(S)-2-methyl-5-(1-methylvinyl)cyclohex-2-en-1-one

Endpoint summary

Description of key information

Acute Oral Toxicity: 

In Acute oral toxicity,LD50 value for target substance d-Carvone (2244-16-8) was considered to be 3710 mg/kg bw and 3560 mg/kg bw in rats. All these studies concluded that the LD50 value is greater than 2000 mg/kg bw.Thus, comparing this value with the criteria of CLP regulation, d-Carvone (2244-16-8) cannot be classified for acute oral toxicity.

Acute Inhalation Toxicity: 

In Acute inhalation toxicity, LD50 value was predicted based on OECD QSAR toolbox for target substance d-Carvone (2244-16-8) was estimated to be 22.07 mg/L in air ( 22070 mg/m3),and for differentstudies available on the structurally similar read across substance 2-Methyl-5-(1-methylethenyl)-2-cyclohexenone (99-49-0) was considered to be >5.66 mg/l in air and for Spearmint Oil (8008-79-5) was considered to be >5.43 mg/l in air. All these studies concluded that the LC50 value is greater than 5 mg/L air. Thus, comparing this value with the criteria of CLP regulation, d-Carvone (2244-16-8) cannot be classified for acute inhalation toxicity.

Acute Dermal Toxicity:

In Acute dermal toxicity, LD50 value for target substance d-Carvone (2244-16-8) was considered to be 4000 mg/kg bw; 3840 mg/kg bw and 3840 mg/kg bw in rabbits. All these studies concluded that the LD50 value is greater than 2000 mg/kg bw. Thus, comparing this value with the criteria of CLP regulation, d-Carvone (2244-16-8) cannot be classified for acute dermal toxicity.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Justification for type of information:

data is from peer-reviewed journal

Qualifier:

according to guideline

Guideline:

other: as mentioned below

Principles of method if other than guideline:

Acute oral toxicity test was carried out to study the effects of d-Carvone (2244-16-8) on rats.

GLP compliance:

not specified

Test type:

other: no data available

Limit test:

no

Specific details on test material used for the study:

- Name of test material (as cited in study report):d-Carvone- Molecular formula :C10H14O- Molecular weight :150.22 g/mol- Substance type:organic

Species:

rat

Strain:

not specified

Sex:

not specified

Details on test animals or test system and environmental conditions:

No data available

Route of administration:

oral: unspecified

Vehicle:

not specified

Details on oral exposure:

No data available

Doses:

3710 mg/kg bw

No. of animals per sex per dose:

No data available

Control animals:

not specified

Details on study design:

No data available

Statistics:

No data available

Preliminary study:

No data available

Sex:

not specified

Dose descriptor:

LD50

Effect level:

3 710 mg/kg bw

Based on:

test mat.

Remarks on result:

other: 50% mortality was observed

Mortality:

50% mortality was observed at dose 3710 mg/kg bw in treated rats

Clinical signs:

other: No data available

Gross pathology:

No data available

Other findings:

No data available

Interpretation of results:

other: not classified

Conclusions:

The lethal concentration (LD50) value for acute oral toxicity test was considered to be 3710 mg/kg bw,when rats were treated with d-Carvone (2244-16-8) orally.

Executive summary:

Acute oral toxicity study was done in rats using test materiald-Carvone(2244-16-8).50% Mortality was observed at dose 3710 mg/kg bw. Hence,LD50 value was considered to be 3710 mg/kg bw,when rats were treated with d-Carvone(2244-16-8) orally.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

3 710 mg/kg bw

Quality of whole database:

Data is Klimisch 2 and from authoritative database

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

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 QMRF report has been attached

Qualifier:

according to guideline

Guideline:

other: as mentioned below

Principles of method if other than guideline:

Prediction was done by using OECD QSAR toolbox v3.3,2017

GLP compliance:

not specified

Test type:

standard acute method

Limit test:

no

Specific details on test material used for the study:

- Name of test material (IUPAC name): (5S)-2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-one- Common name: d-Carvone- Molecular formula: C10H14O- Molecular weight: 150.22 g/mol- Smiles notation: C1[C@H](CC=C(C1=O)C)C(C)=C- InChl: 1S/C10H14O/c1-7(2)9-5-4-8(3)10(11)6-9/h4,9H,1,5-6H2,2-3H3/t9-/m0/s1- Substance type: Organic

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

No data available

Route of administration:

inhalation: vapour

Type of inhalation exposure:

not specified

Vehicle:

not specified

Remark on MMAD/GSD:

No data available

Details on inhalation exposure:

No data available

Analytical verification of test atmosphere concentrations:

not specified

Duration of exposure:

4 h

Remarks on duration:

No data available

Concentrations:

22.07 mg/l in air

No. of animals per sex per dose:

No data available

Control animals:

not specified

Details on study design:

No data available

Statistics:

No data available

Preliminary study:

No data available

Sex:

male/female

Dose descriptor:

LC50

Effect level:

22.07 mg/L air

Based on:

test mat.

Exp. duration:

4 h

Remarks on result:

other: 50% Mortality was Observed

Mortality:

No data available

Clinical signs:

other: No data available

Body weight:

No data available

Gross pathology:

No data available

Other findings:

No data available

The prediction was based on dataset comprised from the following descriptors: LC50
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 ( 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 Michael addition AND Michael addition >> Polarised Alkenes-Michael addition AND Michael addition >> Polarised Alkenes-Michael addition >> Alpha, beta- unsaturated ketones by DNA binding by OECD

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Michael Addition AND Michael Addition >> Michael addition on conjugated systems with electron withdrawing group AND Michael Addition >> Michael addition on conjugated systems with electron withdrawing group >> alpha,beta-Carbonyl compounds with polarized double bonds  by Protein binding by OASIS v1.3

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Michael addition AND Michael addition >> Polarised Alkenes AND Michael addition >> Polarised Alkenes >> Polarised alkene - ketones by Protein binding by OECD

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Vinyl/Allyl Ketones by Aquatic toxicity classification by ECOSAR

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as Michael Addition AND Michael Addition >> Michael addition on conjugated systems with electron withdrawing group AND Michael Addition >> Michael addition on conjugated systems with electron withdrawing group >> alpha,beta-Carbonyl compounds with polarized double bonds  by Protein binding by OASIS v1.3

Domain logical expression index: "f"

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 >> Anhydrides (sulphur analogues of anhydrides)  OR No alert found OR Nucleophilic addition OR Nucleophilic addition >> Addition to carbon-hetero double bonds OR Nucleophilic addition >> Addition to carbon-hetero double bonds >> Ketones by Protein binding by OASIS v1.3

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as Michael addition AND Michael addition >> Polarised Alkenes AND Michael addition >> Polarised Alkenes >> Polarised alkene - ketones by Protein binding by OECD

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as Michael addition >> Polarised Alkenes >> Polarised alkene - amides by Protein binding by OECD

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as Michael addition AND Michael addition >> Polarised Alkenes AND Michael addition >> Polarised Alkenes >> Polarised alkene - ketones by Protein binding by OECD

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as Michael addition >> Acid imides >> Acid imides-MA by Protein binding by OECD

Domain logical expression index: "k"

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

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as Metalloids by Groups of elements

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as Aliphatic Carbon [CH] AND Aliphatic Carbon [-CH2-] AND Aliphatic Carbon [-CH3] AND Carbonyl, aliphatic attach [-C(=O)-] AND Carbonyl, olefinic attach [-C(=O)-] AND Miscellaneous sulfide (=S) or oxide (=O) AND Olefinic carbon [=CH- or =C<] AND Olefinic carbon [=CH2] AND Tertiary Carbon by Organic functional groups (US EPA)

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as Oxygen, aliphatic attach [-O-] by Organic functional groups (US EPA)

Domain logical expression index: "o"

