Benzyl benzoate

Endpoint summary

Description of key information

There are no experimental toxicokinetic data available for the substance and this statement is based on available data as physico-chemical data and toxicological data. This assessment was conducted based on the REACH ECHA “Guidance on information requirements and chemical safety assessment chapter R.7c” of the ECHA guidance document (Version 3.0, June 2017).

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

Title:
Information/Assumptions regarding Toxicokinetics:
Benzyl benzoate (CAS 120-51-4)
Author:
Dr. Harald Schlecker
Bayer AG
Research & Development, Pharmaceuticals, ICMPT
42096 Wuppertal
Germany
Completion Date:
2021-02-19
Sponsor:
LANXESS Deutschland GmbH
51369 Leverkusen
Germany

There are no experimental toxicokinetic data available for the substance and this statement is based on available data as physico-chemical data and toxicological data. This assessment was conducted based on the REACH ECHA “Guidance on information requirements and chemical safety assessment chapter R.7c” of the ECHA guidance document (Version 3.0, June 2017).
Available physico-chemical information taken into account:
Physical state:
Benzyl benzoate is a colourless, low melting point, crystalline solid at 20°C.
The melting point is 21°C and the boiling point is 323.5°C.
It has a relative density of 1.1121 and a vapour pressure of 0.000229 Torr.
The water solubility is 15.3 mg/L at 20°C and the log Pow is 4.0.
Structure:
Benzyl benzoate (CAS 120-51-4)
Molecular weight:
212.25 g/mol
Water solubility:
15.3 mg/L at 20 °C
Log Pow:
4 at 20 °C

Hydrolysis:
The enzymic hydrolysis of benzyl benzoate was investigated in human plasma in vitro. Benzyl benzoate was shown to be hydrolysed relatively rapidly in human plasma in vitro; a half-life of 19 minutes was shown. Benzyl benzoate hydrolyses to benzoic acid (65-85-0) and the corresponding alcohol (benzyl alcohol, CAS 100-51-6). This hydrolysis rate indicates rapid metabolism in vivo and suggests that bioaccumulation of benzyl benzoate is unlikely.
(Nielsen NM & Bundgaard H, Prodrugs as delivery systems, 68. Chemical and plasma-catalyzed hydrolysis of various esters of benzoic acid: a reference system for designing prodrug esters of carboxylic acid agents, International Journal of Pharmaceutics 39: 75-85 (1987).
http://www.inchem.org/documents/jecfa/jecmono/v48je14.htm
Based on the fast hydrolysis to benzoic acid and benzyl alcohol the toxicokinetic of these two substances is considered after absorption of benzyl benzoate.
General considerations:
Absorption is a function of the potential for a substance to diffuse across biological membranes. In addition to molecular weight the most useful parameters providing information on this potential are the octanol/water partition coefficient (log P) value and the water solubility. The log P value provides information on the relative solubility of the substance in water and the hydrophobic solvent octanol (used as a surrogate for lipid) and is a measure of lipophilicity. Log P values above 0 indicate that the substance is more soluble in octanol than water i.e. lipophilic and negative values indicate that the substance is more soluble in water than octanol i.e. hydrophilic. In general, log P values between -1 and 4 are favourable for absorption. Nevertheless, a substance with such a log P value can be poorly soluble in lipids and hence not readily absorbed when its water solubility is very low. It is therefore important to consider both, the water solubility of a substance and its log P value, when assessing the potential of that substance to be absorbed.
In general, substances with a log P between -1 and 4 are favourable regarding oral/GI absorption and respiratory absorption. Substance with a logP between1 and 4 favour dermal absorption.

