5-methyl-3-phenylisoxazole-4-carbonyl chloride

Endpoint summary

Description of key information

Acute oral toxicity: 

LD50 was estimated to be 2987 mg/kg bw when male and female Wistar rats were treated with 5-methyl-3-phenylisoxazole-4-carbonyl chloride by oral gavage route.

Acute Dermal toxicity: 

LD50 was estimated to be 2388 mg/kg bw, when New Zealand White male and female rabbits were treated with 5-methyl-3-phenylisoxazole-4-carbonyl chloride by dermal application semiocclusively.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

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 limited documentation / justification

Justification for type of information:

Data is predicted using OECD QSAR toolbox version 3.3 and the supporting QMRF report has been attached

Qualifier:

according to guideline

Guideline:

other: estimated

Principles of method if other than guideline:

Prediction is done using QSAR Toolbox version 3.3

GLP compliance:

not specified

Test type:

other: not specified

Limit test:

no

Specific details on test material used for the study:

- IUPAC Name: 5-methyl-3-phenylisoxazole-4-carbonyl chloride
- Mol. formula: C11H8ClNO2
- Molecular Weight: 221.642 g/mol
- Smiles: c1(ccccc1)c1c(C(=O)Cl)c(on1)C
- InChI: 1S/C11H8ClNO2/c1-7-9(11(12)14)10(13-15-7)8-5-3-2-4-6-8/h2-6H,1H3

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

not specified

Route of administration:

oral: gavage

Vehicle:

not specified

Details on oral exposure:

not specified

Doses:

2987 mg/kg

No. of animals per sex per dose:

not specified

Control animals:

not specified

Details on study design:

not specified

Statistics:

not specified

Preliminary study:

not specified

Sex:

male/female

Dose descriptor:

LD50

Effect level:

2 987 mg/kg bw

Based on:

test mat.

Remarks on result:

other: 50% mortality was observed

Mortality:

not specified

Clinical signs:

other: not specified

Gross pathology:

not specified

Other findings:

not specified

The prediction was based on dataset comprised from the following descriptors: LD50
Estimation method: Takes average value from the 7 nearest neighbours
Domain  logical expression:Result: In Domain

((((("a" or "b" or "c" or "d" )  and ("e" and ( not "f") )  )  and "g" )  and "h" )  and ("i" and "j" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Acyl halide OR Allyl OR Aryl OR Ketoxime derivatives OR Oxazole/ Izoxazole by Organic Functional groups ONLY

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Acyl halide OR Allyl OR Aryl OR Ketoxime derivatives OR Overlapping groups OR Oxazole/ Izoxazole by Organic Functional groups (nested) ONLY

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Aliphatic Carbon [CH] OR Aliphatic Carbon [-CH2-] OR Aliphatic Carbon [-CH3] OR Aromatic Carbon [C] OR Aromatic Nitrogen, five-member ring OR Aromatic Oxygen OR Carbonyl, olefinic attach [-C(=O)-] OR Chlorine, olefinic attach [-Cl] OR Miscellaneous sulfide (=S) or oxide (=O) OR Olefinic carbon [=CH- or =C<] OR Oxygen, nitrogen attach [-O-] by Organic functional groups (US EPA) ONLY

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Aromatic compound OR Carbonic acid derivative OR Halogen derivative by Organic functional groups, Norbert Haider (checkmol) ONLY

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as SN2 AND SN2 >> Direct acylation involving a leaving group AND SN2 >> Direct acylation involving a leaving group >> Acyl Halides by DNA binding by OASIS v.1.3

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as AN2 OR AN2 >>  Michael-type addition, quinoid structures OR AN2 >>  Michael-type addition, quinoid structures >> Quinones OR AN2 >> Nucleophilic addition to alpha, beta-unsaturated carbonyl compounds OR AN2 >> Nucleophilic addition to alpha, beta-unsaturated carbonyl compounds >> alpha, beta-Unsaturated Aldehydes OR AN2 >> Schiff base formation OR AN2 >> Schiff base formation >> alpha, beta-Unsaturated Aldehydes OR AN2 >> Schiff base formation >> Polarized Haloalkene Derivatives OR AN2 >> Thioacylation via nucleophilic addition after cysteine-mediated thioketene formation OR AN2 >> Thioacylation via nucleophilic addition after cysteine-mediated thioketene formation >> Haloalkenes with Electron-Withdrawing Groups OR AN2 >> Thioacylation via nucleophilic addition after cysteine-mediated thioketene formation >> Polarized Haloalkene Derivatives OR Michael addition OR Michael addition >> Quinone type compounds OR Michael addition >> Quinone type compounds >> Quinone methides OR No alert found OR Non-covalent interaction OR Non-covalent interaction >> DNA intercalation OR Non-covalent interaction >> DNA intercalation >> Quinones OR Radical OR Radical >> Radical mechanism via ROS formation (indirect) OR Radical >> Radical mechanism via ROS formation (indirect) >> Quinones OR Radical >> ROS formation after GSH depletion OR Radical >> ROS formation after GSH depletion >> Quinone methides 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 >> Alkylation, direct acting epoxides and related OR SN2 >> Alkylation, direct acting epoxides and related >> Epoxides and Aziridines 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 >> Haloalkenes with Electron-Withdrawing Groups OR SN2 >> Alkylation, direct acting epoxides and related after P450-mediated metabolic activation >> Polycyclic Aromatic Hydrocarbon Derivatives OR SN2 >> SN2 at sp3 and activated sp2 carbon atom OR SN2 >> SN2 at sp3 and activated sp2 carbon atom >> Polarized Haloalkene Derivatives by DNA binding by OASIS v.1.3