Referential boundary: The target chemical should be classified as Aliphatic Carbon [CH] AND Aliphatic Carbon [-CH2-] AND Aliphatic Carbon [-CH3] AND Carbonyl, aliphatic attach [-C(=O)-] AND Carbonyl, olefinic attach [-C(=O)-] AND Miscellaneous sulfide (=S) or oxide (=O) AND Olefinic carbon [=CH- or =C<] AND Olefinic carbon [=CH2] AND Tertiary Carbon by Organic functional groups (US EPA)

Domain logical expression index: "p"

Referential boundary: The target chemical should be classified as Amino, aliphatic attach [-N<] by Organic functional groups (US EPA)

Domain logical expression index: "q"

Parametric boundary:The target chemical should have a value of log Kow which is >= 0.725

Domain logical expression index: "r"

Parametric boundary:The target chemical should have a value of log Kow which is <= 5.81

Interpretation of results:

other: not classified

Conclusions:

The LC50 value was estimated to be 22.07 mg/L in air when Sprague-Dawley male and female rats were exposed with (5S)-2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-one (cas no:2244-16-8) by inhalation for 4 hours.

Executive summary:

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the acute inhalation toxicity was estimated for (5S)-2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-one (cas no:2244-16-8). The LC50 was estimated to be 22.07 mg/L in air when Sprague-Dawley male and female rats were exposed with (5S)-2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-one (cas no:2244-16-8) by inahaltion for 4 hours.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LC50

Value:

22 070 mg/m³ air

Quality of whole database:

Data is Klimisch 2 and from QSAR toolbox 3.3

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Justification for type of information:

data is from peer-reviewed journal

Qualifier:

according to guideline

Guideline:

other: as mentioned below

Principles of method if other than guideline:

Acute dermal toxicity test was carried out to study the effects of d-Carvone (2244-16-8) on rabbits.

GLP compliance:

not specified

Test type:

other: no data available

Limit test:

no

Specific details on test material used for the study:

- Name of test material (as cited in study report):d-Carvone- Molecular formula :C10H14O- Molecular weight :150.22 g/mol- Substance type:organic

Species:

rabbit

Strain:

not specified

Sex:

not specified

Details on test animals or test system and environmental conditions:

No data available

Type of coverage:

other: dermal

Vehicle:

not specified

Details on dermal exposure:

No data available

Duration of exposure:

No data available

Doses:

4000 mg/kg bw

No. of animals per sex per dose:

No data available

Control animals:

not specified

Details on study design:

- Other examinations performed: clinical signs

Statistics:

No data available

Preliminary study:

No data available

Sex:

not specified

Dose descriptor:

LD50

Effect level:

4 000 mg/kg bw

Remarks on result:

other: 50% mortality was observed at dose 4000 mg/kg bw in treated rabbits

Mortality:

50% mortality was observed at dose 4000 mg/kg bw in treated rabbits

Clinical signs:

other: After systemic exposure,Skin dermatitis and changes in appendages were observed

Gross pathology:

No data available

Other findings:

No data available

Interpretation of results:

other: not classified

Conclusions:

The lethal concentration (LD50) value for acute dermal toxicity test was considered to be 4000 mg/kg bw,when rabbits were treated with d-Carvone (2244-16-8) orally.

Executive summary:

In acute dermal toxicity study,rabbits were treated with d-Carvone(2244-16-8)in the concentration of 4000 mg/kg bw by dermal application.50% mortality was observed at dose 4000 mg/kg bw in treated rabbits.After systemic exposure,Skin dermatitis and changes in appendages were observed.Therefore, LD50 value was considered to be 4000 mg/kg bw,when rabbits were treated with d-Carvone (2244-16-8)by dermal application.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

4 000 mg/kg bw

Quality of whole database:

Data is Klimisch 2 and from authoritative database

Additional information

Acute Oral Toxicity: 

In different studies, d-Carvone (2244-16-8) has been investigated for acute oral toxicity to a greater or lesser extent. Often the studies are based on in vivo experimental data in rodents, i.e. most commonly in rats for d-Carvone (2244-16-8). The studies are summarized as below –

