3-phenylpropionyl chloride

Endpoint summary

Description of key information

Skin Irritation:

The dermal irritation potential of test article was determined according to the OECD 439 test guideline followed for this study. The Mean % tissue viability compared to negative control (n=3) of 3-phenylpropionyl chloride[CAS: 645-45-4] was determined to be 20.9%. Thus, 3-phenylpropionyl chloride[CAS: 645-45-4] was considered to be Irritating to the human skin.

Eye Irritation:

The ocular irritation potential of 3-phenylpropanoyl chloride (CAS No: 645-45-4) was estimated using OECD QSAR toolbox version 3.3 with logPow as the primary descriptor. 3-phenylpropanoyl chloride (CAS No: 645-45-4) was estimated to be not irritating to the eyes of rabbits. Based on the estimated result 3-phenylpropanoyl chloride (CAS No: 645-45-4) can be considered as not irritating to eye and can be classified under the category “Not Classified” as per CLP regulation.

 

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Reference

Endpoint:

skin irritation: in vitro / ex vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

December 04, 2017 to March 13, 2018

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Justification for type of information:

Data is from experimental study report

Qualifier:

according to guideline

Guideline:

OECD Guideline 439 (In Vitro Skin Irritation: Reconstructed Human Epidermis Test Method)

Principles of method if other than guideline:

The purpose of this study is to provide classification of dermal irritation potential of a chemical by using a three-dimensional human epidermis model, according to the OECD Test Guideline No. 439, “In Vitro Skin Irritation: Reconstructed Human Epidermis Test Method”. The EpiDerm™ SIT allows discrimination between irritants of Category 2 and non-irritants, according to the UN Globally Harmonized System of Classification and Labeling of Chemicals (GHS).

GLP compliance:

yes

Specific details on test material used for the study:

- Name of test material (as cited in study report): 3-phenylpropionyl chloride- Molecular formula : C9H9ClO- Molecular weight : 168.622 g/mol- Substance type: Organic- Physical state: liquidSTABILITY AND STORAGE CONDITIONS OF TEST MATERIAL- Storage condition of test material: Room temperature or Fridge storage- Stability under test conditions: No data available- Solubility and stability of the test substance in the solvent/vehicle: No data available- Reactivity of the test substance with the solvent/vehicle of the cell culture medium: No data availableTREATMENT OF TEST MATERIAL PRIOR TO TESTING- Treatment of test material prior to testing: Test articles is tested as provided (neat).- Preliminary purification step (if any): No data available- Final dilution of a dissolved solid, stock liquid or gel: No data available- Final preparation of a solid: No data availableFORM AS APPLIED IN THE TEST: LiquidOTHER SPECIFICS: No data available

Test system:

other: MatTek EpiDerm™ Tissue Model (EPI-200-SIT) kit

Source species:

other: no data

Cell type:

non-transformed keratinocytes

Cell source:

other: EpiDerm™ 3-dimensional human tissues used in this study

Source strain:

other: Not applicable

Details on animal used as source of test system:

EpiDerm™ tissues, Lot No. 27646 Kits I and J, were received from MatTek on 12 Dec 2017, and Lot No. 27654 Kits O and P, were received from MatTek on 19 Dec 2017. See Appendix C for EpiDerm™ tissue Quality Control report. All tissues were refrigerated at 2-8°C upon receipt. Before use, the tissues were incubated (37±1°C, 5±1% CO2) with assay medium (MatTek) for a one-hour equilibration. The tissues were then moved to new wells with fresh medium for an additional overnight equilibrium, for 18±3 hours. Equilibration medium was replaced with fresh medium before dosing.

