prediction with the training set (0.15) is less than the MAE for the entire set (0.34) which provides confidence. The MAE for the prediction with external test set (0.29) is also less than the MAE of the entire set (0.43) supporting the conclusion from the training set. Additionally, high similarity of structural analogues, and high accuracy in the prediction of similar structures further supports the prediction
	3.5	The chemical and biological mechanisms according to the model underpinning the predicted result (OECD principle 5)
					Not applicable since statistical model
4	Adequacy (Optional)
	4.1	Regulatory purpose			Acute toxicity endpoint for REACh registration
	4.2	Approach for regulatory interpretation of the model result
					Result is directly applicable since no conversion of the result is required. Unit conversion is provided by the model.
	4.3	Outcome			Not classified : LD5011522.05 mg/kg bw.
	4.4	Conclusion			The predicted LD50of 11522.05 mg/kg is higher than the CLP classification threshold (2000 mg/kg bw). Furthermore, the results from the three individual models are each above the CLP classification value, further supporting this result. The positive prediction statistics suggest reliability in the results.
*Stedeford, T.; Zhao, Q.J.; Dourson, M.L.; Banasik, M.; Hsu, C.H. The application of non-default uncertainty factors in the US EPA’s Integrated Risk Information System (IRIS). Part I: UFL, UFS, and “Other uncertainty factors”. J. Environ. Sci. Heal. C 2007, 25, 245–279.

Interpretation of results:

GHS criteria not met

Conclusions:

The TEST predictions all show high similarity and good prediction statistics, both for concordance and error, suggesting confidence can be placed in these predictions. The individual methods, hierarchical clustering, FDA, and nearest neighbour, were used to produce the consensus model which is reviewed below, the individual models are also reported in the software printout section. The consensus model predicts a value of 11,522 mg/kg bw, but it is noteworthy that the hierarchical clustering model shows a predicted value of 4,280 mg/kg bw, which would be within the GHS classification criteria (Category 5 <5000 mg/kg bw).
Prediction to be used as part of a weight of evidence.

Reference 4

Endpoint:

acute toxicity: oral

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 and falling into its applicability domain, with adequate and reliable documentation / justification

Justification for type of information:

1. SOFTWARE
QSAR Toolbox 4.2

2. MODEL (incl. version number)
QSAR Toolbox 4.2
Database version: 4.2
TPRF v4.2

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
CCCCCCCCCCOC(=O)CCCCCCCCCCCCCCC(C)C

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
[Explain how the model fulfils the OECD principles for (Q)SAR model validation. Consider attaching the QMRF or providing a link]
see attached justificaiton

5. APPLICABILITY DOMAIN
[Explain how the substance falls within the applicability domain of the model]
see attached ustification

6. ADEQUACY OF THE RESULT
[Explain how the prediction fits the purpose of classification and labelling and/or risk assessment]
Prediction is considered to be of moderate reliability since the nearest neighbours are of only moderate (>50%) similarity to the target, and the mechanism is ill defined. However observation of the resulting category of substances from the subcategorization, concordance of results (all above 2000mg/kg bw) and fulfilment of the multiple categorisations offers some confidence in the prediction.

Qualifier:

no guideline followed

Principles of method if other than guideline:

- Principle of test: QSAR -OECD QSAR Toolbox
- Short description of test conditions: n/a
- Parameters analysed / observed: LD50 prediction

Key result

Sex:

not specified

Dose descriptor:

LD50

Effect level:

15 400 mg/kg bw

Based on:

test mat.

Interpretation of results:

GHS criteria not met

Conclusions:

The toolbox prediction of 15,400 mg/kg bw shows some measure of poor similarity in the report, however a review of the category data shows that the average similarity to the target compound is above 75%, implying that the similarity is not so poor as indicated in the report. The result is derived from the members of the category defined by the profilers identified in the software. All members of the category displayed toxicity ≥ 5,000 mg/kg bw, thus there is concordance between the dataset compounds further supporting the result.
Prediction to be used as part of a weight of evidence.

