p-tolyl acetate

Endpoint summary

Description of key information

The repeated dose toxicity study was predicted using OECD QSAR toolbox version 3.3 (2017) with log kow as the primary descriptor and considering the six closest read across substances; to evaluate the toxic effects of administration of p-tolyl acetate (CAS No. 140-39-6) in rats by the oral route in a 13 weeks of exposure. No adverse effects were observed. Therefore, the no-observed adverse effect level (NOAEL) of p-tolyl acetate (CAS No. 140-39-6) in rat was estimated to be 610.66 mg/kg bw/day.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

repeated dose 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:

Prediction is done using OECD QSAR toolbox version 3.3 and the supporting QMRF report has been attached.

Qualifier:

no guideline available

Principles of method if other than guideline:

Prediction is done using OECD QSAR Toolbox version 3.3 with respect to the descriptor log Kow.

GLP compliance:

not specified

Specific details on test material used for the study:

Name of test material (as cited in study report): 4-methylphenyl acetate
Molecular formula:C9H10O2
Molecular weight:150.176 g/mol
Substance Type: Organic
Physical State: Liquid

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Route of administration:

oral: unspecified

Vehicle:

not specified

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

13 weeks

Frequency of treatment:

Daily

Dose / conc.:

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

Control animals:

not specified

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Not specified
- Time schedule:Not specified
- Cage side observations checked in table [No.?] were included.: Not specified

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: No data

BODY WEIGHT: Yes
- Time schedule for examinations:No data

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Not specified

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Not specified
- Time schedule for examinations:Not specified

OPHTHALMOSCOPIC EXAMINATION: Not specified
- Time schedule for examinations:Not specified
- Dose groups that were examined:Not specified

HAEMATOLOGY: Yes
- Time schedule for collection of blood:Not specified
- Anaesthetic used for blood collection: Not specified
- Animals fasted: Not specified
- How many animals:Not specified
- Parameters checked in table [No.?] were examined.Not specified

CLINICAL CHEMISTRY: Not specified
- Time schedule for collection of blood:Not specified
- Animals fasted:Not specified
- How many animals:Not specified
- Parameters checked in table [No.?] were examined.Not specified

URINALYSIS: Not specified
- Time schedule for collection of urine:Not specified
- Metabolism cages used for collection of urine: Not specified
- Animals fasted: Not specified
- Parameters checked in table [No.?] were examined.Not specified

NEUROBEHAVIOURAL EXAMINATION: Not specified
- Time schedule for examinations: Not specified
- Dose groups that were examined: Not specified
- Battery of functions tested: sensory activity / grip strength / motor activity / other: Not specified

IMMUNOLOGY: Not specified
- Time schedule for examinations:Not specified
- How many animals:Not specified
- Dose groups that were examined:Not specified
- Parameters checked in table [No.?] were examined.Not specified

OTHER: MORTALITY: Yes

Sacrifice and pathology:

GROSS PATHOLOGY: Yes

HISTOPATHOLOGY: Yes

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

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

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

no effects observed

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Key result

Dose descriptor:

NOAEL

Effect level:

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

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

clinical signs

food consumption and compound intake

gross pathology

haematology

histopathology: non-neoplastic

mortality

other: No adverse effects observed.

Critical effects observed:

no

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

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

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Esters (Acute toxicity) by US-EPA New Chemical Categories

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as AN2 AND AN2 >> Shiff base formation after aldehyde release AND AN2 >> Shiff base formation after aldehyde release >> Specific Acetate Esters AND SN1 AND SN1 >> Nucleophilic attack after carbenium ion formation AND SN1 >> Nucleophilic attack after carbenium ion formation >> Specific Acetate Esters AND SN2 AND SN2 >> Acylation AND SN2 >> Acylation >> Specific Acetate Esters AND SN2 >> Nucleophilic substitution at sp3 Carbon atom AND SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Specific Acetate Esters by DNA binding by OASIS v.1.3

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Acylation AND Acylation >> Ester aminolysis or thiolysis AND Acylation >> Ester aminolysis or thiolysis >> Activated aryl esters  by Protein binding by OASIS v1.3

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Acylation AND Acylation >> Direct Acylation Involving a Leaving group AND Acylation >> Direct Acylation Involving a Leaving group >> Acetates by Protein binding by OECD

