Registration Dossier

Administrative data

Description of key information

The substance phenetole does not exhibit repeated dose toxicity via oral,inhalation or dermal 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:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Qualifier:
according to guideline
Guideline:
other: estimated data
Principles of method if other than guideline:
Prediction using category approach; QSAR Toolbox 3.1; Read Across; 5 nearest analogues; Log Kow as descriptor
GLP compliance:
no
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
- Age at study initiation: 42 days
ENVIRONMENTAL CONDITIONS
- Temperature: 20 - 24 °C
- Humidity: 30 - 70 %
- Air changes (per hr): fully air-conditioned rooms
- Photoperiod: 12 hrs dark / 12 hrs light
Route of administration:
oral: gavage
Vehicle:
olive oil
Duration of treatment / exposure:
4 weeks
Frequency of treatment:
5 days/week
No. of animals per sex per dose:
5 animals per sex per dose
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Haematological findings:
no effects observed
Details on results:
No effects observed.
Dose descriptor:
NOEL
Effect level:
93.6 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no substance related changes-CLINICAL EXAMINATIONS,Body weight,Mortality,Hematological examinations
Critical effects observed:
not specified





The prediction was based on dataset comprised from the following descriptors: NOEL,NOAEL
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" or "h" or "i" or "j" )  and ("k" and ( not "l") )  )  and (("m" or "n" or "o" or "p" )  and ("q" and ( not "r") )  )  )  and "s" )  and "t" )  and ("u" and "v" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Alkoxy AND Aryl AND Ether by Organic functional groups

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Alkoxy AND Aryl AND Ether AND Overlapping groups by Organic functional groups (nested)

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Aliphatic Carbon [CH] AND Aliphatic Carbon [-CH2-] AND Aliphatic Carbon [-CH3] AND Aromatic Carbon [C] AND Olefinic carbon [=CH- or =C<] AND Oxygen, one aromatic attach [-O-] by Organic functional groups (US EPA)

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Alkylarylether AND Aromatic compound AND Ether by Organic functional groups, Norbert Haider (checkmol)

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as No alert found by DNA binding by OASIS v.1.1

