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EC number: 204-402-9 | CAS number: 120-51-4
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Repeated dose toxicity: oral
Administrative data
- Endpoint:
- sub-chronic toxicity: oral
- Remarks:
- investigation of chemotherapeutic activity
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Study period:
- published in 1965
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Published literature from peer reviewed journal
Data source
Reference
- Reference Type:
- publication
- Title:
- Unnamed
- Year:
- 1 965
Materials and methods
Test guideline
- Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- Various assays were completed with rats and mice with implanted tumours and the inhibitory effects or cytostatic effects of benzyl benzoate investigated.
- GLP compliance:
- no
- Limit test:
- no
Test material
- Reference substance name:
- Benzyl benzoate
- EC Number:
- 204-402-9
- EC Name:
- Benzyl benzoate
- Cas Number:
- 120-51-4
- Molecular formula:
- C14H12O2
- IUPAC Name:
- benzyl benzoate
- Test material form:
- not specified
- Details on test material:
- - Name of test material (as cited in study report): benzyl benzoate
No other information
Constituent 1
Test animals
- Species:
- rat
- Strain:
- other: Wistar WAG
- Sex:
- male
- Details on test animals or test system and environmental conditions:
- Male Wistar WAG rats were grouped in batches having approximately similar weights (circa 150 g) and approximately the same age (circa 2.5 months).
Administration / exposure
- Route of administration:
- oral: gavage
- Details on oral exposure:
- Use of benzyl benzoate in palliative care of terminal cancer patients resulted in several systematic investigations of the cytostatic effects of benzyl benzoate therapies.
In the first of these assays , two tumour types were investigated - either the solid form of the Erlich carcinoma or the Walker 256 carcinoma. In the Erlich carcinoma test, treatment was initiated 5 days after implantation of the tumour, in the form of intraperitoneal injections for 6 consecutive days. At a dose of 10 mg/kg/day, a 15% inhibition of tumour growth was noted in the treated animals.
In the rat study with the Walker 256 carcinoma, treatment was initiated 3 days after subcutaneous inoculation of the tumour, in the form of intraperitoneal injections for 6 consecutive days. The maximum dose used was 100 mg/kg/day and the maximum tumour inhibition observed was 20%.
The Ornellas publication describes a third and fourth assay in which the lymphotrophic and transplantable Guerin T8 tumour (rat uterus epithelioma) was grafted into rats (this virulent tumour has an almost 100% positive grafting success rate, shows an absence of tumour regression and a constancy of lymphatic metastases). In the first assay with this tumour, inoculation was achieved by implanting the graft subcutaneously on the dorsum. Oral cytostatic treatment commenced 5 days after grafting (Group I) or on the day of grafting (group II). The doses of benzyl benzoate administered were based on human exposure (6g/day) and equated to 166 mg/kg/day.
In the second assay 0.5 mL of pulverised tumour material, equating to circa 0.25 g of tumour was injected under the dorsal skin rather than grafting. Oral cytostatic treatment commenced on the day of injection. Benzyl benzoate was administered at 200 mg/kg /day (Group I) or 800 mg/kg /day (Group II).
The animals were retained until death occurred naturally and the tumours and metastases were excised and weighed separately. - Analytical verification of doses or concentrations:
- no
- Details on analytical verification of doses or concentrations:
- No data
- Duration of treatment / exposure:
- The cytostatic phase was completed and then all of the negative animals were dosed on a daily basis at 800 mg/kg /day such that the total exposure time was 7 months.
- Frequency of treatment:
- daily
Doses / concentrations
- Remarks:
- Doses / Concentrations:
166 , 200 or 800 mg/kg /day
Basis:
no data
- No. of animals per sex per dose:
- 20 males per group for the cytostatic phase
- Control animals:
- yes
- Details on study design:
- Use of benzyl benzoate in palliative care of terminal cancer patients resulted in several systematic investigations of the cytostatic effects of benzyl benzoate therapies.
In the first of these assays , two tumour types were investigated - either the solid form of the Erlich carcinoma or the Walker 256 carcinoma. In the Erlich carcinoma test, treatment was initiated 5 days after implantation of the tumour, in the form of intraperitoneal injections for 6 consecutive days. At a dose of 10 mg/kg/day, a 15% inhibition of tumour growth was noted in the treated animals.
In the rat study with the Walker 256 carcinoma, treatment was initiated 3 days after subcutaneous inoculation of the tumour, in the form of intraperitoneal injections for 6 consecutive days. The maximum dose used was 100 mg/kg/day and the maximum tumour inhibition observed was 20%.
The Ornellas publication describes a third and fourth assay in which the lymphotrophic and transplantable Guerin T8 tumour (rat uterus epithelioma)was grafted into rats (this virulent tumour has an almost 100% positive grafting success rate, shows an absence of tumour regression and a constancy of lymphatic metastases). In the first assay with this tumour, inoculation was achieved by implanting the graft subcutaneously on the dorsum. Oral cytostatic treatment commenced 5 days after grafting (Group I) or on the day of grafting (group II). THe doses of benzyl benzoate administered were based on human exposure (6g/day) and equated to 166 mg/kg/day.