Moderate log P values (between -1 and 4) are favourable for absorption directly across the respiratory tract epithelium by passive diffusion. Any lipophilic compound may be taken up by micellular solubilisation but this mechanism may be of particular importance for highly lipophilic compounds (log P >4), particularly those that are poorly soluble in water (1 mg/l or less) that would otherwise be poorly absorbed.
The log Pow of benzyl benzoate (CAS 120-51-4) is 4 and the water solubility is 15.3 mg/L at 20 °C. The molecular weight of benzyl benzoate (CAS 120-51-4) is 212.25 g/mol. The log Pow of benzyl benzoate (CAS 120-51-4) is at the boundary of favourable absorption. However, the water solubility of 15.3 mg/ml and the small molecular weight supports absorption. Absorption by the oral and dermal route is therefore predicted.
Low water solubility, like small particle size enhances penetration to the lower respiratory tract. For absorption of deposited material similar criteria as for GI absorption apply. Therefore, an absorption by the inhalation route is assumed.
Based on the physicochemical properties of benzyl benzoate (CAS 120-51-4) bioavailability by the oral, dermal or inhalation route is assumed.
Estimation of oral absorption:
In a standard acute oral study in rats, in accordance with test guideline OECD 401, groups of five male and female rats were dosed at 2000 mg/kg bw. Clinical signs including hunched posture, decreased respiratory rate, lethargy, ptosis and pilo-erection were apparent shortly after dosing but recovered within 4 days. The acute oral median lethal dose for benzyl benzoate was greater than 2000 mg/kg bw in rats.
The subacute oral toxicity of benzyl benzoate was determined in a chemotherapeutic activity study. The substance was administered at 200 mg/kg /day (Group I) or 800 mg/kg /day (Group II). The animals were retained until death occurred naturally. The negative animals, following completion of the cytostatic phase were dosed daily for a period of seven months. There were no indications of adverse systemic effects up to the cytostatically effective dose level of 800 mg/kg bw/d.

In a Prenatal Developmental Toxicity benzyl benzoate was administered in diet to pregnant rats at inclusion levels of 0.04% and 1.0%. The low group (0.04%) mean total consumption was 153.4 mg/rat, equivalent to 7.7 mg benzyl benzoate per day. For the high dose group (1%), total consumption was 3886.7 mg/rat and 194.3 mg per day.
There were no noteworthy changes in the general conditions for either treated groups over the gestation period. Benzyl benzoate caused no macroscopic changes attributable to treatment. The effects of benzyl benzoate administration to the pregnant females, on foetuses and neonates were examined. No evidence of teratogenicity or developmental toxicity was observed under the conditions of this assay.
In the acute oral toxicity study signs of intoxication were seen after the application of 2000 mg/kg bw to male and female rats. Clinical signs including hunched posture, decreased respiratory rate, lethargy, ptosis and pilo-erection were apparent shortly after dosing but recovered within 4 days.
In the repeated dose toxicity studies no or little effects were reported.
Due to the reported clinical signs in the acute toxicity study a relevant absorption of benzyl benzoate (CAS 120-51-4) is evident.
Estimation of dermal absorption:
In an early acute dermal toxicity study a LD50 of 4 ml/kg bw (approx. 4000 mg/kg bw) was reported (no further data).
In a subacute dermal toxicity study equivalent or similar to OECD Guideline 410 (Repeated Dose Dermal Toxicity: 21/28-Day Study) benzyl benzoate was applied topically to sites on the dorsum of 36 rats (six groups of three males and three females) at doses of 188, 301, 488, 781, 1250 or 2000 mg/kg bw/d.
Daily checks for mortality, clinical signs of reaction to treatment and assessment of any dermal changes at treatment sites were completed and bodyweights were recorded at weekly intervals. Blood and urine samples were collected shortly prior to termination and all rats were subject to gross necropsy.

No effects of treatment were apparent for rats dosed at 188, 301, 488 or 781 mg/kg bw/d. A slight reduction in bodyweight gain was evident for rats dosed at 1250 mg/kg bw/d in comparison with other treated groups.
Blood analysis indicated a slight increase in mean uric acid levels for rats dosed at 301 mg/kg bw/d but in the absence of similar effects at higher or lower doses, the biological significance of this change was unclear. No biologically significant macroscopic changes were evident at any dose level. Histopathological examinations revealed squamous epithelium hyperplasia, degeneration of hair follicles and sebaceous glands, subcutaneous fibrosis and thyroid gland hyperplasia. A NOAEL of 781 mg/kg bw/d was determined for this study.
In a 90 -day non-guideline assessment of dermal toxicity, rabbits were exposed to 0.5 ml/kg bw/d of benzyl benzoate and higher doses 1-4 ml/kg bw/d. The effects of exposure were generally non-adverse, with no effects on skin observed. However, a threshold of 2.0 ml/kg bw/d was established for causing death, with no preceding evidence of systemic toxicity NOAEL/LOAEL values were not formally established in this study since many of the parameters required in current test guidelines were not examined.
Due to the reported effects an absorption of benzyl benzoate (CAS 120-51-4) is assumed.
Estimation of absorption via inhalation:
No acute or repeated dose toxicity studies are available.
Estimation of distribution:
In general, the smaller the molecule, the wider the distribution. Small water-soluble molecules and ions will diffuse through aqueous channels and pores. The rate at which very hydrophilic molecules diffuse across membranes could limit their distribution. Lipophilic molecules (log P>0) are likely to distribute into cells and the intracellular concentrations may be higher than extracellular concentrations particularly in fatty tissues.
Based on the log Pow of 4 of benzyl benzoate, it is likely to distribute into cells. The molecular weight of 212.25 g/mol l also favours a wide distribution.