Domain logical expression index: "e"

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

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as Esters by Acute aquatic toxicity MOA by OASIS

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as Esters by Aquatic toxicity classification by ECOSAR

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as No alert found by DNA binding by OECD

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as Acylation OR Acylation >> Isocyanates and Isothiocyanates OR Acylation >> Isocyanates and Isothiocyanates >> Isocyanates OR Acylation >> Isocyanates and Isothiocyanates >> Isothiocyanates OR Michael addition OR Michael addition >> P450 Mediated Activation of Heterocyclic Ring Systems OR Michael addition >> P450 Mediated Activation of Heterocyclic Ring Systems >> Furans OR Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals OR Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals >> Alkyl phenols OR Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals >> Arenes OR Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals >> Hydroquinones OR Michael addition >> Polarised Alkenes-Michael addition OR Michael addition >> Polarised Alkenes-Michael addition >> Alpha, beta- unsaturated amides OR Michael addition >> Polarised Alkenes-Michael addition >> Alpha, beta- unsaturated esters OR Michael addition >> Polarised Alkenes-Michael addition >> Alpha, beta- unsaturated ketones OR Schiff base formers OR Schiff base formers >> Direct Acting Schiff Base Formers OR Schiff base formers >> Direct Acting Schiff Base Formers >> Mono aldehydes OR SN1 OR SN1 >> Carbenium Ion Formation OR SN1 >> Carbenium Ion Formation >> Hydrazine OR SN1 >> Iminium Ion Formation OR SN1 >> Iminium Ion Formation >> Aliphatic tertiary amines OR SN1 >> Nitrenium Ion formation OR SN1 >> Nitrenium Ion formation >> Aromatic azo OR SN1 >> Nitrenium Ion formation >> Aromatic nitro OR SN1 >> Nitrenium Ion formation >> Primary aromatic amine OR SN1 >> Nitrenium Ion formation >> Tertiary (unsaturated) heterocyclic amine  OR SN1 >> Nitrenium Ion formation >> Tertiary aromatic amine OR SN1 >> Nitrenium Ion formation >> Unsaturated heterocyclic azo OR SN2 OR SN2 >> Direct Acting Epoxides and related OR SN2 >> Direct Acting Epoxides and related >> Epoxides OR SN2 >> SN2 at an sp3 Carbon atom OR SN2 >> SN2 at an sp3 Carbon atom >> Aliphatic halides OR SN2 >> SN2 at an sp3 Carbon atom >> Phosphonic esters by DNA binding by OECD

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as AN2 AND AN2 >> Shiff base formation after aldehyde release AND AN2 >> Shiff base formation after aldehyde release >> Specific Acetate Esters AND SN1 AND SN1 >> Nucleophilic attack after carbenium ion formation AND SN1 >> Nucleophilic attack after carbenium ion formation >> Specific Acetate Esters AND SN2 AND SN2 >> Acylation AND SN2 >> Acylation >> Specific Acetate Esters AND SN2 >> Nucleophilic substitution at sp3 Carbon atom AND SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Specific Acetate Esters by DNA binding by OASIS v.1.3