Justification for test system used:

The EpiDerm™ Skin Model closely parallels human skin, thus providing a useful in vitro means to assess dermal irritancy and toxicology

Vehicle:

unchanged (no vehicle)

Details on test system:

EpiDerm™ Tissue SamplesEpiDerm™ tissues, Lot No. 27646 Kits I and J, were received from MatTek on 12 Dec 2017, and Lot No. 27654 Kits O and P, were received from MatTek on 19 Dec 2017. See Appendix C for EpiDerm™ tissue Quality Control report. All tissues were refrigerated at 2-8°C upon receipt. Before use, the tissues were incubated (37±1°C, 5±1% CO2) with assay medium (MatTek) for a one-hour equilibration. The tissues were then moved to new wells with fresh medium for an additional overnight equilibrium, for 18±3 hours. Equilibration medium was replaced with fresh medium before dosing.Mesh CompatibilityFive of the test articles supplied were liquids. These test articles were assessed for compatibility withpre-cut nylon mesh supplied with the tissues. The mesh was placed on a slide and 30 μl of a liquid test articles or PBS (negative control) were applied. After 60 minutes of exposure, the mesh was checked microscopically. If no damage or other interaction was observed, indicating that the mesh was compatible with the test article, the mesh was used as a spreading aid.Tissue Viability (MTT Reduction)At the end of the incubation period, each EpiDerm™ tissue was rinsed with PBS and transferred to a 24-well plate containing 300 μl of MTT solution (1 mg/ml MTT in DMEM). The tissues were then returned to the incubator for a three-hour MTT incubation period. Following the MTT incubation period, each EpiDerm™ tissue was rinsed with PBS and then treated with 2.0 ml of extractant solution (isopropanol) per well for at least two hours, with shaking, at room temperature. Two aliquots of the extracted MTT formazan were measured at 540 nm using a plate reader (μQuant Plate Reader, Bio-Tek Instruments, Winooski, VT).For several tissues, the test article had stained the tissues. Therefore, the tissues were extracted with only 1.0 ml, allowing extraction to occur only through the bottom of the insert. After the extraction period, the tissue insert was removed and discarded and 1.0 ml of extraction solution were added to each well, bringing the volume to a total of 2.0 ml.Quality ControlsThe assay meets the acceptance criteria if the mean OD540 of the negative control tissues is between 1.0 and 2.5, inclusive, and the mean viability of positive control tissues, expressed as percentage of the negative control tissues, is at least 20%. In addition, the standard deviation (SD) calculated from individual percent tissue viabilities of the three identically-treated replicates must be less than 18%.Note: Chemicals that provide tissue viabilities in a range of 30% to 70% may provide high SD. If the high SD (above acceptance limits) is typical for the chemical and the classification of the chemical is consistent in all independent runs, MatTek recommends that this result be accepted, although it did not meet the Assay Acceptance Criterion.Analysis of DataSee Table 1 for Experimental Data. The mean absorbance value for each time point was calculated from the optical density (OD) of the duplicate samples and expressed as percent viability for each sample using the following formula:% viability = 100 X (OD sample/OD negative control)Skin Irritation PredictionAccording to the EU1,2 and GHS3 classification (R38 / Category 2 or no label), an irritant is predicted if the mean relative tissue viability of three individual tissues exposed to the test substance is 50% or less of the mean viability of the negative controls.In vitro result In vivo ClassificationMean tissue viability ≤ 50% Category 2Mean tissue viability > 50% Non-irritant (NI)Assessment of direct MTT reduction and assessment of coloring or staining materials was not performed. Therefore, it cannot be fully assessed if the test articles interfered with MTT viability measurements.Retention of DataUpon signing the final report, all raw data, supporting documentation and reports are submitted to the Archivist by the Study Director. The raw data are filed at MB Research by project number. The final report is filed at MB Research by Sponsor name and MB project number.All data generated during the conduct of this study will be archived at MB Research for at least one year from the date of the final report and optionally longer at additional cost. The Sponsor will be contacted in writing to determine final disposition