Estimation of accumulation:
Benzyl benzoate was shown to be hydrolysed relatively rapidly in human plasma in vitro; a half-life of 19 minutes was shown. Benzyl benzoate hydrolyses to benzoic acid (65-85-0) and the corresponding alcohol (benzyl alcohol, CAS 100-51-6). This hydrolysis rate indicates rapid metabolism in vivo and suggests that bioaccumulation of benzyl benzoate is unlikely.
Estimation of metabolism:
Benzyl benzoate was shown to be hydrolysed relatively rapidly in human plasma in vitro; a half-life of 19 minutes was shown. Benzyl benzoate hydrolyses to benzoic acid (65-85-0) and the corresponding alcohol (benzyl alcohol, CAS 100-51-6). This hydrolysis rate indicates rapid metabolism in vivo and suggests that bioaccumulation of benzyl benzoate is unlikely.
For metabolism benzoic acid (65-85-0) and the corresponding alcohol (benzyl alcohol, CAS 100-51-6) has to be considered.
Estimation of excretion:
After systemic bioavailability, benzyl benzoate is rapidly hydrolysed to benzoic acid (CAS 65-85-0) and the corresponding alcohol (benzyl alcohol, CAS 100-51-6). Therefore, the excretion of benzoic acid (65-85-0) and the corresponding alcohol (benzyl alcohol, CAS 100-51-6) has to be considered.
According to the SIDS Initial Assessment Report for 13th SIAM (2001), benzyl alcohol (CAS 100-51-6), benzoic acid (CAS 65-85-0) and its sodium and potassium salt can be considered as a single category regarding human health, as they are all rapidly metabolised and excreted via a common pathway within 24 hrs. Systemic toxic effects of similar nature (e.g. liver, kidney) were observed. However, with benzoic acid and its salts at higher doses than with benzyl alcohol.
https://hpvchemicals.oecd.org/ui/handler.axd?id=aa89d225-a2a7-4ed5-b8d6-c06b5e30b45b

The proposed category of this ICCA HPV Benzoates submission consists of the following
chemicals:
The common metabolic pathway of all these substances, adapted from JECFA 1997 and the
American Conference of Governmental Industrial Hygienists Documentation of the Threshold
Limit Values and Biological Exposure Indices, is provided below (ACGIH, 1986):

“There was no evidence to suggest saturation or reduction of metabolic capacity in either species
over the dose range tested. At much higher dosing the proportion of the dose present as benzoyl
glucuronide increased with dose, indicating a limited capacity for glycine conjugation only at
extreme high dose levels“.
Based on the data of benzylacetate “studies clearly show, that the compound is rapidly absorbed from the gastrointestinal tract of rats and mice, and about 90% of the total dose is recovered as urinary metabolites after 24h. More than 90% of the radio-label in the urine is present as hippuric acid, with minor amounts as benzyl alcohol and benzylmercapturic acid (up to 4%); no unchanged benzyl acetate was found. Only at very high doses, saturation of these pathways will occur.
This clearly shows the rapid pathway of hydrolysis to benzyl alcohol and subsequent oxidation to
benzaldehyde to benzoic acid and subsequent conjugation to the hippuric acid”.
“All data supports a very rapid absorption, distribution, biotransformation, and excretion of thesesubstances [Benzoates]by the common pathway given above”.
Overall conclusion:
Based on the physico-chemical properties of benzyl benzoate a relevant bioavailability can be assumed. After absorption into the blood circulation benzyl benzoate is rapidly hydrolysed to benzoic acid and benzyl alcohol (half-life of 19 minutes). Benzoic acid and benzyl alcohol are rapidly metabolised and excreted via a common pathway within 24hrs.
______________________________________________
Dr. Harald Schlecker
Bayer AG
Industrial Chemicals & Marketed Products Toxicology
42096 Wuppertal, Germany