In experimental study conducted by U.S. National Library of Medicine (Chemidplus Database,U.S. National Library of Medicine,2017); Richard J. Lewis(Sax's Dangerous Properties of Industrial Materials, 12th Edition, 5 Volume Set,2012);RTECS (RTECS (registry of toxic effect of chemical substance data base ), 2017) andWorld Health Organization (the Fifty-first meeting of the Joint FAO/WHO Expert Committee on Food Additives (JECFA), WHO FOOD ADDITIVES SERIES: 42,1999) for the target substance d-Carvone (2244-16-8).Acute oral toxicity study was done in rats using test materiald-Carvone(2244-16-8).50% Mortality was observed at dose 3710 mg/kg bw. Hence,LD50 value was considered to be 3710 mg/kg bw,when rats were treated with d-Carvone(2244-16-8) orally.

 

This study is further supported by IFA GESTIS (Gestis Substance Database ,2017) for thetarget substance d-Carvone (2244-16-8). Acute oral toxicity study was done in rats using test material d-Carvone(2244-16-8).50% Mortality was observed at dose 3560 mg/kg bw. Hence,LD50 value was considered to be 3560 mg/kg bw,when rats were treated with d-Carvone(2244-16-8) orally.

Thus, based on the above studies on d-Carvone(2244-16-8), it can be concluded that LD50 value is greater than 2000 mg/kg bw. Thus, comparing this value with the criteria of CLP regulation, d-Carvone (2244-16-8) cannot be classified for acute oral toxicity.

 

Acute Inhalation toxicity: 

In different studies, d-Carvone(2244-16-8) has been investigated for acute inhalation 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 d-Carvone(2244-16-8) along with the study available on structurally similar read across substances  2-Methyl-5-(1-methylethenyl)-2-cyclohexenone (99-49-0) and Spearmint Oil (8008-79-5). 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 inhalation toxicity was estimated for (5S)-2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-one (cas no:2244-16-8). The LC50 was estimated to be 22.07 mg/L in air when Sprague-Dawley male and female rats were exposed with (5S)-2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-one (cas no:2244-16-8) by inahaltion for 4 hours.

 

The above study is supported by European Chemicals Agency (ECHA) (Proposal for Harmonised Classification and Labelling – Carvone, European Chemicals Agency (ECHA), 21 September 2012);COMMISSIONHEALTH & CONSUMER PROTECTION DIRECTORATE-GENERAL,Standing Committee on the Food Chain and Animal Health  (Review report for the active substance carvone Finalised in the Standing Committee on the Food Chain and Animal Health,  in view of the inclusion of carvone in Annex I of Directive 91/414/EEC,22 January 2008);Committee for Risk Assessment RAC –ECHA (Annex 1 Background document to the Opinion proposing harmonised classification and labelling at Community level of carvone , Committee for Risk Assessment RAC -ECHA ,adopted on 4 june,2013) andEuropean Food Safety Authority (EFSA) (EFSA Journal 2014;12(7):3806) for the structurally similar read across substances 2-Methyl-5-(1-methylethenyl)-2-cyclohexenone (99-49-0).

In acute inhalation toxicity study, rats were exposed to 2-Methyl-5-(1-methylethenyl)-2-cyclohexenone(99-49-0)in the concentration of 5.66 mg/l in air (5660 mg/m3) inhaled as a Single dose. One female died the day after the exposure. During exposure a decreased breathing frequency, and less frequently, post-inspiratory apnoea and superficial breathing were observed. After exposure and increased breathing frequency, post-inspiratory apnoea and dyspnoea were seen. Clinical signs during exposure were restlessness and stress and in coordination and tremors. A dirty and wet fur was observed 24-48h after treatment. Alopecia was observed in a few rats at days 7-13. Body weight gain was impaired in most rats during the first week after treatment. Normal body weight gain was observed in the second week, except for two females that showed only marginal body weight gain.GrossPathology revealed no abnormalities, except in the female that died the day after exposure: dark foamy lungs, light coloured liver and air-filled stomach and intestines were observed. Therefore, LC50 value was considered to be >5.66 mg/l in air (5660 mg/m3), when rats were exposed with 2-Methyl-5-(1-methylethenyl)-2-cyclohexenone (99-49-0) by inhalation according to OECD Guideline 403 (Acute Inhalation Toxicity).