Reference 5

Endpoint:

acute toxicity: oral

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 and falling into its applicability domain, with adequate and reliable documentation / justification

Justification for type of information:

Acute Oral Toxicity of Decyl isostearate - TOPKAT
1 Substance
1.1 CAS number 84605-08-3
1.2 EC number 306-448-6
1.3 Chemical name
IUPAC Decyl 16-methylheptadecanoate
CAS Heptadecanoic acid, 16-methyl-, decyl ester
Other Decyl isostearate
1.4 Structural formula

1.5 Structure codes
SMILES CCCCCCCCCCOC(=O)CCCCCCCCCCCCCCC(C)C
InChI InChI=1S/C28H56O2/c1-4-5-6-7-8-17-20-23-26-30-28(29)25-22-19-16-14-12-10-9-11-13-15-18-21-24-27(2)3/h27H,4-26H2,1-3H3
Other
Stereochemical features N/A

2 General Information
2.1 Date of QPRF 09 March 2018
2.2 Author and contact details Envigo, Shardlow Business Park, London Road, Shardlow, Derbyshire, DE72 2GD


3 Prediction
3.1 Endpoint (OECD Principle 1)
Endpoint Acute oral toxicity
Dependent variable Oral rat LD50 -log10(mol/kg)
3.2 Algorithm (OECD Principle 2)
Model or submodel name BIOVIA (TOPKAT) toxicity prediction model – Rat Oral LD50
Model version 4.5
Reference to QMRF The corresponding QMRF with the identifier Q51-54-55-502 is available at http://qsardb.jrc.it/qmrf/index.jsp.
Predicted values (model result) Default model: LD50 = 21.350 g/kg bw
Extended model: LD50 = 27.879 g/kg bw
Predicted values (comments) The extended model contains a number of identified data points from published literature in addition to those already used by the software. In this instance, the nearest identified structures were the same for both models. While the extended model is considered reliable, was a worst case conservative estimate, the lowest of the two values is used for this assessment. The full printouts for both results and the model extension criteria are provided below.

Input for prediction Smiles
Descriptor values Descriptor Value
LogP 11.392
Molecular weight (g/mol) 424.743
Number of hydrogen bond donors 0
Number of hydrogen bond acceptors 2
Number of rotatable bonds in the molecule 25
The fraction of polar surface area over the total molecular surface area 0.049
ECFP_6: Unitless Extended-connectivity fingerprint with a maximum length of 6 bonds Not applicable
FCFP_6 Unitless Functional class fingerprint with a maximum length of 6 bonds Not applicable
MDL Public Keys Unitless Fingerprint based on the MDL public keys Not applicable

3.3 Applicability domain (OECD Principle 3)
Domains i. All properties and OPS components are within expected ranges.
ii. All fingerprint features of the query molecule are found in the training set
iii. Considerations on the mechanism domain are not applicable since statistical model
Structural analogues i Octadecanoic acid; butyl ester
ii 9;10-Epoxystearicacid; 2-ethylhexylester
iii. bis-(2-Ethylhexyl)decanedioate
iv. Silane; di-(2-ethylbutoxy)-di(2-ethylhexoxy)-

Consideration on structural analogues With 44.15% the average similarity of the four most similar structures to the query structure is considered poor. Predicted and experimental values of similar structures vary by a factor of up to 3.95 which is above a default factor of 10 often used in traditional risk assessment of environmental chemicals to compensate for uncertainties*.Hence concordance between predicted and actual value is High.
3.4 The uncertainty of the prediction (OECD principle 4)
Poor similarity of structural analogues in the prediction of structural analogues may indicate uncertainty in the prediction. However, accuracy and concordance of the measured and predicted results for the similar structures affords some confidence in the prediction.
3.5 The chemical and biological mechanisms according to the model underpinning the predicted result (OECD principle 5)
Not applicable since statistical model

4 Adequacy (Optional)
4.1 Regulatory purpose Acute toxicity endpoint for REACh registration.

4.2 Approach for regulatory interpretation of the model result
Unit conversion not required for the non-extended results as these are reported as g/kg body weight.
For the extended results, the following calculation:
power (10, -TOPKAT_Rat_Oral_LD50)*molecular weight
(g/mol)

4.3 Outcome The predicted acute toxicity LD50 of 21.350 g/kg is greater than the thresholds for classification under CLP and GHS.

