Phenethyl acetate

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route

Endpoint conclusion:

no study available

Quality of whole database:

No data are available

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

Data for benzyl acetate, for use on a read across basis, study summaries are presented in section 7.5.1

 

NTP gavage studies

 

Fourteen-day range-finding gavage studies in the rat (using dose levels of 0, 250, 500, 1000, 2000 or 4000 mg/kg bw/d) and the mouse (using dose levels of 0, 125, 250, 500, 1000 or 2000 mg/kg bw/d) did not show any gross evidence of any effects of treatment on the reproductive system at dose levels causing mortality. It is recognised that no histopathological investigations were performed in these studies, thereby limiting their sensitivity.

 

Thirteen-week studies performed in the rat (using dose levels of 0, 62.5, 15, 250, 500 or 1000 mg/kg bw/d) and mouse (using dose levels of 0, 125, 250, 500, 1000 or 2000 mg/kg bw/d) included histopathological investigation of the seminal vesicles, prostate, testes, ovaries and uterus. The high dose levels in these studies were sufficient to cause mortality. In the rat study, treatment-related effects at gross necropsy were limited to thickened stomach walls in both sexes at 1000 mg/kg bw/d. No treatment-related histopathological effects were observed at any dose level. In the mouse study, no treatment-related gross or microscopic effects were observed at any dose level.

 

Two-year NTP carcinogenicity studies were also performed with benzyl acetate in rats (using gavage dose levels of 0, 250 or 500 mg/kg bw/d) and in mice (using gavage dose levels of 0, 500 or 1000 mg/kg bw/d). The studies included histopathological investigation of the seminal vesicles, prostate, testes, ovaries and uterus. No treatment-related effects on the reproductive system were noted in either species.

 

NTP dietary studies

 

The 13-week dietary studies included gross necropsy of all animals; weights of the prostate, seminal vesicle, testis and uterus (rat) were recorded. Histopathological investigations included assessment of the testes, epididymides, seminal vesicles, ovaries and uterus.

 

The 13-week rat study was performed at dose levels of 0, 3130, 6250, 12500, 25000 or 50000 ppm benzyl acetate. Dietary dose levels were equivalent to mean intakes of 0, 230, 460, 900, 1750 and 3900 mg/kg bw/d in males; 0, 240, 480, 930, 1870 and 4500 mg/kg bw/d in females. Overt toxicity was seen, with high (90%) mortality at the top dose level of 50000 ppm, changes in bodyweight and/or food consumption at 12500, 25000 and 50000 ppm.Testicular changes were seen in male rats at 12500, 25000 and 50000 ppm. Findings were characterised by mild or moderate aspermatogenesis in two rats at 50000 ppm, with atrophy of the seminiferous tubules in two rats at 25000 ppm and one rat at 12500 ppm rats. In one rat at 25000 ppm, seminiferous tubular atrophy was marked in severity and included atypical cells (enlarged, degenerated spermatozoa) in the corresponding epididymis and mild interstitial cell hyperplasia. The seminiferous tubule atrophy was minimal in severity in the single rat affected at 12500 ppm. No testicular findings were observed at dose levels of 6250 ppm or lower exposure levels. Additional findings in rats at 50000 ppm included secretory depletion of the seminal vesicles, and immature, hypoplastic uterus. However it is noted that these changes are frequently observed in rodents and are usually secondary effects of general toxicity. No treatment-related effects in any organ were noted in the two-year study, which was performed at dose levels of 0, 3000, 6000 and 12000 ppm.

 

The 13-week mouse study was performed at dose levels of 0, 3130, 6250, 12500, 25000 or 50000 ppm benzyl acetate. Dietary dose levels were equivalent to mean intakes of 0, 425, 1000, 2000m 3700 and 7900 mg/kg bw/d in males; 0, 650, 1280, 2980, 4300 and 9400 mg/kg bw/d in females.No relevant findings were noted on the tissues of the reproductive tract in either the 13-week study or in the two year study at dose levels of 0, 330, 1000 and 3000 ppm.

 

Additional specific investigations of reproductive function were made in both species at the end of the 13-week dietary studies. Sperm morphology and vaginal cytology of rats and mice from all dose levels were evaluated. No treatment-related effects on sperm morphology occurred in rats or mice.A significant dose-related effect occurred in oestrous cycling occurred in female mice; this effect did not occur in female rats. The lengthening of the oestrous cycle observed in exposed female mice is considered to be related to the reduced body weights seen in this study and is not a direct toxic effect of the test material.

 

The data from the rat 13-week dietary study with benzyl acetate indicate a potential effect on the male reproductive tract. With the exception of a single male at 12500 ppm (with findings described as ‘minimal’), findings were associated with toxicity (including 90% mortality at the top dose level) and bodyweight effects and may therefore be secondary, rather than direct toxic effects of the test material. The single, minimal grade incidence at 12500 ppm is not considered to be clearly related to treatment. It is notable that similar findings were not seen in the gavage study, which used comparable dose levels and in which the bolus dosing would be expected to produce more severe effects. The absence of effects in the rat following gavage or dietary administration for two years is equally notable, and specific investigations at the end of the 13-week dietary study did not reveal any effects on sperm morphology.

 

Read-across data

 

Benzyl acetate is rapidly hydrolysed by plasma and tissue esterases to benzoic acid, with little or no systemic exposure to the intact substance. The related compounds benzaldehdye and benzyl alcohol are similarly metabolised to benzoic acid. Read-across from studies using benzoic acid, benzaldehdye or benzyl alcohol is therefore relevant for benzyl acetate. This approach to substance grouping, based on common metabolism to benzoic acid, has also been taken by a number of international bodies including the WHO in its consideration of the use of benzyl acetate as a food additive (WHO Food Additives Series 37), the SCCP in its consideration of the use of benzoic acid in consumer products (SCCP/0891/050) the OECD (SIDS Initial Assessment Report for 13^thSIAM, 2001) and IPCS (CICAD 26).  