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as AN2 >> Michael-type addition on alpha, beta-unsaturated carbonyl compounds OR AN2 >> Michael-type addition on alpha, beta-unsaturated carbonyl compounds >> Four- and Five-Membered Lactones 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 >> Shiff base formation for aldehydes OR AN2 >> Shiff base formation for aldehydes >> Haloalkane Derivatives with Labile Halogen OR No alert found OR Non-covalent interaction OR Non-covalent interaction >> DNA intercalation OR Non-covalent interaction >> DNA intercalation >> DNA Intercalators with Carboxamide Side Chain OR Non-specific OR Non-specific >> Incorporation into DNA/RNA, due to structural analogy with  nucleoside bases    OR Non-specific >> Incorporation into DNA/RNA, due to structural analogy with  nucleoside bases    >> Specific Imine and Thione Derivatives OR Radical OR Radical >> Generation of reactive oxygen species OR Radical >> Generation of reactive oxygen species >> Thiols OR Radical >> Radical mechanism via ROS formation (indirect) OR Radical >> Radical mechanism via ROS formation (indirect) >> Single-Ring Substituted Primary Aromatic Amines OR Radical >> Radical mechanism via ROS formation (indirect) >> Specific Imine and Thione Derivatives OR SN1 >> Carbenium ion formation OR SN1 >> Carbenium ion formation >> Alpha-Haloethers OR SN1 >> Nucleophilic attack after metabolic nitrenium ion formation OR SN1 >> Nucleophilic attack after metabolic nitrenium ion formation >> Single-Ring Substituted Primary Aromatic Amines OR SN1 >> Nucleophilic substitution on diazonium ions OR SN1 >> Nucleophilic substitution on diazonium ions >> Specific Imine and Thione Derivatives OR SN2 >> Acylation involving a leaving group  OR SN2 >> Acylation involving a leaving group  >> Haloalkane Derivatives with Labile Halogen OR SN2 >> Alkylation, nucleophilic substitution at sp3-carbon atom OR SN2 >> Alkylation, nucleophilic substitution at sp3-carbon atom >> Haloalkane Derivatives with Labile Halogen OR SN2 >> Alkylation, ring opening SN2 reaction OR SN2 >> Alkylation, ring opening SN2 reaction >> Four- and Five-Membered Lactones OR SN2 >> Direct acting epoxides formed after metabolic activation OR SN2 >> Direct acting epoxides formed after metabolic activation >> Quinoline Derivatives OR SN2 >> SN2 at an activated carbon atom OR SN2 >> SN2 at an activated carbon atom >> Quinoline Derivatives OR SN2 >> SN2 at sp3-carbon atom OR SN2 >> SN2 at sp3-carbon atom >> Alpha-Haloethers by DNA binding by OASIS v.1.3

Domain logical expression index: "l"

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

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as Allyl esters (Hepatotoxicity) Rank A by Repeated dose (HESS)

Domain logical expression index: "n"

Parametric boundary:The target chemical should have a value of log Kow which is >= 0.726

Domain logical expression index: "o"

Parametric boundary:The target chemical should have a value of log Kow which is <= 4.42

Conclusions:

The no-observed adverse effect level (NOAEL) of p-tolyl acetate (CAS No. 140-39-6) in rat was estimated to be 610.66 mg/kg bw/day.

Executive summary:

The repeated dose toxicity study was predicted using OECD QSAR toolbox version 3.3 (2017) with log kow as the primary descriptor and considering the six closest read across substances; to evaluate the toxic effects of administration of p-tolyl acetate (CAS No. 140-39-6) in rats by the oral route in a 13 weeks of exposure. No adverse effects were observed. Therefore, the no-observed adverse effect level (NOAEL) of p-tolyl acetate (CAS No. 140-39-6) in rat was estimated to be 610.66 mg/kg bw/day.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

610.66 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

The data is Klimicsh 2 and from OECD QSAR toolbox version 3.3 (2017).

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Repeated dose toxicity: oral

Various repeated dose toxicity studies has been investigated to observe the adverse general toxicological effects occurring as a result of repeated daily dosing with, or exposure, to a substance for a specified period up to the expected lifespan of the test species. Often are the studies based on experiments and estimated data in rodents for p-tolyl acetate along with the studies available on structurally similar read across substances benzyl propionate (CAS No.122-63-4) and benzyl acetate (CAS No. 140-11-4). The predicted data using the OECD QSAR toolbox has also been compared with the experimental data. The studies are summarized as below:

 

The repeated dose toxicity study was predicted using OECD QSAR toolbox version 3.3 (2017) with log kow as the primary descriptor and considering the six closest read across substances; to evaluate the toxic effects of administration of p-tolyl acetate (CAS No. 140-39-6) in rats by the oral route in a 13 weeks of exposure. No adverse effects were observed. Therefore, the no-observed adverse effect level (NOAEL) of p-tolyl acetate (CAS No. 140-39-6) in rat was estimated to be 610.66 mg/kg bw/day.