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as Acylation OR Acylation >> Direct acyation involving a leaving group OR Acylation >> Direct acyation involving a leaving group >> Geminal Polyhaloalkanes OR Elimination (E2) OR Elimination (E2) >> E2 elimination reaction with epoxide formation OR Elimination (E2) >> E2 elimination reaction with epoxide formation >> Haloalcohols OR Michael addition OR Michael addition >> alpha, beta-unsaturated carabonyl compounds OR Michael addition >> alpha, beta-unsaturated carabonyl compounds >> Alpha, Beta-Unsaturated Aldehydes OR Michael addition >> alpha, beta-unsaturated carabonyl compounds >> Four- and Five-Membered Lactones OR Michael addition >> Quinone type compounds OR Michael addition >> Quinone type compounds >> Quinoneimine Derivatives OR Michael addition >> Quinone type compounds >> Quinones OR Nucleophilic addition OR Nucleophilic addition >> Nucleophilic addition reaction with cycloisomerization OR Nucleophilic addition >> Nucleophilic addition reaction with cycloisomerization >> Hydrazine Derivatives OR Radical OR Radical >> Free radical formation OR Radical >> Free radical formation >> Arenediazonium Salts OR Radical >> Generation of reactive oxygen species OR Radical >> Generation of reactive oxygen species >> Coumarins OR Radical >> Generation of reactive oxygen species >> Thiols OR Radical >> Radical decomposition OR Radical >> Radical decomposition >> Alkylnitrites OR Radical >> Radical mechanism by ROS formation OR Radical >> Radical mechanism by ROS formation >> Diazenes OR Radical >> Radical mechanism by ROS formation >> Geminal Polyhaloalkanes OR Radical >> Radical mechanism by ROS formation >> Hydrazine Derivatives OR Radical >> Radical mechanism by ROS formation >> Nitro Compounds OR Radical >> Radical mechanism by ROS formation >> Nitroso compounds OR Radical >> Radical mechanism by ROS formation >> Organic Peroxy Compounds OR Radical >> Radical mechanism by ROS formation >> Quinones OR Radical >> Radical mechanism by ROS formation >> Specific Imine and Thione Derivatives OR Radical >> ROS formation after GSH depletion OR Radical >> ROS formation after GSH depletion >> Aromatic and Heterocyclic Primary Amines OR Radical >> ROS formation after GSH depletion >> Haloalcohols OR Radical >> ROS formation after GSH depletion >> Quinoneimine Derivatives OR Schiff base fomers OR Schiff base fomers >> Direct acting Schiff base formers OR Schiff base fomers >> Direct acting Schiff base formers >> Alkylnitrites OR Schiff base fomers >> Direct acting Schiff base formers >> Alpha, Beta-Unsaturated Aldehydes OR Schiff base fomers >> Direct acting Schiff base formers >> Geminal Polyhaloalkanes OR Schiff base fomers >> Direct acting Schiff base formers >> Specific Acetate Esters OR Schiff base fomers >> Multi-step Shiff base formation OR Schiff base fomers >> Multi-step Shiff base formation >> Haloalkanes Containing Electron-Withdrawing Groups OR SN1 OR SN1 >> Carbenium ion formation OR SN1 >> Carbenium ion formation >> Alpha-Haloethers OR SN1 >> Carbenium ion formation >> Nitroso compounds OR SN1 >> Carbenium ion formation >> Polycyclic Aromatic Hydrocarbons OR SN1 >> Carbenium ion formation >> Specific Acetate Esters OR SN1 >> Glutathione-induced nitrenium ion formation OR SN1 >> Glutathione-induced nitrenium ion formation >> Nitroso compounds OR SN1 >> Nitrenium and/or Carbenium ion formation OR SN1 >> Nitrenium and/or Carbenium ion formation >> Urea Derivatives OR SN1 >> Nitrenium ion and/or Acyl ion formation OR SN1 >> Nitrenium ion and/or Acyl ion formation >> N-acyloxy-N-alkoxyamides OR SN1 >> Nitrenium ion formation OR SN1 >> Nitrenium ion formation >> Aminoacridine Derivatives OR SN1 >> Nitrenium ion formation >> Aromatic and Heterocyclic Primary Amines OR SN1 >> Nitrenium ion formation >> N-hydroxylamines OR SN1 >> Nitrenium ion formation >> Nitro Compounds OR SN1 >> Nitrenium ion formation >> Sulfonyl Azides OR SN1 >> Nitrosation OR SN1 >> Nitrosation >> Alkylnitrites OR SN1 >> Non-enzymatic nitroso radical and/or nirtosonium cation formation OR SN1 >> Non-enzymatic nitroso radical and/or nirtosonium cation formation >> Nitroso compounds OR SN1 >> Non-enzymatic nitroso radical and/or nirtosonium cation formation >> Urea Derivatives OR SN2 OR SN2 >> Acylating agents OR SN2 >> Acylating agents >> Specific Acetate Esters OR SN2 >> Carbenium Ion Formation OR SN2 >> Carbenium Ion Formation >> Acyclic Triazenes OR SN2 >> Carbenium Ion Formation >> Arenediazonium Salts OR SN2 >> Carbenium Ion Formation >> Diazoalkanes OR SN2 >> Diazonium ion formation OR SN2 >> Diazonium ion formation >> Specific Imine and Thione Derivatives OR SN2 >> Direct acting aziridines OR SN2 >> Direct acting aziridines >> Aminoacridine Derivatives OR SN2 >> Direct Acting Epoxides and Related OR SN2 >> Direct Acting Epoxides and Related >> Epoxides, Aziridines OR SN2 >> Direct Acting Epoxides and Related >> Nitrogen Mustards OR SN2 >> Direct acylation involving a leaving group OR SN2 >> Direct acylation involving a leaving group >> Acyl Halides OR SN2 >> Epoxidation of Aliphatic Alkenes OR SN2 >> Epoxidation of Aliphatic Alkenes >> Polarized Haloalkene Derivatives OR SN2 >> Internal SN2 reaction with aziridinium and/or cyclic sulfonic ion formation OR SN2 >> Internal SN2 reaction with aziridinium and/or cyclic sulfonic ion formation >> Vicinal Dihaloalkanes OR SN2 >> Nucleophilic substitution at sp3 Carbon atom OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Geminal Polyhaloalkanes OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Haloalkanes Containing Electron-Withdrawing Groups OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Haloalkanes Containing Heteroatom OR SN2 >> P450-mediated epoxidation OR SN2 >> P450-mediated epoxidation >> Coumarins OR SN2 >> P450-mediated epoxidation >> Polarized Haloalkene Derivatives OR SN2 >> P450-mediated epoxidation >> Polycyclic Aromatic Hydrocarbons OR SN2 >> Ring opening SN2 reaction OR SN2 >> Ring opening SN2 reaction >> Four- and Five-Membered Lactones OR SN2 >> SN2 at Nitrogen Atom OR SN2 >> SN2 at Nitrogen Atom >> N-acetoxyamines OR SN2 >> SN2 at sp3 and activated sp2 carbon atom OR SN2 >> SN2 at sp3 and activated sp2 carbon atom >> Polarized Haloalkene Derivatives OR SN2 >> SN2 at sp3-carbon atom OR SN2 >> SN2 at sp3-carbon atom >> Alkylphosphates, Alkylthiophosphates and Alkylphosphonates OR SN2 >> SN2 at sp3-carbon atom >> Alpha-Haloethers OR SN2 >> SN2 at sp3-carbon atom >> Specific Acetate Esters OR SN2 >> SN2 at sp3-carbon atom >> Sulfonates and Sulfates OR SN2 >> SN2 at sulfur atom OR SN2 >> SN2 at sulfur atom >> Sulfonyl Halides by DNA binding by OASIS v.1.1

