2-cyclohexylidene-2-phenylacetonitrile

Endpoint summary

Description of key information

Based on the available study data the test substance 2-cyclohexylidene-2-phenylacetonitrile was non hazardous in repeated exposure by oral,dermal and inhalation route.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Data is from test report

Qualifier:

according to guideline

Guideline:

other: 92/69/EEC

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

other: (Crl:CD (SD) BR strain (VAF plus))

Sex:

male/female

Details on test animals or test system and environmental conditions:

No data

Route of administration:

oral: gavage

Vehicle:

maize oil

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

Test duration: 28 days

Frequency of treatment:

Dosing regime: 7 days/week

Remarks:

Doses / Concentrations:0,10,45,200 mg/kg bw/dayBasis:no data

No. of animals per sex per dose:

Male: 12 animals at 0 mg/kg bw/dayMale: 6 animals at 10 mg/kg bw/dayMale: 6 animals at 45 mg/kg bw/dayMale: 12 animals at 200 mg/kg bw/dayFemale: 12 animals at 0 mg/kg bw/dayFemale: 6 animals at 10 mg/kg bw/dayFemale: 6 animals at 45 mg/kg bw/dayFemale: 12 animals at 200 mg/kg bw/day

Control animals:

not specified

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: YesDETAILED CLINICAL OBSERVATIONS: YesBODY WEIGHT: Yes FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):No dataFOOD EFFICIENCY:No dataWATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study):No dataOPHTHALMOSCOPIC EXAMINATION: No dataHAEMATOLOGY: Yes CLINICAL CHEMISTRY: YesURINALYSIS: Yes NEUROBEHAVIOURAL EXAMINATION: No data

Sacrifice and pathology:

No data

Other examinations:

No data

Statistics:

No data

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

not specified

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

no effects observed

Behaviour (functional findings):

not specified

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

not specified

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Details on results:

Clinical observations:One male and one female from the top dose group died on day 9 and 7 respectively. Cause of death could not be identified. All top dose animals and occasionally mid dose animals showed post-dosing salivation. An increase in the incidence of hairloss and yellow/brown fur staining was observed in top dose animals, particularly females.Bodyweight gain was reduced in top dose animals and mid dose males such that at the end of treatment, top dose males weighed 92% of controls, top dose females 88% of controls and mid dose males 88% of controls. Bodyweight gains recovered once treatment stoppped. Other signs of toxicity continued until the end of the recovery period.Laboratory findings:Haematology: there were no treatment-related effects.Blood chemistry: alanine aminotransferase was moderately increased in females dosed at 200 mg/kg/day to 147% of controls. Aspartate aminotransferase was slightly increased in both sexes dosed at 200 mg/kg/day (148% of controls in males and 112% of controls in females). Triglycerides wereslightly decreased in both sexes dosed at 200 mg/kg/day (to around 70-73% of controls for both sexes). Triglyceride levels remained decreased in females dosed at 200 mg/kg/day (to 58% of controls) at the end of the treatment-free period.Urinalysis: no treatment-related findings were observed.Effects in organs:Organ weights: the relative liver weight was slightly increased in both sexes (to around 116% of control) dosed at 200 mg/kg/day. This finding was not apparent at the end of the treatment-free period.No treatment-related findings were observed at necropsy macroscopically or histopathologically in decedents or animals surviving until their scheduled sacrifice.

Dose descriptor:

NOAEL

Effect level:

45 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: original NCD unit is mg/kg/day

Dose descriptor:

NOEL

Effect level:

10 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: original NCD unit is mg/kg/day

Critical effects observed:

not specified

Conclusions:

In subacute repeated oral dose toxicity conducted for 28 days at dose concentration 0,10,45,200 mg/kg bw/day on male and female Rat (Crl:CD (SD) BR strain (VAF plus)) showed NOAEL at 45 mg/kg bw/day (nominal) and NOEL 10 mg/kg bw/day (nominal).

Executive summary:

In subacute repeated oral dose toxicity conducted for 28 days at dose concentration 0,10,45,200 mg/kg bw/day on male and female Rat (Crl:CD (SD) BR strain (VAF plus)) showed following effects:

Clinical observations:

One male and one female from the top dose group died on day 9 and 7 respectively. Cause of death could not be identified. All top dose animals and occasionally mid dose animals showed post-dosing salivation. An increase in the incidence of hairloss and yellow/brown fur staining was observed in top dose animals, particularly females.