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as Class 3 (unspecific reactivity) by Acute aquatic toxicity classification by Verhaar (Modified) ONLY

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as Acyl halide AND Allyl AND Aryl AND Ketoxime derivatives AND Oxazole/ Izoxazole by Organic Functional groups ONLY

Domain logical expression index: "i"

Parametric boundary:The target chemical should have a value of log Kow which is >= 0.0156

Domain logical expression index: "j"

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

Interpretation of results:

Category 5 based on GHS criteria

Conclusions:

LD50 was estimated to be 2987 mg/kg bw when male and female Wistar rats were treated with 5-methyl-3-phenylisoxazole-4-carbonyl chloride by oral gavage route.

Executive summary:

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the acute oral toxicity was estimated for  5-methyl-3-phenylisoxazole-4-carbonyl chloride (16883 -16 -2). The LD50 was estimated to be 2987 mg/kg bw when male and female Wistar rats were treated with 5-methyl-3-phenylisoxazole-4-carbonyl chloride by oral gavage route.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 987 mg/kg bw

Quality of whole database:

Data is Klimicsh 2 and QSAR toolbox 3.3

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:

(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 predicted using OECD QSAR toolbox version 3.3 and the supporting QMRF report has been attached

Qualifier:

according to guideline

Guideline:

other: estimated

Principles of method if other than guideline:

Prediction is done using QSAR Toolbox version 3.3

GLP compliance:

not specified

Test type:

other: not specified

Limit test:

no

Specific details on test material used for the study:

- IUPAC Name: 5-methyl-3-phenylisoxazole-4-carbonyl chloride
- Mol. formula: C11H8ClNO2
- Molecular Weight: 221.642 g/mol
- Smiles: c1(ccccc1)c1c(C(=O)Cl)c(on1)C
- InChI: 1S/C11H8ClNO2/c1-7-9(11(12)14)10(13-15-7)8-5-3-2-4-6-8/h2-6H,1H3

Species:

rabbit

Strain:

New Zealand White

Sex:

male/female

Details on test animals or test system and environmental conditions:

not specified

Type of coverage:

semiocclusive

Vehicle:

not specified

Details on dermal exposure:

not specified

Duration of exposure:

24 h

Doses:

2388 mg/kg

No. of animals per sex per dose:

not specified

Control animals:

not specified

Details on study design:

not specified

Statistics:

not specified

Preliminary study:

not specified

Sex:

male/female

Dose descriptor:

LD50

Effect level:

2 388

Based on:

test mat.

Remarks on result:

other: 50% mortality was observed

Mortality:

not specified

Clinical signs:

other: not specified

Gross pathology:

not specified

Other findings:

not specified

The prediction was based on dataset comprised from the following descriptors: LD50
Estimation method: Takes average value from the 5 nearest neighbours
Domain  logical expression:Result: In Domain

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

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Acyl halide OR Allyl OR Aryl OR Ketoxime derivatives OR Oxazole/ Izoxazole by Organic Functional groups ONLY

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Acyl halide OR Allyl OR Aryl OR Ketoxime derivatives OR Overlapping groups OR Oxazole/ Izoxazole by Organic Functional groups (nested) ONLY

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Aliphatic Carbon [CH] OR Aliphatic Carbon [-CH2-] OR Aliphatic Carbon [-CH3] OR Aromatic Carbon [C] OR Aromatic Nitrogen, five-member ring OR Aromatic Oxygen OR Carbonyl, olefinic attach [-C(=O)-] OR Chlorine, olefinic attach [-Cl] OR Miscellaneous sulfide (=S) or oxide (=O) OR Olefinic carbon [=CH- or =C<] OR Oxygen, nitrogen attach [-O-] by Organic functional groups (US EPA) ONLY