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as Alkoxy AND Aryl AND Ether by Organic functional groups

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as Alkoxy AND Aryl AND Ether AND Overlapping groups by Organic functional groups (nested)

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as Aliphatic Carbon [CH] AND Aliphatic Carbon [-CH2-] AND Aliphatic Carbon [-CH3] AND Aromatic Carbon [C] AND Olefinic carbon [=CH- or =C<] AND Oxygen, one aromatic attach [-O-] by Organic functional groups (US EPA)

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as Alkylarylether AND Aromatic compound AND Ether by Organic functional groups, Norbert Haider (checkmol)

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as Non binder, without OH or NH2 group by Estrogen Receptor Binding

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as Moderate binder, NH2 group OR Moderate binder, OH grooup OR Non binder, impaired OH or NH2 group OR Non binder, MW>500 OR Non binder, non cyclic structure OR Strong binder, NH2 group OR Strong binder, OH group OR Weak binder, NH2 group OR Weak binder, OH group OR Very strong binder, OH group by Estrogen Receptor Binding

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as Alkoxy AND Aryl AND Ether by Organic functional groups

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as Alkoxy AND Aryl AND Ether AND Overlapping groups by Organic functional groups (nested)

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 Aromatic Carbon [C] AND Olefinic carbon [=CH- or =C<] AND Oxygen, one aromatic attach [-O-] by Organic functional groups (US EPA)

Domain logical expression index: "p"

Referential boundary: The target chemical should be classified as Alkylarylether AND Aromatic compound AND Ether by Organic functional groups, Norbert Haider (checkmol)

Domain logical expression index: "q"

Referential boundary: The target chemical should be classified as No alert found by Protein binding by OASIS v1.1

Domain logical expression index: "r"