4.4 Conclusion There is only moderate confidence in the prediction due to the poor similarity of structural analogues, despite the identified accuracy and concordance of the measured and predicted results for the similar structures.
Therefore, application of further QSAR models is recommended to create a weight of evidence.

*Stedeford, T.; Zhao, Q.J.; Dourson, M.L.; Banasik, M.; Hsu, C.H. The application of non-default uncertainty factors in the US EPA’s Integrated Risk Information System (IRIS). Part I: UFL, UFS, and “Other uncertainty factors”. J. Environ. Sci. Heal. C 2007, 25, 245–279.

Qualifier:

no guideline followed

Principles of method if other than guideline:

- Principle of test: QSAR - TOPKAT
- Short description of test conditions: n/a
- Parameters analysed / observed: 2 methods of LD50 prediciton

Key result

Sex:

not specified

Dose descriptor:

LD50

Effect level:

21 350 mg/kg bw

Based on:

test mat.

Remarks on result:

other: Non extended model

Sex:

not specified

Dose descriptor:

LD50

Effect level:

27 879 mg/kg bw

Based on:

test mat.

Remarks on result:

other: extended model

Acute Oral Toxicity of Decyl isostearate - TOPKAT
1	Substance
	1.1	CAS number			84605-08-3
	1.2	EC number			306-448-6
	1.3	Chemical name
			IUPAC		Decyl 16-methylheptadecanoate
			CAS		Heptadecanoic acid, 16-methyl-, decyl ester
			Other		Decyl isostearate
	1.4	Structural formula
	1.5	Structure codes
			SMILES		CCCCCCCCCCOC(=O)CCCCCCCCCCCCCCC(C)C
			InChI		InChI=1S/C28H56O2/c1-4-5-6-7-8-17-20-23-26-30-28(29)25-22-19-16-14-12-10-9-11-13-15-18-21-24-27(2)3/h27H,4-26H2,1-3H3
			Other
			Stereochemical features		N/A
2	General Information
	2.1	Date of QPRF			09 March 2018
	2.2	Author and contact details			Envigo, Shardlow Business Park, London Road, Shardlow, Derbyshire, DE72 2GD
3	Prediction
	3.1	Endpoint (OECD Principle 1)
			Endpoint		Acute oral toxicity
			Dependent variable		Oral rat LD50 -log10(mol/kg)
	3.2	Algorithm (OECD Principle 2)
			Model or submodel name		BIOVIA (TOPKAT) toxicity prediction model – Rat Oral LD50
			Model version		4.5
			Reference to QMRF		The corresponding QMRF with the identifier Q51-54-55-502 is available at http://qsardb.jrc.it/qmrf/index.jsp.
			Predicted values (model result)		Default model:      LD50= 21.350 g/kg bw Extended model:   LD50= 27.879 g/kg bw
			Predicted values (comments)		The extended model contains a number of identified data points from published literature in addition to those already used by the software. In this instance, the nearest identified structures were the same for both models. While the extended model is considered reliable, was a worst case conservative estimate, the lowest of the two values is used for this assessment. The full printouts for both results and the model extension criteria are provided below.
			Input for prediction		Smiles
			Descriptor values		Descriptor Value LogP 11.392 Molecular weight (g/mol) 424.743 Number of hydrogen bond donors 0 Number of hydrogen bond acceptors 2 Number of rotatable bonds in the molecule 25 The fraction of polar surface area over the total molecular surface area 0.049 ECFP_6: Unitless Extended-connectivity fingerprint with a maximum length of 6 bonds Not applicable FCFP_6 Unitless Functional class fingerprint with a maximum length of 6 bonds Not applicable MDL Public Keys Unitless Fingerprint based on the MDL public keys Not applicable
	3.3	Applicability domain (OECD Principle 3)
			Domains		i.	All properties and OPS components are within expected ranges.
					ii.	All fingerprint features of the query molecule are found in the training set
					iii.	Considerations on the mechanism domain are not applicable since statistical model
			Structural analogues		i Octadecanoic acid; butyl ester ii 9;10-Epoxystearicacid; 2-ethylhexylester iii. bis-(2-Ethylhexyl)decanedioate iv. Silane; di-(2-ethylbutoxy)-di(2-ethylhexoxy)-
			Consideration on structural analogues		With 44.15% the average similarity of the four most similar structures to the query structure is considered poor. Predicted and experimental values of similar structures vary by a factor of up to 3.95 which is above a default factor of 10 often used in traditional risk assessment of environmental chemicals to compensate for uncertainties*.Hence concordance between predicted and actual value is High.
	3.4	The uncertainty of the prediction (OECD principle 4)
					Poor similarity of structural analogues in the prediction of structural analogues may indicate uncertainty in the prediction. However, accuracy and concordance of the measured and predicted results for the similar structures affords some confidence in the prediction.
	3.5	The chemical and biological mechanisms according to the model underpinning the predicted result (OECD principle 5)
					Not applicable since statistical model
4	Adequacy (Optional)
	4.1	Regulatory purpose			Acute toxicity endpoint for REACh registration.
	4.2	Approach for regulatory interpretation of the model result
					Unit conversion not required for the non-extended results as these are reported as g/kg body weight. For the extended results, the following calculation: power (10, -TOPKAT_Rat_Oral_LD50)*molecular weight (g/mol)
	4.3	Outcome			The predicted acute toxicity LD50of 21.350 g/kg is greater than the thresholds for classification under CLP and GHS.
	4.4	Conclusion			There is only moderate confidence in the prediction due to the poor similarity of structural analogues, despite the identified accuracy and concordance of the measured and predicted results for the similar structures. Therefore, application of further QSAR models is recommended to create a weight of evidence.
*Stedeford, T.; Zhao, Q.J.; Dourson, M.L.; Banasik, M.; Hsu, C.H. The application of non-default uncertainty factors in the US EPA’s Integrated Risk Information System (IRIS). Part I: UFL, UFS, and “Other uncertainty factors”. J. Environ. Sci. Heal. C 2007, 25, 245–279.