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Aromatic compound OR Carbonic acid derivative OR Halogen derivative by Organic functional groups, Norbert Haider (checkmol) ONLY

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as Not possible to classify according to these rules by DPRA Lysine peptide depletion

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as High reactive OR High reactive >> Acrylic acid esters OR High reactive >> Activated 1,3,5-triazine derivatives OR Low reactive OR Low reactive >> Epoxides OR Low reactive >> Short-chain alpha-alkyl cinnamaldehyde derivatives OR Moderate reactive OR Moderate reactive >> Cinnamaldehyde type compounds by DPRA Lysine peptide depletion

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as Not possible to classify according to these rules (GSH) by Protein binding potency

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as Highly reactive (GSH) OR Highly reactive (GSH) >> Furamates (MA) OR Moderately reactive (GSH) OR Moderately reactive (GSH) >> 2-Vinyl carboxamides (MA) OR Moderately reactive (GSH) >> 2-Vinylpyridine (MA) OR Moderately reactive (GSH) >> Alkyl 2-alkenoates (MA) OR Moderately reactive (GSH) >> Substituted 1-Alken-3-ones (MA) OR Moderately reactive (GSH) >> Substituted 2-Alken-1-als (MA) OR Slightly reactive (GSH) OR Slightly reactive (GSH) >> 2-Alkenyl carbonitriles (MA) OR Slightly reactive (GSH) >> Methacrylates (MA) by Protein binding potency

Domain logical expression index: "i"

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

Domain logical expression index: "j"

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

Domain logical expression index: "k"

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

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as Group 14 - Carbon C AND Group 15 - Nitrogen N AND Group 16 - Oxygen O AND Group 17 - Halogens Cl AND Group 17 - Halogens F,Cl,Br,I,At by Chemical elements

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as Group 15 - Phosphorus P by Chemical elements

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as Acyl halide AND Allyl AND Aryl AND Ketoxime derivatives AND Overlapping groups AND Oxazole/ Izoxazole by Organic Functional groups (nested) ONLY

Domain logical expression index: "o"

Similarity boundary:Target: CC1=C(C(=O)Cl)C(c2ccccc2)=NO1
Threshold=10%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "p"

Parametric boundary:The target chemical should have a value of log Kow which is >= -0.474

Domain logical expression index: "q"

Parametric boundary:The target chemical should have a value of log Kow which is <= 3.44

Interpretation of results:

Category 5 based on GHS criteria

Conclusions:

LD50 was estimated to be 2388 mg/kg bw when New Zealand White male and female rabbits were treated with 5-methyl-3-phenylisoxazole-4-carbonyl chloride by dermal application semiocclusively.

Executive summary:

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the acute dermal toxicity was estimated for  5-methyl-3-phenylisoxazole-4-carbonyl chloride (16883 -16 -2). The LD50 was estimated to be 2388 mg/kg bw when New Zealand White male and female rabbits were treated with 5-methyl-3-phenylisoxazole-4-carbonyl chloride by dermal application semiocclusively.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 388 mg/kg bw

Quality of whole database:

Data is Klimicsh 2 and QSAR toolbox 3.3

Additional information

Acute oral toxicity:

In different studies, 5-methyl-3-phenylisoxazole-4-carbonyl chloride (CAS no: 16883-16-2) has been investigated for acute oral toxicity to a greater or lesser extent. Often are the studies based on in vivo experiments in rodents, i.e. most commonly in rats for 5-methyl-3-phenylisoxazole-4-carbonyl chloride along with the study available on structurally similar read across substance Benzoyl chloride (98-88-4) and Methyl benzoylformate (15206-55-0). The predicted data using the OECD QSAR toolbox has also been compared with the experimental studies. The studies are summarized as below –

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the acute oral toxicity was estimated for 5-methyl-3-phenylisoxazole-4-carbonyl chloride (16883 -16 -2). The LD50 was estimated to be 2987 mg/kg bw when male and female Wistar rats were treated with 5-methyl-3-phenylisoxazole-4-carbonyl chloride by oral gavage route.