Referential boundary: The target chemical should be classified as Acylation OR Acylation >> Acyl transfer via nucleophilic addition reaction OR Acylation >> Acyl transfer via nucleophilic addition reaction >> Isocyanates and isothiocyanates OR Acylation >> Direct acylation involving a leaving group OR Acylation >> Direct acylation involving a leaving group >> Acid anhydrides OR Acylation >> Direct acylation involving a leaving group >> Acyl halide of carboxylic acids OR Acylation >> Direct acylation involving a leaving group >> Azalactones OR Acylation >> Direct acylation involving a leaving group >> Carbamates OR Acylation >> Direct acylation involving a leaving group >> N-acylamides OR Acylation >> Direct acylation involving a leaving group >> N-acylated heteroaromatic amines OR Acylation >> Direct acylation involving a leaving group >> N-acylsulphonamides OR Acylation >> Direct acylation involving a leaving group >> Omega-haloalkyl carboxylic acid esters OR Acylation >> Direct acylation involving a leaving group >> Sulphonyl azides OR Acylation >> Direct acylation involving a leaving group >> Sulphonyl halides OR Acylation >> Ester aminolysis OR Acylation >> Ester aminolysis >> Amides OR Acylation >> Ester aminolysis >> Dithiocarbamates OR Acylation >> Ester aminolysis >> Dithioesters OR Acylation >> Ester aminolysis or thiolysis OR Acylation >> Ester aminolysis or thiolysis >> Activated alkyl or aryl esters OR Acylation >> Ester aminolysis or thiolysis >> Diarylesters OR Acylation >> Ring opening acylation OR Acylation >> Ring opening acylation >> Active cyclic agents OR Ionic OR Ionic >> Electrostatic interaction of tetraalkylammonium ions with protein carboxylates OR Ionic >> Electrostatic interaction of tetraalkylammonium ions with protein carboxylates >> Tetraalkylammonium ions OR Michael addition OR Michael addition >> a,b-unsaturated carbonyl compounds OR Michael addition >> a,b-unsaturated carbonyl compounds >> a,b-unsatuarted aldehydes OR Michael addition >> Michael addition on conjugated systems with electron withdrawing group OR Michael addition >> Michael addition on conjugated systems with electron withdrawing group >> alpha,beta-carbonyl compounds with polarized double bonds OR Michael addition >> Michael addition on conjugated systems with electron withdrawing group >> Cyanoalkenes OR Michael addition >> Michael addition on conjugated systems with electron withdrawing group >> Nitroalkenes OR Michael addition >> Michael addition on conjugated systems with electron withdrawing group >> N-sulfonylazomethyne compounds OR Michael addition >> Michael addition on conjugated systems with electron withdrawing group >> Vinyl sulfonyl compounds OR Michael addition >> Michael type addition on vinyl pirydines and activated ethenylarenes OR Michael addition >> Michael type addition on vinyl pirydines and activated ethenylarenes >> Activated electrophilic ethenylarenes OR Michael addition >> Michael type addition on vinyl pirydines and activated ethenylarenes >> Vinyl pyridines OR Michael addition >> Michael-type addition on azoxy compounds OR Michael addition >> Michael-type addition on azoxy compounds >> Azoxy compounds OR Michael addition >> Quinone type compounds OR Michael addition >> Quinone type compounds >> Naphtoquinone and naphtoquinone imines OR Michael addition >> Quinone type compounds >> Quinone (di)imines OR Michael addition >> Quinone type compounds >> Quinone methides OR Michael addition >> Quinone type compounds >> Quinones OR Nucleophilic addition OR Nucleophilic addition >> Addition to Carbon-hetero double/triple bond OR Nucleophilic addition >> Addition to Carbon-hetero double/triple bond >> Ketones OR Nucleophilic addition >> Addition to Carbon-hetero double/triple bond >> Thiocyanates OR Nucleophilic addition >> Nucleophilic addition at polarized N-functional double bond OR Nucleophilic addition >> Nucleophilic addition at polarized N-functional double bond >> C-Nitroso compounds OR Nucleophilic addition >> Nucleophilic addition reaction across carbodiimide bond OR Nucleophilic addition >> Nucleophilic addition reaction across carbodiimide bond >> Carbodiimides OR Radical OR Radical >> Free radical formation OR Radical >> Free radical formation >> Organic peroxy compounds OR Schiff base formation OR Schiff base formation >> Nucleophilic cycloaddition to diketones OR Schiff base formation >> Nucleophilic cycloaddition to diketones >> Diketones OR Schiff base formation >> Pyrazolones and pyrazolidinones derivatives OR Schiff base formation >> Pyrazolones and pyrazolidinones derivatives >> Pyrazolones and pyrazolidinones OR Schiff base formation >> Schiff base formation with carbonyl compounds OR Schiff base formation >> Schiff base formation with carbonyl compounds >> Aldehydes OR SN1 OR SN1 >> Carbenium ion formation OR SN1 >> Carbenium ion formation >> Azoxy compounds-forming carbenium ion OR SN1 >> Nucleophilic substitution (SN1) on alkyl (aryl) mercury cations OR SN1 >> Nucleophilic substitution (SN1) on alkyl (aryl) mercury cations >> Mercury compounds OR SN2 OR SN2 >> Interchange reaction with sulphur containing compounds OR SN2 >> Interchange reaction with sulphur containing compounds >> Thiols and disulfide compounds OR SN2 >> Nucleophilic substitution at Nitrogen atom OR SN2 >> Nucleophilic substitution at Nitrogen atom >> N-nitroso compounds OR SN2 >> Nucleophilic substitution at Nitrogen atom >> N-oxicarbonyl amides OR SN2 >> Nucleophilic substitution at sp3 Carbon atom OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Activated alkyl esters OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> alpha-activated haloalkanes OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> alpha-haloalkanes OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> N-nitroso compounds OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Phosphates OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Phosphonates OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Sulfonates OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Thiophosphates OR SN2 >> Nucleophilic substitution on benzylic carbon atom OR SN2 >> Nucleophilic substitution on benzylic carbon atom >> alpha-activated benzyls OR SN2 >> Nucleophilic substitution on benzylic carbon atom >> Benzylic esters OR SN2 >> Nucleophilic substitution on heterocyclic sulfenamides OR SN2 >> Nucleophilic substitution on heterocyclic sulfenamides >> Heterocyclic sulfenamides OR SN2 >> Nucleophilic substitution to the central carbon atom of N-nitroso compounds OR SN2 >> Nucleophilic substitution to the central carbon atom of N-nitroso compounds >> N-nitroso compouns excluding aromatic OR SN2 >> Ring opening SN2 reaction OR SN2 >> Ring opening SN2 reaction >> Epoxides, Aziridines and Sulfuranes OR SN2 >> Ring opening SN2 reaction >> Isothiazolones derivatives OR SN2 Ionic OR SN2 Ionic >> Nucleophilic substitution at sulfur atom in disulfides OR SN2 Ionic >> Nucleophilic substitution at sulfur atom in disulfides >> Arenesulfinic acids OR SNAr OR SNAr >> Nucleophilic aromatic substitution on activated halogens OR SNAr >> Nucleophilic aromatic substitution on activated halogens >> Activated haloarenes by Protein binding by OASIS v1.1