of the records.Any remaining test article will be discarded upon submission of the report.Amendment to the ProtocolThere were no amendments to the protocol. See Appendix C for the protocol in its entiretyEvaluation of Test Article in the Cell Models:1. Cell system: Upon receipt, the MatTek EpiDerm™ tissue cultures were placed in 0.9 mL of fresh Maintenance medium (in a 6-well plate). The culture inserts are incubated for ~one hour. The tissues were then transferred to 6-well plates containing 0.9 mL fresh Maintenance medium and they were incubated overnight at ~37°C, 5% CO2 in a humidified incubator.2. Control and Test Article Exposures: On the day of dosing, the tissues are then removed from the incubator and the controls and the test article are applied topically to tissues by pipette. Tissues were exposed to controls and the test articles for one hour, with ~35 minutes in a 37°C, 5% CO2 humidified incubator and the remaining 25 minutes at room temperature.a) Controls30 µL of negative control DPBS, positive control 5% SDS was applied topically to the tissue and gently spread by placing a nylon mesh on the apical surface of each tissue, if necessary.b)Test ArticleFor solid test article, the tissues were moistened with 25 μL of ultrapure water to improve contact of the tissue surface with the test article. Approximately 25 mg of each test article was evenly applied to the apical surface of each tissue (n=3). All the tissues were placed into the ~37°C incubator with 5% CO2. The exposure times were approximately 1 hour, with ~35 minutes exposure in the incubator and ~25 minutes at room temperature. 3.Post-exposure treatmentAfter the 1 hour exposure, the tissues were rinsed 20 to 25 times with 1 mL of DPBS. The apical surface was gently blotted with a cotton swab. The tissues were placed in 0.9 mL of fresh Maintenance medium (6-well plate) for either 25 hours, 38 minutes and 23 seconds or for 24 hours, 10 minutes and 09 seconds (as there were numerous tissues, they had to be broken down into 2 sets to complete dosing in a timely manner). After this initial ~24 hour incubation, the tissues were placed in 6-well plates containing 0.9 mL fresh Maintenance medium and incubated for another 17 hours, 03 minutes and 34 seconds prior to performing the MTT assay, for a total of an approximately 42 hour post-exposure incubation.RECONSTRUCTED HUMAN EPIDERMIS (RHE) TISSUE- Model used: The EpiDerm™ 3 dimensional human tissue model- Tissue Lot number(s): 26459- Date of initiation of testing: 6/08/2017TEMPERATURE USED FOR TEST SYSTEM- Temperature used during treatment / exposure: 37°C- Temperature of post-treatment incubation (if applicable): 37°CREMOVAL OF TEST MATERIAL AND CONTROLS-Volume and number of washing steps: TwiceMTT DYE USED TO MEASURE TISSUE VIABILITY AFTER TREATMENT / EXPOSURE- MTT concentration: 300 µL MTT medium (1.0 mg/mL).- Incubation time: After 2 hours, 57 minute and 25 second MTT incubation- Spectrophotometer: Synergy H4 spectrophotometer - Wavelength: 570 nm- Filter: No data- Filter bandwidth: No data- Linear OD range of spectrophotometer: No dataNUMBER OF REPLICATE TISSUES: 3CALCULATIONS and STATISTICAL METHODSAll data were background subtracted before analysis. MTT data are presented as % viable compared to negative control. Data were generated as follows: MTT AssayBlanks:·        The optical density (OD) mean from all replicates for each plate (ODblank). Negative Controls (NC):Identity: Phosphate-Buffered Saline (PBS), Lot No. AC10239794Provided by:MatTekDate Received:12 Dec 2017 and 19 Dec 2017Expiration Date:18 Jul 2018Storage:Room temperature and humidityDescription:Clear colorless liquidSample Preparation:Used as receivedPositive Control (PC):Identity: 5% Sodium Dodecyl Sulfate (SDS), Lot No. 071817MABProvided by:MatTekDate Received:12 Dec 2017 and 19 Dec 2017Expiration Date:18 Jul 2018Storage:Room temperature and humidityDescription:Clear colorless liquidSample Preparation:Used as received- Assay quality controls- Negative Controls (NC)The Dulbecco’s phosphate buffered saline (DPBS) was used as a NC. The assay passed all acceptance criteria if the ODs of the negative control exposed tissues were between ≥0.8 and ≤2.8.  - Positive Controls (PC)5% solution of sodium dodecyl sulfate was used as a PC. The assay is meeting the acceptance criteria if the viability of the PC is ≤20% of the negative control.   - Standard Deviation (SD)The standard deviation (SD) calculated from individual percent tissue viabilities of the test article exposed replicates was ≤18.