Bodyweight gain was reduced in top dose animals and mid dose males such that at the end of treatment, top dose males weighed 92% of controls, top dose females 88% of controls and mid dose males 88% of controls. Bodyweight gains recovered once treatment stoppped. Other signs of toxicity continued until the end of the recovery period.

Laboratory findings:

Haematology: there were no treatment-related effects.

Blood chemistry: alanine aminotransferase was moderately increased in females dosed at 200 mg/kg/day to 147% of controls. Aspartate aminotransferase was slightly increased in both sexes dosed at 200 mg/kg/day (148% of controls in males and 112% of controls in females). Triglycerides were

slightly decreased in both sexes dosed at 200 mg/kg/day (to around 70-73% of controls for both sexes). Triglyceride levels remained decreased in females dosed at 200 mg/kg/day (to 58% of controls) at the end of the treatment-free period.

Urinalysis: no treatment-related findings were observed.

Effects in organs:

Organ weights: the relative liver weight was slightly increased in both sexes (to around 116% of control) dosed at 200 mg/kg/day. This finding was not apparent at the end of the treatment-free period.

No treatment-related findings were observed at necropsy macroscopically or histopathologically in decedents or animals surviving until their scheduled sacrifice.

Thus NOAEL was considered to be at 45 mg/kg bw/day (nominal) and NOEL 10 mg/kg bw/day (nominal).

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

45 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

Data is K2 level from study report to which permission to refer granted by ECHA

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records

Reference

Endpoint:

repeated dose toxicity: inhalation

Data waiving:

exposure considerations

Justification for data waiving:

other:

Critical effects observed:

not specified

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: dermal

Type of information:

(Q)SAR

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Data is from QSAR Toolbox version 3.3

Justification for type of information:

QSAR prediction: migrated from IUCLID 5.6

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 410 (Repeated Dose Dermal Toxicity: 21/28-Day Study)

Principles of method if other than guideline:

Method: other: API procedure

GLP compliance:

not specified

Limit test:

no

Species:

rabbit

Strain:

New Zealand White

Sex:

male/female

Type of coverage:

occlusive

Vehicle:

not specified

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

28 days

Frequency of treatment:

3 times per week

Remarks:

Doses / Concentrations:200, 1000 and 2000 mg/kg/dayBasis:no data

No. of animals per sex per dose:

no data

Control animals:

yes

Clinical signs:

no effects observed

Dermal irritation:

not specified

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

not specified

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Dose descriptor:

NOAEL

Effect level:

1 234.375 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: clinical chemistry and Organ weights and organ/body weight

Critical effects observed:

not specified

The prediction was based on dataset comprised from the following descriptors: NOAEL
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 "f" )  and ("g" and "h" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Alkene AND Allyl AND Cycloalkane AND Nitrile by Organic Functional groups

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Allyl AND Cycloalkane AND Nitrile AND Overlapping groups by Organic Functional groups (nested)

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Acetylenic Carbon [#C] AND Aliphatic Carbon [CH] AND Aliphatic Carbon [-CH2-] AND Olefinic carbon [=CH- or =C<] AND Tertiary Carbon by Organic functional groups (US EPA)

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as No functional group found by Organic functional groups, Norbert Haider (checkmol)

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as Moderate by Bioaccumulation - metabolism half-lives ONLY

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as Not bioavailable by Lipinski Rule Oasis ONLY

Domain logical expression index: "g"

Parametric boundary:The target chemical should have a value of log Kow which is >= 5.11

Domain logical expression index: "h"

Parametric boundary:The target chemical should have a value of log Kow which is <= 6.73

Conclusions:

Based on the QSAR Toolbox version 3.3 prediction the No Observed Adverse Effect Level of test substance 2-cyclohexylidene-2-phenylacetonitrile by dermal exposure was estimated to be 1234.375 mg/kg bw/day based on the clinical chemistry and Organ weights and organ/body weight effects.