Interpretation of results:

GHS criteria not met

Conclusions:

The two predictions for the extended (27,879 mg/kg bw) and non-extended model (21,350 mg/kg bw) from the TOPKAT software both show poor similarity between the closest structures to the target compound and the target compound itself. The default prediction shows a lower value than the extended model. The extension is built upon published data which has been included into the model. An assessment for the predicted and measured values for the nearest structures in the dataset showed that the concordance between these values was high. However, while the prediction statistics suggest the model is reliable, the lack of similarity is cause for concern.
Prediction to be used as part of a weight of evidence.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

The available information comprises adequate, reliable (Klimisch score 2) and consistent studies, from reference substances with similar structure and intrinsic properties. Read-across is justified based on common precursors and breakdown products of hydrolysis and consistent trends in environmental fate, eco-toxicological and toxicological profile (refer to the endpoint discussion for further details). The selected studies are thus sufficient to fulfil the standard information requirements set out in Annex VII, 8.5, in accordance with Annex XI, 1.5, of Regulation (EC) No. 1907/2006.

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Remarks:

Summary of available data used for the endpoint assessment of the target substance

Adequacy of study:

key study

Justification for type of information:

refer to analogue justification provided in IUCLID section 13

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: Source: 3687-46-5

The acute dermal toxicity study performed with the source substance decyl oleate (CAS 3687-46-5) was selected as key study for reasons of structural similarity and data availability. Besides this, an acute dermal toxicity study with the source substance 2-octyldodecyl isooctadecanoate (CAS 93803-87-3) was taken into account as supporting information. In this study the LD50 was > 2000 mg/kg bw, the recommended limit value in the current OECD guideline.