Domain logical expression index: "s"

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

Domain logical expression index: "t"

Similarity boundary:Target: c1(OCC)ccccc1
Threshold=30%,
Dice(Atom centered fragments)

Domain logical expression index: "u"

Parametric boundary:The target chemical should have a value of log Kow which is >= 2.42

Domain logical expression index: "v"

Parametric boundary:The target chemical should have a value of log Kow which is <= 5.28

Conclusions:
Repeated dose toxicity NOEL (No observed effect level) of phenetole in rat (Wistar ) by the oral route was predicted at a dose concentration of 93.599998474 mg/kg bw.On the basis of this NOEL it is concluded that the test substance is not toxic to rat (Wistar)by oral route below the mentioned dose.
Executive summary:

The NOEL for phenetole is estimated to be 93.599998474 mg/kg bw/day forratfor 28 days using the toolbox version 3.2. The data is estimated to be based on the data summarized below

CAS no.

End point

Value

Species

Doses

Duration

Effects

Remarks

104-93-8

NOEL

100 mg / kg bw/ day

Rat(Wistar)

100, 300, 1000 mg/kg bw in olive oil DAB 9

4 weeks

no substance related changes.

Parameters-body weight,clinical symptoms,food consumption

13335-71-2

NOEL

50 mg / kg bw/ day

Rat(Sprague DawleyCrl:CD(SD)BR)

0,5,15, 30 mg/kg

28 days

No effects.

Parameters-Clinical signs and mortality,bodyweight,hamaetology,gross and histopathology.

138113-08-3

NOAEL

150 mg/ kg bw / day

Sprague-Dawley rats

Not available

Not available

No effects

Parameters-Details not available

133467-41-1

NOAEL

300 mg / kg bw/ day

Rats (Sprague-Dawley)

Not available

Not available

No effects

Parameters-Details not available

99607-70-2

NOEL

91.7 mg/kg bw/day (actual dose received)

Rat(Albino RAIf (SPF))

0, 18.6, 91.7, 381 mg/kg/day (females)

4 weeks

No effects

clinical signs; mortality; body weight; food consumption; food efficiency; water consumption and compound intake; ophthalmoscopic examination; haematology; clinical chemistry; urinalysis; gross pathology; organ weights; histopathology;

 

LOEL

0.42 mg /kg /day

Not available

Not available

Not available

Thyroid-Proliferative

-

 

Based on the above values it can be concluded  that estimated value 93.599998474 mg/kg bw/day for the target substance phenetole is more close to NOEL value 91.7 mg/kg bw/day of readacross CAS 99607-70-2.Hence the estimated value of target is considered as an NOEL value. Thus it can be concluded that repeated dose toxicity NOEL (No observed effect level) of phenetole in rat(Albino RAIf (SPF)) via oral route in 28 days study is predicted to be 93.599998474 mg/kg bw/day.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
93.6 mg/kg bw/day
Study duration:
subacute
Species:
mouse
Quality of whole database:
The data is K2 level as the data has been obtained from QSAR model considered by OECD.