 

These results are further supported by European Food Safety Authority (EFSA) (Spearmint Oil - DAR - Vol. 1 of the fourth stage of the review programme referred to in Article 8(2) of Council Directive 91/414/EEC, European Food Safety Authority (EFSA), August 2008) and AGRITOX (AGRITOX - Plant Protection Phentopharmaceuticals Database,2017) for the Spearmint Oil (8008-79-5). In acute inhalation toxicity study, male and female rats were exposed to Spearmint Oil(8008-79-5)in the concentration of 5430 mg/ m3 inhaled as a Single dose for 4 hour. No mortality was observed at dose 5.43 mg/L (5430 mg/m3) in treated rats. Therefore, LC50 value was considered to be >5430 mg/m3 (5.43 mg/L),when both male and female rats were exposed with Spearmint Oil(8008-79-5)by inhalation for 4 hours.

Thus, based on the above studies on d-Carvone(2244-16-8) and it’s structurally similar read across substances 2-Methyl-5-(1-methylethenyl)-2-cyclohexenone (99-49-0) and Spearmint Oil(8008-79-5), it can be concluded that LC50 value is greater than 5 mg/L air. Thus, comparing this value with the criteria of CLP regulation, d-Carvone(2244-16-8) cannot be classified for acute inhalation toxicity.

Acute Dermal Toxicity:

In different studies, d-Carvone(2244-16-8) has been investigated for acute dermal toxicity to a greater or lesser extent. Often the studies are based on in vivo experimental data in rodents, i.e. most commonly in rabbits for d-Carvone(2244-16-8). The studies are summarized as below –

In experimental study conducted by D. L. J. Opdyke (Food and Cosmetics Toxicology,Vol. 16, Pg. 673, 1978); U.S. National Library of Medicine (Chemidplus Database,U.S. National Library of Medicine,2017) andRTECS (RTECS (registry of toxic effect of chemical substance data base ), 2017) for the target substance d-Carvone(2244-16-8).In acute dermal toxicity study,rabbits were treated with d-Carvone(2244-16-8)in the concentration of 4000 mg/kg bw by dermal application.50% mortality was observed at dose 4000 mg/kg bw in treated rabbits.After systemic exposure,Skin dermatitis and changes in appendages were observed.Therefore, LD50 value was considered to be 4000 mg/kg bw,when rabbits were treated with d-Carvone (2244-16-8) by dermal application.

This study is further supported by US EPA. Office of Pesticide Programs (Technical Document for l-Carvone also referred to as a BRAD, US EPA. Office of Pesticide Programs,31-august-2009)for the target substance d-Carvone(2244-16-8).In acute dermal toxicity study,rabbits were treated with d-Carvone(2244-16-8)in the concentration of 3860 mg/kg bw by dermal application.50% mortality was observed at dose 3860 mg/kg bw in treated rabbits.Therefore, LD50 value was considered to be 3860 mg/kg bw,when rabbits were treated with d-Carvone(2244-16-8)by dermal application.  

The above study was further supported by IFA GESTIS (Gestis Substance Database ,2017)for the target substance d-Carvone(2244-16-8).In acute dermal toxicity study,rabbits were treated with d-Carvone(2244-16-8)in the concentration of 3840mg/kg bw by dermal application.50% mortality was observed at dose 3840 mg/kg bw in treated rabbits.Therefore, LD50 value was considered to be 3840 mg/kg bw,when rabbits were treated with d-Carvone(2244-16-8)by dermal application.

Thus, based on the above studies on d-Carvone (2244-16-8), it can be concluded that LD50 value is greater than 2000 mg/kg bw. Thus, comparing this value with the criteria of CLP regulation, d-Carvone (2244-16-8) cannot be classified for acute dermal toxicity.

Justification for classification or non-classification

Based on the above experimental studies and prediction on d-Carvone (2244-16-8),and it’s structurally similar 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, d-Carvone (2244-16-8) cannot be classified for acute oral,acute inhalation and acute dermal toxicity.