Interpretation of results:

other: CLP/EU GHS criteria not met, no classification required according to Regulation (EC) No. 1272/2008

Conclusions:

In the acute dermal toxicity studies with the source substances no adverse effects were observed and the determined LD50 values were higher than 2000 mg/kg bw, the recommended limit value in the current OECD guideline. As explained in the analogue justification, this result is considered to be valid also for the target substance.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

The available information comprises adequate, reliable (Klimisch score 1 and 2) and consistent studies, from reference substances with similar structure and intrinsic properties. Read-across is justified based on common precursors and breakdown products of hydrolysis and consistent trends in environmental fate, eco-toxicological and toxicological profile (refer to the endpoint discussion for further details). The selected study is thus sufficient to fulfil the standard information requirements set out in Annex VII, 8.5, in accordance with Annex XI, 1.5, of Regulation (EC) No. 1907/2006.

Additional information

Justification for read-across

Experimental data on acute oral and dermal toxicity of Monoesters of C16 and C18 (branched and linear) fatty acids with decan-1-ol are not available. The assessment of acute oral and dermal toxicity was therefore based on studies conducted with analogue source substances as part of a read across approach, which is in accordance with Regulation (EC) No. 1907/2006, Annex XI, 1.5. For each specific endpoint the source substance(s) structurally closest to the target substance is/are chosen for read-across, with due regard to the requirements of adequacy and reliability of the available data. Structural similarities and similarities in properties and/or activities of the source and target substance are the basis of read-across. A detailed justification for the analogue read-across approach is provided in the technical dossier (see IUCLID Section 13).

Oral

In silico

The toxicological properties of decyl isooctanoate (CAS 84605-08-3) have been evaluated by quantitative structure activity relationship (QSAR) modelling performed in the Biovia Discovery Studio (TOPKAT) 4.5 (extensible), US EPA TEST 4.2, DEREK NEXUS and OECD QSAR Toolbox 4.2.

There is confidence in the prediction of acute toxicity for decyl isostearate and together with expert reasoning the results are regarded as conclusive. The summarized results of the predictions are presented in the table below.

 

Table 1: Results of the prediction of acute oral toxicity

Model	Acute Oral Toxicity (LD50, mg/kg bw)
Biovia Discovery Studio (TOPKAT) 4.5 (extensible)	21,350 (non-extended) 27,879 (extended)
US EPA TEST 4.2	11,522 (Consensus) 4,280 (Hierarchical clustering) 26,996 (FDA) 13,240 (Nearest neighbour)
OECD QSAR Toolbox 4.2.	15,400
DEREK	No alerts identified

All models predicted the LD50 to be well above the 2000 mg/kg bw value for acute toxicity category 4 according to CLP. The GHS category 5 criteria is 5000 mg/kg bw, here the TEST Hierarchical clustering model does show potential toxicity below this region (4,280 mg/kg bw). However, the majority of models show values much higher than this. The DEREK assessment highlighted no alerts for the molecule further supporting the predictions. In conclusion, from the models used it has been assessed that it is unlikely that the substance should be classified for acute oral toxicity and its toxicity can be assumed to be >2000 mg/kg bw with a worst-case value of 4,280 mg/kg bw.

In vivo

The acute oral toxicity study performed with the source substance decyl oleate (CAS 3687-46-5) was selected as key study for reasons of structural similarity and data availability. In addition, acute oral toxicity studies conducted with the source substances 2-octododecyl myristate (CAS 22766-83-2) in rats and with Fatty acids, C8-10, C12-18-alkyl esters (CAS 95912-86-0) in mice were taken into account as supporting information.

CAS 3687-46-5

A reliable acute oral toxicity study (limit test) was performed with decyl oleate (CAS 3687-46-5) and similar to OECD guideline 401 (EVIC-CEBA, 1994). 5 Female NMRI EOPS mice received a single oral dose of 2000 mg kg bw. No mortality occurred. No signs of clinical toxicity were reported. The acute oral LD50 value in mice was found to be greater than 2000 mg/kg bw.

CAS 95912-87-1

An acute oral toxicity study (limit test) was performed with Fatty acids, C16-18, C12-18-alkyl esters (CAS 95912-87-1) similar to OECD guideline 401 (EVIC-CEBA, 1977).10 male Wistar rats received a single oral (gavage) dose of 5000 mg/kg bw. No mortality occurred. No signs of clinical toxicity were reported. The acute oral LD50 value in rat was found to be greater than 5000 mg/kg bw.