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records
Reference
Endpoint:
chronic toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
4 (not assignable)
Qualifier:
according to guideline
Guideline:
other:
Principles of method if other than guideline:
Data is from RTECS database
GLP compliance:
not specified
Species:
rat
Strain:
not specified
Sex:
not specified
Route of administration:
inhalation
Type of inhalation exposure:
not specified
Vehicle:
not specified
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
122 days
Frequency of treatment:
Intermittent
Control animals:
not specified
Dose descriptor:
other: TCLo
Effect level:
200 mg/m³ air
Based on:
test mat.
Sex:
not specified
Basis for effect level:
other: not specified
Remarks on result:
other: not specified
Critical effects observed:
not specified
System:
other: not specified
Organ:
not specified
Treatment related:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified
Conclusions:
The repeated dose toxicity TCLo(Lowest published toxic concentration) of anisole was observed at a dose concentration of 200 mg/m3 air in a 122 days study period where the dosage of anisole was intermittently given to rodent-rat by inhalative route.This indicates that anisole shall not exhibit toxic effect to rodent-rat by the inhalative route below the above mention dose.
Executive summary:

The repeated dose toxicity TCLo(Lowest published toxic concentration) of anisole was observed at a dose concentration of 200 mg/m3 air in a 122 days study period where the dosage of anisole was intermittently given to rodent-rat by inhalative route.This indicates that anisole shall not exhibit toxic effect to rodent-rat by the inhalative route below the above mention dose.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
200 mg/m³
Study duration:
chronic
Species:
rat
Quality of whole database:
The data is K4 level as the data has been obtained from RTECS database.

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:
sub-chronic toxicity: dermal
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Qualifier:
according to guideline
Guideline:
other:
Principles of method if other than guideline:
Subchronic dermal toxicity of 2-phenoxy ethanol was assessed in New Zealand White Rabbit in 90 days study period
GLP compliance:
not specified
Limit test:
no
Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals or test system and environmental conditions:
Details on test animal
TEST ANIMALS
- Source: Hazleton-Dutchland, Denver, PA
- Age at study initiation: 5 months of age
- Housing: individually (in cages with wire floors)
- Diet (e.g. ad libitum): Certified Laboratory Rabbit Chow
- Water (e.g. ad libitum): Tap water (ad libitum)
- Acclimation period: 3 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 deg C
- Humidity (%): relative humidity at 50%
- Photoperiod (hrs dark / hrs light): 12 hr light: 12 hr dark photocycle


















Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on exposure:
Details on Dermal exposure
Dosing volume: approximately 0.05 to 0.50 ml/kg/day

2-phenoxyethanol was uniformly spread over a clipped area (approximately 10 X 15 cm) using a syringe and Hunt-tipped needle. The application site was reclipped as required during the study to keep it free of hair. An occlusive wrap of absorbent gauze and nonabsorbent cotton was placed over the application area and was held in place using an elastic jacket. The wraps and jackets were removed approximately 6 hr after each dose was applied. The backs of the rabbits were not wiped since no appreciable amount of test material was apparent at the site of application after the 6-hr exposure period.
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
90 days (13 weeks)
Frequency of treatment:
5 days/week (6 hr/day)
Remarks:
Doses / Concentrations:
0,50, 150,or 500 mg/kg/day
Basis:
nominal per unit body weight
No. of animals per sex per dose:
10 animals per sex per dose
Control animals:
yes, concurrent vehicle
Details on study design:
Ten New Zealand White rabbits/sex/group were treated with 0, 50, 150, or 500 mg/kg/day of undiluted 2-phenoxyethanol for 6 hr/day, 5 days/week, for 13 weeks by dermal route. Dosing volume was approximately 0.05 to 0.50 ml/kg/day and was adjusted weekly based upon body weight Control rabbits received 0.5 ml/kg/day distilled water.
Observations and examinations performed and frequency:
Observations and examinations performed & frequency
BODY WEIGHT: Yes
Body weight observed

HAEMATOLOGY: Yes
Blood samples (approximately 7 ml) for hematology determinations were obtained from the auricular artery of all rabbits approximately 1 week prior to dosing and after 4 and 13 weeks of treatment. Samples for hematologic determinations were collected using vacuum tubes, and mixed with potassium EDTA anticoagulant. RBC, WBC, and PLAT counts, HGB concentration, PCV, and RBC indices (MCV, MCH, MCHQ were determined on all samples. Differential leukocyte and reticulocytes (RETICS) counts and RBC morphologic determinations were conducted on samples from all control and high dose group rabbits by direct microscopic examination of stained smears after 13 weeks of treatment only.