Control samples:

yes, concurrent negative control

yes, concurrent positive control

Amount/concentration applied:

TEST MATERIAL- Amount(s) applied (volume or weight with unit): 30 μl- Concentration (if solution): neat (undiluted)VEHICLE (Not used)- Amount(s) applied (volume or weight with unit): none- Concentration (if solution): none- Lot/batch no. (if required): none- Purity: noneNEGATIVE CONTROL- Amount(s) applied (volume or weight): 30 µL- Concentration (if solution): neatPOSITIVE CONTROL- Amount(s) applied (volume or weight): 30 µL- Concentration (if solution): 5% solution of sodium dodecyl sulfate

Duration of treatment / exposure:

Tissues will be topically exposed to the test article and control articles for 60 minutes.

Duration of post-treatment incubation (if applicable):

After dosing, the tissues will be returned to the incubator for 35 ±1 minute, and then returned to the sterile hood for the remainder of the 60-minute exposure period.

Number of replicates:

All treatments with test articles and controls will be dosed in triplicate EpiDerm™ tissues.

Duration of treatment / exposure:

The duration of the EpiDerm™ Skin Irritation Test (SIT) is approximately five days

Irritation / corrosion parameter:

% tissue viability

Run / experiment:

Run 1

Value:

20.9

Vehicle controls validity:

not specified

Negative controls validity:

valid

Positive controls validity:

valid

Remarks on result:

positive indication of irritation

Other effects / acceptance of results:

All treatments with test articles and controls will be dosed in triplicate EpiDerm™ tissues.In vitro result In vivo ClassificationMean tissue viability ≤ 50% Category 2Mean tissue viability > 50% Non-irritant

Test and Control Article Identity	Tissue Viability	Irritancy Classification
	Mean
3-phenylpropionyl chloride, CAS No. 645-45-4	20.9	Irritant

Interpretation of results:

other: irritating

Conclusions:

The dermal irritation potential of test article was determined according to the OECD 439 test guideline followed for this study. The Mean % tissue viability compared to negative control (n=3) of 3-phenylpropionyl chloride[CAS: 645-45-4] was determined to be 20.9%. Thus, 3-phenylpropionyl chloride[CAS: 645-45-4] was considered to be Irritating to the human skin.

Executive summary:

The dermal irritation potential of test article was determined according to the OECD 439 In Vitro Skin Irritation: Reconstructed Human Epidermis Test Method”. The MatTek EpiDerm™ model was used to assess the potential dermal irritation of the test article by determining the viability of the tissues following exposure to the test article via MTT. The objective of this study was to assess the dermal irritation potential of test article Tissues were exposed to test article and controls for ~one hour, followed by a 42 hour post-exposure recovery period. The viability of each tissue was determined by MTT assay. 

The MTT data shows that the assay quality controls were met. The mean tissue viabilities for the Positive control, Methyl acetate were 6.5%, 10.7% respectively in the first and second run, whereas the tissue viabilities of the negative control, Tissue culture water remained at 100% in the both the runs.

The Mean % tissue viability compared to negative control (n=3) of 3-phenylpropionyl chloride[CAS: 645-45 -4] was determined to be 20.9%.

Hence, under the experimental test conditions it was concluded that 3-phenylpropionyl chloride[CAS: 645-45-4 ]was considered to be irritating to the human skin and being classified as ''Irritating to skin in Category 2” as per CLP Regulation.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Eye irritation

Link to relevant study records

Reference

Endpoint:

eye irritation: in vivo

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 limited documentation / justification

Justification for type of information:

Data is from QSAR Toolbox version 3.3 and QMRF report has been attached

Qualifier:

according to guideline

Guideline:

other: estimated data

Principles of method if other than guideline:

Prediction is done using QSAR Toolbox version 3.3

GLP compliance:

not specified

Specific details on test material used for the study:

- Name of test material (as cited in study report): 3-phenylpropanoyl chloride- Molecular formula: C9H9ClO- Molecular weight: 168.622 g/mol- Substance type: organic - Physical state: Liquid- Smiles notation: c1cc(CCC(Cl)=O)ccc1- InChl: 1S/C9H9ClO/c10-9(11)7-6-8-4-2-1-3-5-8/h1-5H,6-7H2

Species:

rabbit

Strain:

not specified

Details on test animals or tissues and environmental conditions:

no data available

Amount / concentration applied:

no data available

Duration of treatment / exposure:

no data available

Observation period (in vivo):

no data available

Duration of post- treatment incubation (in vitro):

no data available

Irritation parameter:

overall irritation score

Basis:

mean

Reversibility:

not specified

Remarks on result:

no indication of irritation

Estimation method: Takes mode value from the 5 nearest neighbours
Domain  logical expression:Result: In Domain

((((((((("a" or "b" or "c" or "d" )  and "e" )  and ("f" and ( not "g") )  )  and "h" )  and ("i" and ( not "j") )  )  and ("k" and ( not "l") )  )  and ("m" and ( not "n") )  )  and ("o" and ( not "p") )  )  and ("q" and "r" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Acylation OR Acylation >> Direct Addition of an Acyl Halide OR Acylation >> Direct Addition of an Acyl Halide >> Acyl halide OR Michael addition OR Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals OR Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals >> Arenes by DNA binding by OECD ONLY

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Acylation AND Acylation >> Direct acylation involving a leaving group AND Acylation >> Direct acylation involving a leaving group >> (Thio)Acyl and (thio)carbamoyl halides and cyanides  by Protein binding by OASIS v1.3

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Acylation OR Acylation >> Direct acylation involving a leaving group OR Acylation >> Direct acylation involving a leaving group >> (Thio)Acyl and (thio)carbamoyl halides and cyanides  by Protein binding by OASIS v1.3 ONLY

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Acylation OR Acylation >> Direct Acylation Involving a Leaving group OR Acylation >> Direct Acylation Involving a Leaving group >> Acyl halides (including benzyl and carbamoyl deriv.) by Protein binding by OECD

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as Bioavailable by Lipinski Rule Oasis ONLY

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as Halogens AND Non-Metals by Groups of elements

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as Alkali Earth OR Metalloids OR Transition Metals by Groups of elements

Domain logical expression index: "h"

Similarity boundary:Target: O=C(Cl)CCc1ccccc1
Threshold=30%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as Not categorized by Repeated dose (HESS)

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as 3-Methylcholantrene (Hepatotoxicity) Alert OR Aliphatic amines (Mucous membrane irritation) Rank C OR Allyl esters (Hepatotoxicity) Rank A OR Amineptine (Hepatotoxicity) Alert OR Aromatic hydrocarbons (Liver enzyme induction) Rank C OR Benzene/ Naphthalene sulfonic acids (Less susceptible) Rank C OR Chlorphentermine (Hepatotoxicity) Alert OR Dantrolene (Hepatotoxicity) Alert OR Oxyphenistain (Hepatotoxicity) Alert OR Perhexiline (Hepatotoxicity) Alert OR Tamoxifen (Hepatotoxicity) Alert OR Thiocarbamates/Sulfides (Hepatotoxicity) No rank OR Valproic acid (Hepatotoxicity) Alert by Repeated dose (HESS)

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as Inclusion rules not met by Eye irritation/corrosion Inclusion rules by BfR

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as Aliphatic esters of chloro formic acid OR Organic sulphonic salts by Eye irritation/corrosion Inclusion rules by BfR

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as No alert found by DNA alerts for AMES, MN and CA by OASIS v.1.3