The above study supported by U. S. Environmental Protection Agency (2012), for the structurally similar read across substance Benzoyl chloride (98-88-4). Acute oral toxicity study was conducted in 60 (10/dose) male Wistar rats using undiluted Benzoyl chloride. Doses were given in concentration 1210, 1820, 2420, 3030, 3750 or 6040 mg/kg via oral gavage route and observed for 14 days. Mortality was observed at 1820(2), 2420(5), 3030(6), 3750(9) and 6040(10) mg/kg. 50% mortality was observed at dose 2528 mg/kg bw with the Signs of intoxication, sedation, extention spasm, reduced general condition of animals were observed. Hence, LD50 was considered to be 2528 mg/kg bw, when male Wistar rats were treated with Benzoyl chloride (98-88-4) orally.

This is further supported by EUROPEAN COMMISSION – European Chemicals Bureau, IUCLID DATASET (2000), for the structurally similar read across substance Methyl benzoylformate (15206-55-0). Acute oral toxicity study was done in 15 rats using test material Methyl benzoylformate orally. No Mortality was observed at dose 5000 mg/kg bw. Hence, LD50 value was considered to be >5000mg/kg body weight when rats were treated with Methyl benzoylformate (CAS no. 15206-55-0) orally.

Thus, based on the above studies on 5-methyl-3-phenylisoxazole-4-carbonyl chloride (CAS no: 16883-16-2) and it’s read across substances, it can be concluded that LD50 value is greater than 2000 mg/kg bw. Thus, comparing this value with the criteria of CLP regulation, 5-methyl-3-phenylisoxazole-4-carbonyl chloride can be classified as category V of acute oral toxicity.

Acute Dermal toxicity:

In different studies, 5-methyl-3-phenylisoxazole-4-carbonyl chloride (CAS no: 16883-16-2) has been investigated for acute dermal toxicity to a greater or lesser extent. Often are the studies based on in vivo experiments in rodents, i.e. most commonly in rabbits for 5-methyl-3-phenylisoxazole-4-carbonyl chloride along with the study available on structurally similar read across substance 2-ethylhexanoyl chloride (760-67-8) and Benzoyl Chloride (98-88-4). The predicted data using the OECD QSAR toolbox has also been compared with the experimental studies. The studies are summarized as below –

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the acute dermal toxicity was estimated for 5-methyl-3-phenylisoxazole-4-carbonyl chloride (16883 -16 -2). The LD50 was estimated to be 2388 mg/kg bw when New Zealand White male and female rabbits were treated with 5-methyl-3-phenylisoxazole-4-carbonyl chloride by dermal application semiocclusively.

This is further supported by EUROPEAN COMMISSION – European Chemicals Bureau (IUCLID Dataset, 2000), for the structurally similar read across substance 2-ethylhexanoyl chloride (760-67-8). The acute dermal toxicity was tested in rabbits at the concentration of 2010 mg/kg bw. No mortality was observed at 2010 mg/kg bw. Therefore, LD50 was considered to be > 2010 mg/kg bw, when rabbits were treated with 2-ethylhexanoyl chloride (760-67-8) by dermal application.

The above study supported by U. S. Environmental Protection Agency (2012), for the structurally similar read across substanceBenzoyl chloride (98-88-4).The acute dermal toxicity was tested in Male and Female New Zealand White rabbits (2/sex) at the concentration of 2000 mg/kg bw to the unabraded or abraded skin under occluded conditions for 24 hours. The hair was clipped from the backs of 2 male and 2 female rabbits; the skin of 1 male and 1 female was abraded. The test compound was applied only once to the back of each animal at a dose of 2000 mg/kg. The area was wrapped with gauze and plastic wrap. 24 hours later, the bandages were removed and the backs washed with tepid water. No mortality was observed at 2000 mg/kg bw; whereas, all rabbits exhibited fissuring on the site of application with normal body weight gains observed in 3 out of 4 rabbits. Therefore, LD50 was considered to be > 2000 mg/kg bw, when Male and Female New Zealand White rabbits were treated with Benzoyl Chloride (CASRN 98-88-4) by dermal application to the abraded skin under occluded conditions for 24 hours.

Thus, based on the above studies on 5-methyl-3-phenylisoxazole-4-carbonyl chloride (CAS no: 16883-16-2) and it’s read across substances, it can be concluded that LD50 value is greater than 2000 mg/kg bw. Thus, comparing this value with the criteria of CLP regulation, 5-methyl-3-phenylisoxazole-4-carbonyl chloride can be classified as category V of acute dermal toxicity.

Justification for classification or non-classification

Based on the above studies and prediction on 5-methyl-3-phenylisoxazole-4-carbonyl chloride (CAS no: 16883-16-2) and it’s read across substances, it can be concluded that LD50 value is greater than 2000 mg/kg bw. Thus, comparing this value with the criteria of CLP regulation, 5-methyl-3-phenylisoxazole-4-carbonyl chloride can be classified as category V for acute oral and dermal toxicity.