CLINICAL CHEMISTRY: Yes
Blood samples (approximately 7 ml) for clinical chemistry determinations were obtained from the auricular artery of all rabbits approximately 1 week prior to dosing and after 4 and 13 weeks of treatment.
Blood samples for clinical chemistry determinations were allowed to clot at 0-5 °C and serum was harvested by centrifugation. Alanine aminotransferase activity, aspartate aminotransferase activity, urea nitrogen, alkaline phosphatase activity, glucose, total protein, albumin, globulin, and total bilirubin were determined on all samples.

ORGAN WEIGHT: Yes
On the day following the last dermal application of 2-phenoxyethanol each rabbit was euthanatized with CO2, weighed and examined for gross pathological alterations. Brain, heart, liver, kidneys, and testes were weighed and relative organ weights (g/100 g body weight) were calculated.
Sacrifice and pathology:
Sacrifice and pathology
HISTOPATHOLOGY: Yes
Sample of all organ systems and tissues were collected from each rabbit at necropsy and preserved in neutral, phosphate-buffered 10% formalin. All tissues collected from control and high dose animals were processed by conventional histological techniques, stained with hematoxylin and eosin and evaluated by light microscopy.
Statistics:
Descriptive statistics (means and standard deviation) were evaluated for body weight, RBC indices, RBC Met-HGB, RBC GSH, RBC fragility, WBC differential count, serum EGPE, and PAA residue
Clinical signs:
no effects observed
Description (incidence and severity):
No overt signs of systemic toxicity (including hemoglobinuria) or early mortality of treated rabbits were noted over the 13-week dosing period.
Dermal irritation:
no effects observed
Mortality:
no mortality observed
Description (incidence):
No overt signs of systemic toxicity (including hemoglobinuria) or early mortality of treated rabbits were noted over the 13-week dosing period.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
No effects observed on Body weight
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Description (incidence and severity):
No effects observed on Hematology
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
No effects observed on clinical chemistry
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
No effects observed on organ weights
Gross pathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
No gross or microscopic changes attributable to EGPE exposure were observed in any tissue examined.
Histopathological findings: neoplastic:
not examined
Details on results:
Other effects:
The only potentially treatment-related effect was the sporadic observation of erythema and very slight-to-slight scaling of the skin at the site of test material application in male and female rabbits exposed to 500 mg EGPE/kg/day. However, as these effects were not associated with gross or histological changes in the skin they were not considered to be of toxicologic significance.
Dose descriptor:
NOAEL
Effect level:
500 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No effects observed on Mortality, Body weight, organ weight, Clinical chemistry, hematology, histopathology
Critical effects observed:
not specified
Conclusions:
The NOAEL of EGPE (i.e. 2-phenoxy ethanol) on New Zealand White rabbits in a 90 days dermal exposure study was considered to be 500 mg/kg/day.
Executive summary:

In conclusion, dermal exposure of rabbits to high doses (500 mg/kg/day) EGPE(i.e.2-phenoxy ethanol)does not result in systemic toxicity. Other effects observed were not considered to be of toxicological significance.

Therefore, the NOAEL of EGPE was considered to be 500 mg/kg/day when administered dermally.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
500 mg/kg bw/day
Study duration:
subchronic
Species:
rabbit
Quality of whole database:
K2 level publication data of readacross.

Additional information

Repeated dose toxicity: oral

Based on the various studies available with Klimish rating 2 for the read across substances for CAS 103-73-1 based on the category approach of organic functional group along with similar mechanistic approach and having structural similarities defined by QSAR toolbox. This data is combined with the prediction done using the QSAR toolbox for the target chemical based on similar category approach, the results is summarized as follows-

Sr. No

End point

Value

Species

Route

Effects

Remarks

1.

NOEL

93.599998474 mg/kg bw/day (nominal)

Mouse

Oral

No substance related changes-Clinical examinations,Body weight,Mortality,Hematological examinations

Predicted data

2.

