p-tolyl acetate

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

The reproductive toxicity study was predicted using OECD QSAR toolbox version 3.3 (2017) with respect to the descriptor log Kow; to evaluate the toxic effects of administration of p-tolyl acetate (CAS No. 140-39-6) in rat by the oral route. No effects was observed. Therefore, the no observed adverse effect level (NOAEL) of p-tolyl acetate for reproductive toxicity study was estimated to be 806.0 mg/kg bw/day. 

Link to relevant study records

Reference

Endpoint:

toxicity to reproduction

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

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

male/female

Route of administration:

oral: gavage

Type of inhalation exposure (if applicable):

not specified

Vehicle:

not specified

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

Premating exposure period: 2 weeks for male rats
2 weeks for female rats
Exposure period: 22 days
Duration of the test: approx. 54 days

Frequency of treatment:

Daily

Dose / conc.:

806 mg/kg bw/day

Control animals:

not specified

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: No data

DETAILED CLINICAL OBSERVATIONS: Yes

BODY WEIGHT: Yes

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

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data

Postmortem examinations (parental animals):

GROSS NECROPSY: Yes
HISTOPATHOLOGY / ORGAN WEIGHTS: Yes

Clinical signs:

no effects observed

Dermal irritation (if dermal study):

not specified

Mortality:

not specified

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

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

not specified

Other effects:

not examined

Reproductive function: oestrous cycle:

no effects observed

Reproductive function: sperm measures:

no effects observed

Reproductive performance:

no effects observed

Key result

Dose descriptor:

NOAEL

Effect level:

806 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

clinical signs

body weight and weight gain

food consumption and compound intake

gross pathology

histopathology: non-neoplastic

reproductive function (oestrous cycle)

reproductive function (sperm measures)

reproductive performance

other: No effects observed.

Critical effects observed:

no

Clinical signs:

not specified

Dermal irritation (if dermal study):

not specified

Mortality / viability:

not specified

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:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Sexual maturation:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

not specified

Histopathological findings:

not specified

Other effects:

not specified

Behaviour (functional findings):

not specified

Developmental immunotoxicity:

not specified

Remarks on result:

not measured/tested

Critical effects observed:

not specified

Reproductive 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 ("k" and ( not "l") )  )  and ("m" and ( not "n") )  )  and ("o" and ( not "p") )  )  and "q" )  and ("r" and ( not "s") )  )  and ("t" and "u" )  )

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 >> Isothiocyanates OR Michael addition 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 aldehydes 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 >> 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 by DNA binding by OECD

Domain logical expression index: "j"

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

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 Alkali Earth by Groups of elements

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as Group 14 - Carbon C AND Group 16 - Oxygen O by Chemical elements

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as Group 15 - Nitrogen N OR Group 16 - Sulfur S by Chemical elements

Domain logical expression index: "o"

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

Domain logical expression index: "p"

Referential boundary: The target chemical should be classified as Alcohol OR Alkyne OR Carbonic acid diester OR Carbonyl compound OR CO2 derivative (general) OR Dialkylether OR Ether OR Heterocyclic compound OR Hydroxy compound OR Ketone OR Lactone OR No functional group found OR Phenol by Organic functional groups, Norbert Haider (checkmol)

Domain logical expression index: "q"

Similarity boundary:Target: Cc1ccc(OC(C)=O)cc1
Threshold=20%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "r"

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

Domain logical expression index: "s"

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

Domain logical expression index: "t"

Parametric boundary:The target chemical should have a value of log Kow which is >= 0.357

Domain logical expression index: "u"

Parametric boundary:The target chemical should have a value of log Kow which is <= 3.35

Conclusions:

The no observed adverse effect level (NOAEL) of p-tolyl acetate for reproductive toxicity study was estimated to be 806.0 mg/kg bw/day.

