1-hydroxyoctan-2-one

Endpoint summary

Description of key information

A combination of in silico QSAR and a single read-across study (for octan-2 -one) have been used in a WoE approach to determine the acute oral toxicity of 1 -hydroxyoctan-2 -one.

Interpretation of QSAR Results

REACHAcross™v3.1.4 estimates an 82% probability that 1 -hydroxyoctan-2 -one (SMILES: O=C(CO)CCCCCC) is not an acute oral hazard.

Interpretation of read-across results for structural analogue

In a acute oral toxicity study summarised in a peer reviewed literature paper from 1975, rats were treated with octan-2-one in the concentration of 5000 mg/kg orally. No mortality was observed in treated rats at 5000 mg/kg bw. Therefore, LD50 was considered to be >5000 mg/kg when rats were treated with methyl hexyl ketone orally.

Conclusion

Based on the considerations above, it can be confidently concluded that read-across and QSAR arguments can be used in a weight of evidence approach, to satisfy the acute oral toxicity endpoint for EXPINN PC17032 (1-hydroxyoctan-2-one) and it is appropriate and scientifically justified.

 

The substance is not expected to pose an acute toxic hazard via the oral route and a result of LD50 >2000 mg/kg will be used for regulatory notification and product safety/risk assessment purposes.

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:

(Q)SAR

Adequacy of study:

weight of evidence

Study period:

2018

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:

Software:
http://ulreachacross.com/

Model (incl. version number):
REACHAcross™ v3.1.4

Mechanistic interpretation: N/A

Applicability domain:
Descriptor domain: Pubchem2D Fingerprints and Similarity Network Features
Structural and mechanistic domains: Defined by model predictions
Similarity with analogues in the training set: NA
Other considerations (as appropriate): NA

Principles of method if other than guideline:

REACHAcross™ software is a new kind of platform described as a hybrid QSAR and read across model that uses chemical similarities paired with supervised learning to make probabilistic estimates on hazard. Cluster computing in combination with an integrated chemical property database serves to create an enormous network of over 31 billion chemical similarities. REACHAcross™ Software version 3.1.4 platform provides hazard estimation for 6 human health hazard propertiesrequired by REACH regulation at all tonnage bands.

Chemical similarity claims that chemical structures that share many chemical features share biological activity. REACH employs chemical similarity in read-across submissions, wherein subject matter experts manually describe how structurally similar chemicals should induce similar biological effects. REACHAcross™ Software breaks the traditional chemical similarity workflow into three main components:

1. Fingerprinting: Chemical fingerprints are vectors describing features of a chemical. Is it a halogen? What is the molecular weight? How many rings does it contain? REACHAcross™ Software uses Pubchem2D a popular fingerprinter supported by Pubchem.

2. Similarity: Chemical Similarity is a function of two chemical fingerprints. Similarity functions approximate a probability that two chemicals fingerprints will have the same hazard. REACHAcross™ Software uses tanimoto similarity which is simply the fraction of shared features over total number of features in both chemical fingerprints.

3. Network Features: The UL integrated database contains 250,000 chemicals with hazard labelling data. Steps 1 and 2 are repeated for every pair of two chemicals. This results in a large network of 250,000 chemicals with 31 billion similarities.

4. Machine Learning: Once the global similarity network is constructed in step 3, REACH Across Software derives network features for each chemical. These features are chemical and endpoint specific. Chemicals tend to be hazardous when they are very similar to another hazardous compound, particularly when they are not close to any negative compounds. REACHAcross™ Software trains a statistical model (logistic regression) on a large training set of labelled chemicals with network features to predict probabilities of hazard.

Additional information concerning the REACHAcross™ software can be accessed via the developer’s website and associated publications (Luechtefeld et al. 2018).

GLP compliance:

no

Test type:

other: In silico QSAR Assessment

Limit test:

no

Specific details on test material used for the study:

The REACHAcross™ v3.1.4 Platform was applied to assess the acute oral toxicity hazard associated with the target substance, 1-hydroxyoctan-2-one.

Input
SMILES: O=C(CO)CCCCCC

Species:

rat

Route of administration:

oral: unspecified

Vehicle:

not specified

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Each read-across analogue (source substance) identified by the model is assigned a (%) similarity score by comparing with the target substance.

 

Several read-across analogues for 1-hydroxyoctan-2-one were identified. These exhibited both positive and negative acute oral toxicity hazard properties (where a positive hazard = LD50 <2000 mg/kg and a negative hazard = LD50 >2000 mg/kg).

 

The results were tabulated in a report automatically generated by the model (Attached to IUCLID Chapter 7.2.1 and Chapter 13).

Interpretation of results:

GHS criteria not met

Conclusions:

REACHAcross™v3.1.4 estimates an 82% probability that 1 -hydroxyoctan-2 -one (SMILES: O=C(CO)CCCCCC) is not an acute oral hazard.

Executive summary:

The REACHAcross™ v3.1.4 Platform was applied to assess the acute oral toxicity hazard associated with the target substance, 1-hydroxyoctan-2-one.

 

Input

SMILES:O=C(CO)CCCCCC

 

Output

Each read-across analogue (source substance) identified by the model is assigned a (%) similarity score by comparing with the target substance.

 

Several read-across analogues for 1-hydroxyoctan-2-one were identified. These exhibited both positive and negative acute oral toxicity hazard properties (where a positive hazard = LD50 <2000 mg/kg and a negative hazard = LD50 >2000 mg/kg).

 

Interpretation of Results

 

REACHAcross™v3.1.4 estimates an 82% probability that 1 -hydroxyoctan-2 -one (SMILES: O=C(CO)CCCCCC) is not an acute oral hazard.

Reference 2

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

1975

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Justification for type of information:

Read-across data for a structurally analagous source substance to the registration/target substance. Data from peer reviewed scientific journal. Read-across justification report for acute oral toxicity attached to section 13.

Qualifier:

according to guideline

Guideline:

other: As described below

Deviations:

not specified

Principles of method if other than guideline:

The acute oral toxicity study has been performed on rat for the chemical methyl hexyl ketone.

GLP compliance:

no

Test type:

other: not specified

Limit test:

yes

Specific details on test material used for the study:

- Name of test material: Octan-2-one
- Molecular formula: C8H16O
- Molecular weight: 128.21 g/mol
- Substance type: Organic
- Physical state: Liquid

Species:

rat

Strain:

not specified

Sex:

not specified

Details on test animals or test system and environmental conditions:

Not available

Route of administration:

oral: unspecified

Vehicle:

not specified

Details on oral exposure:

No data available

Doses:

5000 mg/kg bw

No. of animals per sex per dose:

No data available

Control animals:

not specified

Details on study design:

Not data available

Statistics:

Not data available

Key result

Sex:

not specified

Dose descriptor:

LD50

Effect level:

> 5 000 mg/kg bw

Based on:

test mat.

Mortality:

No data available

Clinical signs:

other: Not data available

Gross pathology:

Not data available

Other findings:

Not data available

Interpretation of results:

Category 5 based on GHS criteria

Conclusions:

LD50 was considered to be >5000 mg/kg when rats were treated with methyl hexyl ketone orally.

Executive summary:

In a acute oral toxicity study, rats were treated with octan-2-one in the concentration of 5000 mg/kg orally. No mortality was observed in treated rats at 5000 mg/kg bw. Therefore, LD50 was considered to be >5000 mg/kg when rats were treated with methyl hexyl ketone orally.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

5 000 mg/kg bw