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as AN2 OR AN2 >> Schiff base formation by aldehyde formed after metabolic activation OR AN2 >> Schiff base formation by aldehyde formed after metabolic activation >> Geminal Polyhaloalkane Derivatives OR AN2 >> Shiff base formation for aldehydes OR AN2 >> Shiff base formation for aldehydes >> Geminal Polyhaloalkane Derivatives OR Radical OR Radical >> Radical mechanism by ROS formation (indirect) or direct radical attack on DNA OR Radical >> Radical mechanism by ROS formation (indirect) or direct radical attack on DNA >> Organic Peroxy Compounds OR Radical >> Radical mechanism via ROS formation (indirect) OR Radical >> Radical mechanism via ROS formation (indirect) >> Geminal Polyhaloalkane Derivatives OR SN1 OR SN1 >> Alkylation after metabolically formed carbenium ion species OR SN1 >> Alkylation after metabolically formed carbenium ion species >> Polycyclic Aromatic Hydrocarbon Derivatives OR SN2 OR SN2 >> Acylation involving a leaving group  OR SN2 >> Acylation involving a leaving group  >> Geminal Polyhaloalkane Derivatives OR SN2 >> Acylation involving a leaving group after metabolic activation OR SN2 >> Acylation involving a leaving group after metabolic activation >> Geminal Polyhaloalkane Derivatives OR SN2 >> Alkylation, direct acting epoxides and related after P450-mediated metabolic activation OR SN2 >> Alkylation, direct acting epoxides and related after P450-mediated metabolic activation >> Polycyclic Aromatic Hydrocarbon Derivatives OR SN2 >> Direct acylation involving a leaving group OR SN2 >> Direct acylation involving a leaving group >> Acyl Halides OR SN2 >> Nucleophilic substitution at sp3 carbon atom after thiol (glutathione) conjugation OR SN2 >> Nucleophilic substitution at sp3 carbon atom after thiol (glutathione) conjugation >> Geminal Polyhaloalkane Derivatives OR SN2 >> SN2 at sulfur atom OR SN2 >> SN2 at sulfur atom >> Sulfonyl Halides by DNA alerts for AMES, MN and CA by OASIS v.1.3

Domain logical expression index: "o"

Referential boundary: The target chemical should be classified as Acyl halides (Genotox) AND Structural alert for genotoxic carcinogenicity by Carcinogenicity (genotox and nongenotox) alerts by ISS

Domain logical expression index: "p"

Referential boundary: The target chemical should be classified as (Poly) Halogenated Cycloalkanes (Nongenotox) OR Aliphatic halogens (Genotox) OR alpha,beta-unsaturated aliphatic alkoxy group (Genotox) OR alpha,beta-unsaturated carbonyls (Genotox) OR Aromatic N-acyl amine (Genotox) OR Coumarins and Furocoumarins (Genotox) OR Dicarboximide (Nongenotox) OR Halogenated benzene (Nongenotox) OR Hydrazine (Genotox) OR Imidazole, benzimidazole (Nongenotox) OR Isocyanate and isothiocyanate groups (Genotox) OR Nitro-aromatic (Genotox) OR N-methylol derivatives (Genotox) OR No alert found OR Primary aromatic amine,hydroxyl amine and its derived esters (Genotox) OR Structural alert for nongenotoxic carcinogenicity OR Structural alerts for both genotoxic and nongenotoxic carcinogenicity OR Substituted n-alkylcarboxylic acids (Nongenotox) by Carcinogenicity (genotox and nongenotox) alerts by ISS

Domain logical expression index: "q"

Parametric boundary:The target chemical should have a value of log Kow which is >= 1.35

Domain logical expression index: "r"

Parametric boundary:The target chemical should have a value of log Kow which is <= 4.44

Interpretation of results:

other: not irritating

Conclusions:

The test chemical 3-phenylpropanoyl chloride (CAS No: 645-45-4) was estimated to be not irritating to the eyes of rabbits.

Executive summary:

The ocular irritation potential of 3-phenylpropanoyl chloride (CAS No: 645-45-4) was estimated using OECD QSAR toolbox version 3.3 with logPow as the primary descriptor. 3-phenylpropanoyl chloride (CAS No: 645-45-4) was estimated to be not irritating to the eyes of rabbits. Based on the estimated result 3-phenylpropanoyl chloride (CAS No: 645-45-4) can be considered as not irritating to eye and can be classified under the category “Not Classified”as per CLP regulation.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Skin irritation:

