Prop-2-yn-1-yl 1H-imidazole-1-carboxylate

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

Remarks:

28-day Repeated dose Oral toxicity study, Rats

Type of information:

(Q)SAR

Remarks:

28-day Repeated dose Oral toxicity study, Rats

Adequacy of study:

key study

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
OECD QSAR toolbox 4.5 SP1

2. MODEL (incl. version number)
QSAR model for 28-day Repeated dose Oral toxicity of Rats

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
CAS#: 83395-38-4
EC Number:6955952
Smiles: O=C(OCC#C)n1ccnc1

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
- Defined endpoint: Human Health Hazards -> Repeated Dose Toxicity -> NOAEL -> rat

- Unambiguous algorithm: Linear approximation
Model equation: NOAEL = 3.66 (±0.542) + 1.31 (±0.703) * log Kow, log(1/mol/kg bdwt/d)
Active descriptor: log Kow (calculated)
Data usage: All values*

- Defined domain of applicability: log Kow: from -1.17 to 0.35, NOAEL: from 5 to 1E+03 mg/kg bdwt/d, target chemical is in domain.

- Appropriate measures of goodness-of-fit and robustness and predictivity:
The prediction is based on 7 values within range 5 - 1E+03 mg/kg bdwt/d
Prediction confidence range (95%): ± 1.12 log(1/mol/kg bdwt/d)
Statistics of the prediction model:
N = 7; count of data points
R2 = 0.822; coefficient of detemination
R2adj = 0.786; adjusted coefficient of detemination
Q2 = 0.633; coefficient of detemination by "leave-one-out" validation
SSR = 0.675; sum of squared residuals
s = 0.310; sample standard deviation of residuals
F = 23.1; Fisher function

- Mechanistic interpretation:
By using different grouping methods to group chemicals into chemical categories according to different measures of similarity so that within a category a QSAR model can be established. We use the predefined profile criteria “US-EPA New Chemical Categories” to narrow the scope of the model. The endpoint specific profiles "Repeated dose (HESS)", "Skin irritation/corrosion Exclusion rules by BfR" and “Bioaccumulation - metabolism half-lives” are relevant to the endpoint of Repeated dose toxicity. Besides, repeated oral toxicity depends on the solubility, shape and reactivity of the chemicals. Therefore, we select "logkow" to describe solubility, empiric profiles “Lipinski Rule Oasis”, "Groups of elements" to describe the shape, general mechanistic profiles "Protein binding potency Cys (DPRA 13%)", “Uncouplers (MITOTOX)", "Biodegradation probability (Biowin 5)", "Biodegradation primary (Biowin 4)", "Toxic hazard classification by Cramer (extended)" to describe the reactivity.
See the attachment.

5. APPLICABILITY DOMAIN
[Explain how the substance falls within the applicability domain of the model]
- Descriptor domain: log Kow: from -1.17 to 0.35, target chemical is in domain.
- Structural domain: Classified as Not categorized by US-EPA New Chemical Categories; Classified as Non-Metals by Groups of elements; Classified as Bioavailable by Lipinski Rule Oasis.
- Mechanistic domain: Classified as DPRA less than 9% (DPRA 13%) >> No protein binding alert by Protein binding potency Cys (DPRA 13%); classified as Non concern for uncoupling of OxPhos (logKow < 1.5) by Uncouplers (MITOTOX), classified as Does NOT Biodegrade Fast Biodegradation probability (Biowin 5), classified as Days to weeks by Biodegradation primary (Biowin 4), classified as High (Class III) by Toxic hazard classification by Cramer (extended).
- Similarity with analogues in the training set: Not specified.
- Other considerations (as appropriate): Classified as Not categorized byRepeated dose (HESS), Classified as Undefined by Skin irritation/corrosion Exclusion rules by BfR; Classified as Very fast by Bioaccumulation - metabolism half-lives”.

6. ADEQUACY OF THE RESULT
R2 = 0.822; R2adj = 0.786; Q2 = 0.633;.

Data source

Reference

Reference Type:

other: OECD QSAR Toolbox Report

Title:

Unnamed

Year:

2022

Report date:

2022

Materials and methods

Principles of method if other than guideline:

- Software tool(s) used including version: OECD QSAR Toolbox 4.5 SP1
- Model(s) used: QSAR model for 28-day Repeated dose Oral toxicity of Rats
- Model description: see field 'Justification for non-standard information', 'Attached justification' and/or 'Cross-reference'
- Justification of QSAR prediction: see field 'Justification for type of information', 'Attached justification' and/or 'Cross-reference'

Test material

Test material information

Constituent 1

Reference substance name:

prop-2-yn-1-yl 1H-imidazole-1-carboxylate

EC Number:

695-595-2

Cas Number:

83395-38-4

Molecular formula:

C7H6N2O2

IUPAC Name:

prop-2-yn-1-yl 1H-imidazole-1-carboxylate

Test material form:

solid

Test animals

Species:

rat

Administration / exposure

Route of administration:

oral: gavage

Duration of treatment / exposure:

28 d

Results and discussion

Results of examinations

Description (incidence and severity):

NOAEL

Other effects:

no effects observed

Description (incidence and severity):

NOAEL = 23.8 mg/kg bw/d

Effect levels

Key result

Dose descriptor:

NOAEL

Effect level:

ca. 23.8 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

not specified

Basis for effect level:

clinical signs

Remarks on result:

other:

Target system / organ toxicity

Key result

Critical effects observed:

not specified

Organ:

not specified

Applicant's summary and conclusion

Conclusions:

Based on the QSAR prediction result of 28-day Repeated dose Oral toxicity, the NOAEL of target material to rat is 23.8 mg/kg bw/d.