CAS 22766-83-2

In an acute oral toxicity study performed according to OECD guideline 401 and in compliance with GLP, 29.75 g 2-octyldodecyl myristate/kg bw was administered via gavage to 5 OFA.Sprague-Dawley (IOPS Caw) rats/sex (Hazleton, 1989). No mortality occurred during the 14-day observation period. No clinical signs were observed in the animals during the study period. Therefore, the oral LD50 value for male and female rats is > 29.75 g/kg bw.

Dermal

The acute dermal toxicity study performed with the source substance decyl oleate (CAS 3687-46-5) was selected as key study for reasons of structural similarity and data availability. An acute dermal toxicity study with the source substance 2-octyldodecyl isooctadecanoate (CAS 93803-87-3) was taken into account as supporting information.

CAS 3687-46-5

An acute dermal toxicity study (limit test) was performed with decyl oleate (CAS 3687-46-5) similar to OECD guideline 402 (Notox, 2010). 2000 mg/kg body weight of the test substance was applied to the skin of 5 Wistar rats/sex for 24 hours under occlusive conditions. Animals were subjected to daily observations and weekly determination of body weight. Macroscopic examination was performed after terminal sacrifice (Day 15). No mortality occurred. Piloerection and/ or chromodacryorrhoea were noted in all males on Day 1 and/ or 2. No clinical signs of systemic toxicity were noted in females. Scales, scabs, focal erythema were seen in the treated skin area of all females and three males for up to 9 days during Day 7-15 of the observation period. The changes noted in bodyweight gain in males and females were within the range expected for rats used in this type of study. No abnormalities were found during the macroscopic post mortem examination of the animals. The LD50 value was > 2000 mg/kg bw.

CAS 93803-87-3

The potential acute dermal toxicity of 2-octyldodecyl isooctadecanoate (CAS 93803-87-3) was assessed in a study (limit test) performed according to a protocol similar to OECD guideline 402 (Notox, 1998). 2000 mg/kg bw of the test substance was applied to the skin of 5 Wistar rats/sex/dose under an occlusive dressing for 24 hours. No mortality occurred. No toxicologically relevant clinical signs were noted during the 14-day observation period. The body weight increases were within the range expected for rats used in this type of study and no treatment-related findings were reported during the necropsy. The LD50 value is considered to be > 2000 mg/kg bw.

Overall conclusion for acute toxicity

The data available for source substances indicate a very low level of acute toxicity following the oral and dermal route, as LD50 values were greater than the recommended guideline limit values. Moreover, the prediction of acute oral toxicity potential of the target substance by different QSAR models showed that it is unlikely that the target substance should be classified for acute oral toxicity and its toxicity can be assumed to be >2000 mg/kg bw with a worst-case value of 4,280 mg/kg bw. Therefore, as the available data did not identify any acute toxicity, the target substance Monoesters of C16 and C18 (branched and linear) fatty acids with decan-1-ol is not considered to be hazardous following acute exposure via the oral and dermal route.

Justification for classification or non-classification

According to Article 13 of Regulation (EC) No. 1907/2006 "General Requirements for Generation of Information on Intrinsic Properties of substances", information on intrinsic properties of substances may be generated by means other than tests e.g. from information from structurally related substances (grouping or read-across), provided that conditions set out in Annex XI are met. Annex XI, "General rules for adaptation of this standard testing regime set out in Annexes VII to X” states that “substances whose physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity may be considered as a group, or ‘category’ of substances. This avoids the need to test every substance for every endpoint". Since the analogue concept is applied to decyl isooctadecanoate (CAS 84605-08-3) data will be generated from data for reference source substance(s) to avoid unnecessary animal testing. Additionally, once the analogue read-across concept is applied, substances will be classified and labelled on this basis.

Therefore, based on the analogue read-across approach, the available data on acute oral and dermal toxicity do not meet the classification criteria according to Regulation (EC) No. 1272/2008 and are therefore conclusive but not sufficient for classification.