Various studieshas been investigated for the test chemical 3-phenylpropanoyl chloride (CAS No: 645-45-4)to observe the potential for dermal irritation to a greater or lesser extent. The studies are based on in vitro and in vivo experiments for target chemical 3-phenylpropanoyl chloride (CAS No: 645-45-4) and its structurally similar read across substancesBenzyl acetate (CAS No: 140-11-4), 2-phenylethyl formate (CAS No: 104-62-1) and Benzyl propionate (CAS No: 122-63-4).The predicted data using the OECD QSAR toolbox has also been compared with the experimental data and summarized as below;

The dermal irritation potential of test article was determined according to the OECD 439 In Vitro Skin Irritation: Reconstructed Human Epidermis Test Method”. The MatTek EpiDerm™ model was used to assess the potential dermal irritation of the test article by determining the viability of the tissues following exposure to the test article via MTT. The objective of this study was to assess the dermal irritation potential of test article Tissues were exposed to test article and controls for ~one hour, followed by a 42 hour post-exposure recovery period. The viability of each tissue was determined by MTT assay. 

The MTT data shows that the assay quality controls were met. The mean tissue viabilities for the Positive control, Methyl acetate were 6.5%, 10.7% respectively in the first and second run, whereas the tissue viabilities of the negative control, Tissue culture water remained at 100% in the both the runs.

The Mean % tissue viability compared to negative control (n=3) of 3-phenylpropionyl chloride[CAS: 645-45 -4] was determined to be 20.9%.

Hence, under the experimental test conditions it was concluded that 3-phenylpropionyl chloride[CAS: 645-45-4 ]was considered to be irritating to the human skin and being classified as ''Irritating to skin in Category 2” as per CLP Regulation.

The above result was supported by a patch test study conducted by D. McGinty , D. Vitale, C.S. Letizia, A.M. Api (2012) forstructurally similar read across substancesBenzyl acetate (CAS No: 140-11-4) in three New Zealand White rabbits.The rabbits were exposed to 0.5ml of undiluted Benzylacetate (CAS No: 140-11-4) for 4 hours under semi-occlusion. The skin reactions were examined after patch removal at 1, 24, 48, 72 and 168 hours (7 days). Well defined erythema was seen in two rabbits and well-defined edema in one rabbit at the initial evaluation. After 7 days irritation lessened, but very slight erythema, edema, and desquamation persisted. Hence Benzyl acetate (CAS No: 140-11-4)was considered to be irritating to the skin ofNew Zealand White rabbits.

The RIFM Expert Panel; D. Belsito , D. Bickers , M. Bruze , P. Calow , M.L. Dagli , A.D. Fryer , H. Greim , Y. Miyachi , J.H. Saurat , I.G. Sipes reported two skin irritation studies on two anotherstructurally similar read across substances2-phenylethyl formate (CAS No: 104-62-1) and Benzyl propionate (CAS No: 122-63-4) which have been summarized as follows;

The first Primary skin irritation test was conducted on rabbits to assess the skin irritation potential of test chemical 2-phenylethyl formate (CAS No: 104-62-1). Each rabbit received undiluted Primary skin irritation test dermally for 4 hour exposure period and rabbits were observed for skin irritation over a period of 3 days.The treated animals showed slight to very slight erythema, Cracking and scaling. Therefore 2-phenylethyl formate (CAS No: 104-62-1) was considered to be irritating to the rabbits skin.

The next skin irritation test was conducted on five rabbits Benzyl propionate (CAS No: 122-63-4) to determine its skin irritation efficacy. In this test, the undiluted Benzyl propionate was applied topically onto the skin of each rabbits and later observed for skin reactions. Since the chemical was able to induce moderate skin effects, the Benzyl propionate (CAS No: 122-63-4) was considered to be irritating to the rabbits skin.

Based on the available data for the target chemical3-phenylpropanoyl chloride (CAS No: 645-45-4) and its structurally similar read across substancesBenzyl acetate (CAS No: 140-11-4), 2-phenylethyl formate (CAS No: 104-62-1) and Benzyl propionate (CAS No: 122-63-4),it can be concluded thatchemical 3-phenylpropanoyl chloride (CAS No: 645-45-4) is able to cause skin irritation and considered as irritating.Comparing the above annotations with the criteria of CLP regulation, it can be classified under the category “Category 2”.