LOAEL

100 mg/kg bw/day (nominal)

Rabbit

Oral

Mortality, Body weight, Urinalysis, hematological parameter,

Publication

RA-122-99-6

3.

1.LOAEL

2.NOAEL

1. 8750 mg/kg bw/day (nominal)

2. 4375 mg/kg bw/day (nominal)

Mouse

Oral

1.Reduction in body weight gain

2.Overall effects

NTP Study report(RA-122-99-6)

4.

TDLo

1500 mg/kg bw (total dose)

Rabbit

Oral

LIVER: Liver function tests impaired; BLOOD: Changes

in other cell count (unspecified)

Publication

RA-100-66-3

5.

TDLo

118.3 mg/kg bw (total dose)

Rabbit

Oral

ENDOCRINE: Other changes;

Publication

RA-100-66-3

 

Based on the studies summarized in the above table it can be observed that No observed effect level(NOEL-Target,NOAEL-Readacross) is expected to be in the range 93.599998474 - 4375 mg/kg bw/day as well as LOAEL value for readacross substance varies from 100-8750 mg/kg bw/day. The predicted value of target falls within the ranges mentioned above and considered to be more conservative value. The effects observed/no effects observed on these doses was listed as follows-

Mortality observed, change in body weight and hematological changes.

Clinical chemistry- Liver function tests impaired

Endocrine changes observed.

No effects observed on clinical examinations.

      

Thus based on above discussion it can be concluded that substance CAS: 103-73-1 is expected to show the similar toxicological effect based on the effects observed on the other category members. Since the no effective dose value (NOEL) is higher than 93.599998474 mg/kg bw /day, LOAEL value is more than 100 mg/kg bw/day of read across. Thus based on this value it can be concluded that substance CAS: 103-73-1 is considered to be not toxic to repeated dose via oral route. Also there is no known evidence of adverse effect on Human of CAS: 103-73-1 as well as estrogen receptor binding affinity does not indicates any mechanistic trigger as the substance is found to be a weak binder and would not raise any concern of CAS: 103-73-1 on toxicity to human.

Repeated dose toxicity: inhalation

The repeated dose toxicity TCLo(Lowest published toxic concentration) of anisole was observed at a dose concentration of 200 mg/m3 air in a 122 days study period where the dosage of anisole was intermittently given to rodent-rat by inhalative route.This indicates that anisole shall not exhibit toxic effect to rodent-rat by the inhalative route below the above mention dose.

Repeated dose dermal-

Based on the various studies available with Klimish rating 2 and 4 for the read across substances for CAS 103-73-1 based on the category approach of organic functional group along with similar mechanistic approach and having structural similarities defined by QSAR toolbox. This data is combined with the prediction done using the QSAR toolbox for the target chemical based on similar category approach, the results is summarized as follows-

Sr. No

End point

Value

Species

Route

Effects

Remarks

1.

NOAEL

500 mg/kg bw/day (actual dose received)

Rabbit

Dermal

No effects observed on Mortality, Body weight, organ weight, Clinical chemistry, hematology, histopathology

Publication

RA-122-99-6

2.

LOAEL

1000 mg/kg bw/day (nominal)

Rabbit

Dermal

High mortality

Study report

RA-122-99-6

Based on the above results of readarcoss for the target CAS it can be assessed that the test substance is not expected to show repeated dose toxicity via dermal route below 500 mg/kg bw/day and 1000 mg/kg bw/day.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:

Repeated dose toxicity NOEL (No  observed  effect level) of phenetole in rat (Wistar ) by the oral route was predicted at a dose concentration of 93.599998474 mg/kg bw.On the basis of this NOEL it is concluded that the test substance is not toxic to rat (Wistar)by oral route below the mentioned dose.

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:

The repeated dose toxicity TCLo(Lowest published toxic concentration) of anisole was observed at a dose concentration of 200 mg/m3 air in a 122 days study period where the dosage of anisole was intermittently given to rodent-rat by inhalative route.This indicates that anisole shall not exhibit toxic effect to rodent-rat by the inhalative route below the above mention dose.

Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:

The NOAEL of EGPE (i.e. 2-phenoxy ethanol) on New Zealand White rabbits in a 90 days dermal exposure study was considered to be 500 mg/kg/day.

Justification for classification or non-classification

The substancesodium phenetole is not expected toshow repeated dose toxicity effect for oral inhalation or dermal route and thus will not be considered for further classification.