 

The WHO (Food Additives Series 37) Committee concluded that the data reviewed on the substances in this group (including the NTP studies) were sufficient to demonstrate a lack of reproductive toxicity potential.

 

The SCCP evaluation of benzoic acid (SCCP/0891/05) notes the results of a 4-generation reproductive toxicity study in rats at dietary dose levels of up to1%. No adverse effects were noted in this study and a NOAEL equivalent to 500 mg/kg bw/d was determined for this study.

 

The IPCS evaluation of benzoic acid includes an assessment of the available data for benzoic acid and related substances (including benzyl acetate) and concludes that reproductive toxicity is unlikely at dose levels not causing maternal toxicity.

 

The OECD SIDS for the benzoate group of compounds including benzoic acid and benzyl alcohol (SIDS Initial Assessment Report for 13^thSIAM, 2001) evaluated the data available for this group of compounds (including benzyl acetate) and concluded that the absence oftreatment-related effects on reproductive organs in the (sub)chronic studies with all compounds supports the lack of reproductive potential.

 

Conclusion

 

The high quality repeated dose toxicity NTP studies for benzyl acetate do not show any clear effects of the substance on the reproductive tract of males or females and no effects on sperm morphology or vaginal cytology. Findings therefore do not indicate a potential for reproductive toxicity. Read-across data for related compounds including a 4-generation study performed with benzoic acid has been reviewed by a number of international bodies, who conclude that the group of related substances including benzyl acetate is without reproductive toxicity potential.

 

Additional, specific testing for the reproductive toxicity of phenyl ethyl acetate in a screening study for reproductive or developmental toxicity or in a multi-generation study is therefore not considered to be justified, both scientifically and for reasons of animal welfare, based on read across to results for the structurally similar substance benzyl acetate

 

Short description of key information:

No specific studies of reproductive toxicity are available for the test substance phenylethyl  acetate;  available evidence (from repeated dose toxicity studies with benzyl acetate and  read-across reproductive toxicity data for benzyl acetate) clearly indicates a lack of reproductive toxicity potential for the read across material and by association the absence of effects is considered applicable to phenylethyl acetate.  Specific testing for reproductive toxicity in a screening study or in a multi-generation study is not considered appropriate where a suitable argument for waiving vertebrate testing can be advanced from available data. Benzyl acetate is a justifiable read-across candidate and the reproductive data generated using benzyl acetate can be applied to phenylethyl acetate.

A number of high quality repeated dose toxicity studies (US NTP) using gavage and dietary administration, performed in the rat and mouse are available for benzyl acetate.  The NTP studies include histopathological evaluation of reproductive tract tissues and a specific assessment of reproductive toxicity potential by investigation of sperm morphology and vaginal cytology in the 13-week dietary studies. These parameters gave no basis for concern regarding adverse reproductive effects Relevant read-across data on reproductive toxicity are also available and similarly do not indicate a concern regarding reproductive performance or fertility following exposure to phenylethyl acetate.

Justification for selection of Effect on fertility via oral route:

Study requirement waived on basis of absence of triggers for reproductive toxicity investigations resulting from observations in several repeated exposure investigations.  The parameters investigated did not lead to concerns regarding possible reproductive effects or fertility that would have triggered a two-generation study.

Effects on developmental toxicity

Description of key information

One published guideline-comparable rat study is available.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

500 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

Published, guideline-comparable study

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

In a guideline-comparable developmental toxicity study, mated female Wistar rats (20 -22/group) were gavaged with benzyl acetate at dose levels of 10, 100, 500 or 1000 mg/kg bw/d on days 6 -15 of gestation. Additional groups were administered the vehicle alone or were untreated. Animals were terminated on Day 20 of gestation and the uterine contents examined: foetuses were assessed for external, visceral and skeletal findings.

A tendency to reduced weight gain was seen in females at 1000 mg/kg bw/d and to a lesser extent at 500 mg/kg bw/d. Numbers of corpora lutea were comparable in all groups; the numbers of implantations and live foetuses were marginally lower at 1000 mg/kg bw/d. A single dead foetus was observed at 1000 mg/kg bw/d. Resorptions were comparable in al groups. Mean male foetal weight was marginally but significantly higher at 10 and 100 mg/kg bw/d; mean male and female foetal weights were significantly lower at 1000 mg/kg bw/d. No external or visceral malformations were observed in any group. The number of visceral variations was significantly higher at 500 and 1000 mg/kg bw/d; increased incidences of ventricular dilation and renal pelvis dilation indicate an effect of treatment at 1000 mg/kg bw/d but not at 500 mg/kg bw/d. A single skeletal malformation (fused rib) was seen at 1000 mg/kg bw/d but is not considered to be clearly related to treatment. The incidence of skeletal variations was significantly increased at 1000 mg/kg bw/d; incidences of wavy rib, lumbar rib and other parameters indicative of reduced ossification were increased at this dose level.

Maternal and developmental toxicity was observed in this study at the highest dose level of 1000 mg/kg bw/d. Maternal and developmental NOAELs of 500 mg/kg bw/d are therefore derived.

Justification for selection of Effect on developmental toxicity: via oral route:

Only one study available for this endpoint

Justification for classification or non-classification

No data are available for reproductive toxicity; however the results of repeated dose toxicity studies do not indicate the reprodcutive tract as a target. No evidence of teratogenicity or specific developmental toxicity was seen in a rat developmental toxicity study performed with the read-across substance benzyl acetate. No classification for reproductive toxicity is proposed for phenyl ethyl acetate according to the CLP Regulation.