Eye irritation

In different studies,test chemical 3-phenylpropanoyl chloride (CAS No: 645-45-4) has been investigated for potential for ocular irritation to a greater or lesser extentThe studies are based on in vivo experiments in rabbits for target chemical 3-phenylpropanoyl chloride (CAS No: 645-45-4) and its structurally similar read across substances2-phenylethyl 2-methylpropanoate (CAS no: 103-48-0), Benzyl acetate (CAS No: 140-11-4).The predicted data using the OECD QSAR toolbox has also been compared with the experimental data and summarized as below;

The prediction modelOECD QSAR toolbox version 3.3 with logPow as the primary descriptor, estimated an eye irritation potential for test chemical3-phenylpropanoyl chloride (CAS No: 645-45-4). The test substance3-phenylpropanoyl chloride (CAS No: 645-45-4) is estimated to be not irritating to eye of Rabbits.

The above result was supported by aneye irritation study conducted by The RIFM Expert Panel; D. Belsito , D. Bickers , M. Bruze , P. Calow , M.L. Dagli , A.D. Fryer , H. Greim , Y. Miyachi , J.H. Saurat , I.G. Sipes (2012) forstructurally similar read across substances2-phenylethyl 2-methylpropanoate (CAS no: 103-48-0) in four rabbits in accordance with OECD test guideline 405.The undiluted 2-phenylethyl 2-methylpropanoate was administrated into the eye of each rabbits and reactions were scored for 48 hours. Slight conjunctive irritation (4/4) was observed 1 h after application. All effects were reversible within 48 h.As all the observed effects were not persisted over a period of 48 hours, the chemical 2-phenylethyl 2-methylpropanoate was considered to be not irritating to the rabbits’ eye.

D. McGinty , D. Vitale, C.S. Letizia, A.M. Api(2012) reported two eye irritation studies which further supports the above results for anotherstructurally similar read across substancesBenzyl acetate (CAS No: 140-11-4)on rabbits to determine eye irritating potency as follows;

In the first study, about 0.1 mL aliquot of 3%, 7.5% or 18.7% benzyl acetate petrolatum was instilled into the right eye of three albino rabbits. The left eye of the rabbits served as the control. The reactions were examined once every 24 h for the first 4 days and at day 7. The eyes were scored according to the Draize scale.None of the treated animal showed significant eye irritation reaction. Thus chemicalBenzyl acetate (CAS No: 140-11-4)was considered to be not irritating to eye of albino rabbits.

The next Eye irritation study was carried out on six albino rabbits for chemicalBenzyl acetate (CAS No: 140-11-4in accordance to the Draize eye irritation procedure. A 0.1-mL aliquot of benzyl acetate was installed into the right eye of each rabbit and the other eye served as control. The eyes were examined at 24, 48 and 72 h; then again on - days 4 and 7. Since no known irritating effects were observed the chemicalBenzyl acetate (CAS No: 140-11-4) was considered to be not irritating to the eye of six albino rabbits.

On the basis of available data for target chemical3-phenylpropanoyl chloride (CAS No: 645-45-4)its structurally similar read across substances2-phenylethyl 2-methylpropanoate (CAS no: 103-48-0), Benzyl acetate (CAS No: 140-11-4), it can be concluded that the chemical 3-phenylpropanoyl chloride (CAS No: 645-45-4) is unlikely to cause eye irritation and considered as not irritating.Comparing the above annotations with the criteria of CLP regulation, it can be classified under the category“Not Classified”.

Justification for classification or non-classification

The skin and eye irritation potential of test chemical3-phenylpropanoyl chloride (CAS No: 645-45-4)and its structurally similar read across substanceswere observed in various studies. The results obtained from these studies indicates that the chemical3-phenylpropanoyl chloride (CAS No: 645-45-4)is likely to cause skin irritation, but it is unable to cause eye irritation.Hence 3-phenylpropanoyl chloride (CAS No: 645-45-4)can be classified under the category “Category 2” for skin and “Not Classified” for eye as per CLP.