Executive summary:

Based on the QSAR Toolbox version 3.3 prediction the No Observed Adverse Effect Level of test substance 2-cyclohexylidene-2-phenylacetonitrile by dermal exposure was estimated to be 1234.375 mg/kg bw/day based on the clinical chemistry and Organ weights and organ/body weight effects.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 234.375 mg/kg bw/day

Study duration:

subacute

Species:

rabbit

Quality of whole database:

Data is K2 level from QSAR Toolbox version 3.3

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Repeated dose toxicity: oral:

In subacute repeated oral dose toxicity conducted for 28 days at dose concentration 0,10,45,200 mg/kg bw/day on male and female Rat (Crl:CD (SD) BR strain (VAF plus)) showed following effects:

Clinical observations:

One male and one female from the top dose group died on day 9 and 7 respectively. Cause of death could not be identified. All top dose animals and occasionally mid dose animals showed post-dosing salivation. An increase in the incidence of hairloss and yellow/brown fur staining was observed in top dose animals, particularly females.

Bodyweight gain was reduced in top dose animals and mid dose males such that at the end of treatment, top dose males weighed 92% of controls, top dose females 88% of controls and mid dose males 88% of controls. Bodyweight gains recovered once treatment stoppped. Other signs of toxicity continued until the end of the recovery period.

Laboratory findings:

Haematology: there were no treatment-related effects.

Blood chemistry: alanine aminotransferase was moderately increased in females dosed at 200 mg/kg/day to 147% of controls. Aspartate aminotransferase was slightly increased in both sexes dosed at 200 mg/kg/day (148% of controls in males and 112% of controls in females). Triglycerides were

slightly decreased in both sexes dosed at 200 mg/kg/day (to around 70-73% of controls for both sexes). Triglyceride levels remained decreased in females dosed at 200 mg/kg/day (to 58% of controls) at the end of the treatment-free period.

Urinalysis: no treatment-related findings were observed.

Effects in organs:

Organ weights: the relative liver weight was slightly increased in both sexes (to around 116% of control) dosed at 200 mg/kg/day. This finding was not apparent at the end of the treatment-free period.

No treatment-related findings were observed at necropsy macroscopically or histopathologically in decedents or animals surviving until their scheduled sacrifice.

Thus NOAEL was considered to be at 45 mg/kg bw/day (nominal) and NOEL 10 mg/kg bw/day (nominal).

Repeated dose toxicity: inhalation:

The chemical 2-cyclohexylidene-2-phenylacetonitrile has a low vapour pressure and thus repeated exposure by the inhalation route is highly unlikely. Thus, the chemical is not likely to have repeated dose toxicity effects via the inhalation route.

Repeated dose toxicity: dermal:

Based on the QSAR Toolbox version 3.3 prediction the No Observed Adverse Effect Level of test substance 2-cyclohexylidene-2-phenylacetonitrile by dermal exposure was estimated to be 1234.375 mg/kg bw/day based on the clinical chemistry and Organ weights and organ/body weight effects.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
In subacute repeated oral dose toxicity conducted for 28 days at dose concentration 0,10,45,200 mg/kg bw/day on male and female Rat (Crl:CD (SD) BR strain (VAF plus)) showed NOAEL at 45 mg/kg bw/day (nominal) and NOEL 10 mg/kg bw/day (nominal).
This NOAEL value indicate that the test substance 2-cyclohexylidene-2-phenylacetonitrile is not classified as per CLP criteria.

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
The chemical 2-cyclohexylidene-2-phenylacetonitrile has a low vapour pressure and thus repeated exposure by the inhalation route is highly unlikely. Thus, the chemical is not likely to have repeated dose toxicity effects via the inhalation route.

Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:
Based on the QSAR Toolbox version 3.3 prediction the No Observed Adverse Effect Level of test substance 2-cyclohexylidene-2-phenylacetonitrile by dermal exposure was estimated to be 1234.375 mg/kg bw/day based on the clinical chemistry and Organ weights and organ/body weight effects.

Justification for classification or non-classification

On the basis of NOAEL'S value available, the substance 2-cyclohexylidene-2-phenylacetonitrile non toxic by oral,inhalation and dermal route.Thus not consider for the further classification as per CLP criteria.