 

Also, a subacute study was conducted by SSS (2014) to evaluate the toxic effects of repeated administration of read across substance benzyl propionate in male and female Sprague-Dawley rats by gavage. Benzyl propionate was administered to 6 animals/sex/species in Corn oil at doses of 0, 250, 500 and 1000 mg/kg/bw/day for 28 days. All rats of 250, 500 and 1000 mg/kg/bw/day dose group survive though-out the study. Benzyl propionate have no effect on mortality. Blood samples for clinical biochemistry and haematology were collected. No abnormalities occurred that could be directly attributed to benzyl propionate treatment. Although significant change in relative weights of liver, ovaries and lungs of female were observed in 1000 mg/kg/bw/day dose groups. No benzyl propionate related gross pathological or histological changes were seen and findings were not benzyl propionate dependent and hence considered to be of no toxicological importance. Therefore NOEAL for repeated dose toxicity study was considered to be 1000 mg/kg/bw/day in male and female Sprague-Dawley rats when exposed to benzyl propionate by oral route for 28 days. 

 

Moreover, the NTP (1993) studied the toxicology of benzyl acetate in F344/N rats using the dosed feed route of administration. In these repeat studies, male and female F344/N rats received benzyl acetate (at least 98% pure) in feed for 13 weeks. Groups of 10 male and 10 female F344/N rats were fed diets containing 0, 3,130, 6,250, 12,500, 25,000, or 50,000 ppm (0, 230, 460, 900, 1,750, or 3,900 mg/kg body weight for males and 0, 240, 480, 930, 1,870, or 4,500 mg/kg for females) benzyl acetate for 13 weeks. Nine male and nine female rats receiving 50,000 ppm benzyl acetate died or were killed moribund bet ween weeks 2 and 8 of the study. The mean body weight gain and the final mean body weight of 25,000 ppm males were significantly lower (P <0.01) than those of the control group. Feed consumption by exposed rats, except the 25,000 and 50,000 ppm males and 50,000 ppm females, was similar to that by the controls. The reduced feed consumption by 25,000 and 50,000 ppm males and 50,000 ppm females, was similar to that by the controls. The reduced feed consumption by 25,000 and 50,000 ppm males and 50,000 ppm females may have been due to toxicity or decreased palatability. Tremors and ataxia occurred only in the 50,000 ppm rats. These findings were first observed on day 15 in nine males and six females and continued until the end of the study. Cholesterol levels in 12,500 and 25,000 ppm females and triglyceride levels in 25,000 ppm females were lower than those in the controls. Chemical-related lesions occurred in the brain, kidney, tongue, and skeletal muscles of the thigh. Necrosis of the brain involving the cerebellum and/or hippocampus, degeneration and regeneration of the renal tubule epithelium, and degeneration and sarcolemma nuclear hyperplasia of the tongue and skeletal muscles occurred in most male and female 50,0 00 ppm rats. Thus, the no-observed adverse effect level (NOAEL) of Benzyl acetate (CAS No.- 140-11-4) in this 13 weeks feed study was determined to be as follows.

NOAEL (male/female) = 6,250 ppm

NOAEL (male) = 460 mg/kg bw/day

NOAEL (female) = 480 mg/kg bw/day

 

On the basis of evidence from above studies (target substance and to its read across substances) in experimental animals, it can be presumed that there is no potential to be harmful to human health following repeated exposure. The substancep-tolyl acetate (CAS No. 140-39-6) is unclassified because no specific target organ toxicity was seen at or below the dose/concentration guidance value for animal testing. Thus, on the basis of CLP classification criteria the substance is not classified. 

Repeated dose toxicity: inhalation

According to Annex IX of the REACH regulation, testing by the inhalation route is appropriate only if exposure of humans via inhalation is likely. Taking into account the low vapour pressure of the substance p-tolyl acetate, which is reported as 0.164 mmHg. Thus, exposure to inhalable dust, mist and vapour of the chemical p-tolyl acetate is highly unlikely. Therefore this study is considered for waiver.

 

Repeated dose toxicity: dermal

The acute toxicity value for p-tolyl acetate (as provided in section 7.2.3) is >2000 mg/kg body weight. The substance was also found to be not irrtating to skin. Also, given the use of the chemical as flavour and fragrance agent; repeated exposure by the dermal route is unlikely. Thus, it is expected that p-tolyl acetate shall not exhibit 28 day repeated dose toxicity by the dermal route. In addition, there is no dermal absorption data as well as no data available that suggests that p-tolyl acetate shall exhibit repeated dose toxicity by the dermal route. Hence this end point was considered for waiver.

Justification for classification or non-classification

Based on the available data for the assessment of repeated dose toxicity by oral, inhalation and dermal route and following CLP Regulation (EC) No 1272/2008 , the substance p-tolyl acetate is not classified.