Executive summary:

The reproductive toxicity study was predicted using OECD QSAR toolbox version 3.3 (2017) with respect to the descriptor log Kow; to evaluate the toxic effects of administration of p-tolyl acetate (CAS No. 140-39-6) in rat by the oral route. No effects was observed. Therefore, the no observed adverse effect level (NOAEL) of p-tolyl acetate for reproductive toxicity study was estimated to be 806.0 mg/kg bw/day.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

806 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).

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

Various studies including predicted results from the validated model and experimental study has been investigated for reproductive toxicity to a greater or lesser extent for the test chemical p-tolyl acetate (CAS No. 140-39-6) along with its structurally similar read across substance benzyl acetate (CAS No.- 140-11-4) and methyl salicylate (CAS No.- 119-36-8) . The predicted data for target chemical p-tolyl acetate (CAS No. 140-39-6) has been compared with experimental study for a read across substance. The studies are summarized as below:

 

The reproductive toxicity study was predicted using OECD QSAR toolbox version 3.3 (2017) with respect to the descriptor log Kow; to evaluate the toxic effects of administration of p-tolyl acetate (CAS No. 140-39-6) in rat by the oral route. No effects was observed. Therefore, the no observed adverse effect level (NOAEL) of p-tolyl acetate for reproductive toxicity study was estimated to be 806.0 mg/kg bw/day. 

 

The above study is supported by the read across substance benzyl acetate which is used as a flavoring agent in foods, as a fragrance in soaps and perfumes, as a solvent for cellulose acetate and nitrate, and as a component of printing inks and varnish removers. In this study conducted by NTP (1993), 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, ppm (0, 230, 460, 900, or 1,750 mg/kg body weight for males and 0, 240, 480, 930 , or 1,870 mg/kg for females) benzyl acetate for 13 weeks. In male rats, terminal body weights were decreased (specific dose levels not report ed). There was no effect on reproductive organ weights, sperm motility, density or morphology. There was a great variation in the length of the estrus cyc le in control animals and therefore it was difficult to determine the biological significance of any findings in the treated animals. Benzyl acetate und er these test conditions did not show any effects on reproductive parameters tested. Thus, the no-observed adverse effect level (NOAEL) of Benzyl acetate (CAS No.- 140-11-4) in reproductive toxicity study was determined to be as follows.

NOAEL (male/female) = 25,000 ppm

NOAEL (male) = 1,750 mg/kg bw/day

NOAEL (female) = 1,870 mg/kg bw/day

 

Moreover, in another reproductive toxicity study conducted by NTP (1984), CD-1 albino male and female mice were treated with Methyl Salicylate in the concentration of 0, 100, 250 and 500 mg/kg/day by oral gavage. 2 male and 2 female were died in 100 and 250 mg/kg/day dose group and 4 rats were died in 500 mg/kg/day dose group as compared to control. The cause of death varied from case to case but it was neither chemical nor dose related. No treatment related sign of toxicity and change in body weight were observed in treated rats as compared to control. No effect on fertility index were observed but significant decrease in litters per pair, proportion of pups born alive and sex of pups born alive when treated with 500 mg/kg/day as compared to control. In addition, significant decrease in number of live pups, live pup weight and adjusted live pup weight was observed in 500 mg/kg/day treated rats as compared to control. Therefore, NOAEL was considered to be 250 mg/kg/dy for F0 and F1 generation when CD-1 albino male and female mice were treated with methyl salicylate.

 

Based on the above mentioned studies for target substance and to its read across substance by applying weight of evidence approach and also according to CLP criteria, it can be concluded that no adverse effects on sexual function and fertility was observed, therefore the substance p-tolyl acetate (CAS No. 140-39-6) cannot be classified as reproductive toxicant.

Justification for classification or non-classification

Based on the available data for the assessment of reproductive toxicity and following CLP Regulation EC No. 1272/2008 no classification of p-tolyl acetate (CAS No. 140-39-6) as reproductive toxicant is warranted.