In the second assay 0.5 mL of pulverised tumour material, equating to circa 0.25g of tumour was injected under the dorsal skin rather than grafting. Oral cytostatic treatment commenced on the day of injection. Benzyl benzoate was administered at 200 mg/kg /day (Group I) or 800 mg/kg /day (Group II).
The animals were retained until death occurred naturally and the tumours and metastases were excised and weighed separately.
The negative animals, following completion ofte cytostatic phase were dosed daily for a period of seven months. - Positive control:
- No data
Examinations
- Observations and examinations performed and frequency:
- Cytostatic activity. Inhibition of tumour growth was assessed in rats that died naturally following tumour graft or subcutaneous injection.
Weight gains were monitored through the treatment phase.
Survival, prolongation of life, and tumour or metastases development were monitored. - Sacrifice and pathology:
- No details provided. The rats were allowed to die naturally and tumours and metastases were excised and weighed at time of death.
- Other examinations:
- No data
- Statistics:
- No data
Results and discussion
Results of examinations
- Clinical signs:
- not examined
- Mortality:
- not examined
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- increased weight gain in treated animals
- 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:
- not specified
- Clinical biochemistry findings:
- not specified
- Urinalysis findings:
- not specified
- Behaviour (functional findings):
- not specified
- Organ weight findings including organ / body weight ratios:
- not specified
- Gross pathological findings:
- not specified
- Histopathological findings: non-neoplastic:
- not specified
- Histopathological findings: neoplastic:
- not specified
- Details on results:
- Cytostatic activity
Inhibition of tumour growth in group I (200 mg/kg benzyl benzoate) was about 16%, relative to the controls. In the assay with a tumour graft rather than pulverised tumour material , the level of inhibition was 33%, the differences were attributed to differences in the assay techniques employed. In addition, the development of tumours from pulverized material is less influenced by external conditions: operative shock, local infections and early ulcerations.
Group II (800 mg/kg /day) gave higher mean values than the control group because of two excessively high figures. The individual influence can only be removed by working with a much larger number of animals and in this case it appears the outlier results were retained in the data set..
Statistical analysis showed no significant results, even when the weight of the tumours and of the metastases of each group with the control are analysed together.
Bodyweight gains
Treated animals had larger weight gains than the controls. This was taken to indicate the animals' general condition was not disturbed by dosing with benzyl benzoate, and possibly that the treated animals ate more than the control animals.
The weight gain curve of the control animals was compared with the weight gain curve of normal animals. There was a very slight gap between the two curves, which can be attributed to the graft itself.
Survival
The survival curve for rats dosed at 200 or 800 mg/kg /day showed no significant benefit for treated animals in comparison with controls. Although there was a indication of prolongation of life for group II (800 mg/kg/day), the development of tumours and of metastases was not delayed. Overall statistical analysis was not significant, when the values for each group were compared with the controls.
Numerous compounds of the aromatic series have been investigated for cytostatic or mito-inhibitory effects. Details on the mito-inhibitory activity of most of the functions of the aromatic series on the root meristem of wheat were previiously investigated and the authors noted that absence of the carboxyl function or its esterification are the only practical conditions of the mito-inhibitory activity (which resembles that of colchicine). The particular cytostatic activity of benzyl benzoate had not been investigated prior to the assays detailed in this publication.
Benzoic acid is toxic and inactive as a cytostatic agent, showing a distinction between toxicity and specific activity. However, not all aromatic acids are devoid of mito-inhibitory capacity. Furthermore, the excitomitotic action at low dose levels seems to be associated with the presence of a carboxyl function. By comparing certain physical properties of the acid and of the ester of the benzene series, the authors concluded that the salts and esters are less polar than free benzoic acid and the lower water-solubility of the salts and esters must influence their mito-inhibitory capacity
Fat-solubility also has a role in mito-inhibition . The authors concluded that there is an inverse ratio between intensity of action and solubility in water. The mito-inhibitory action cannot be explained by a purely lipoid mechanism, but a more direct action must be assumed in the synthesis of proteins.
It should also be noted that most benzoic antiseptics, and generally the commonly used external antiseptics, exert a direct action on cellular respiration, specifically on the dehydrogenases. Cytotoxicity is exerted by different effects on the cytoplasm or on the nucleus.
Effect levels
- Dose descriptor:
- other: cytostatic activity
- Effect level:
- 800 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- other: see 'Remark'
Target system / organ toxicity
- Critical effects observed:
- not specified
Applicant's summary and conclusion
- Conclusions:
- While the overall results from these investigations were generally consistent they cannot be regarded as biologically significant.
Benzyl benzoate shows definite cytostatic activity, which is limited by rapid hydrolysis in the tissues or in the duodenum.
The action by direct contact when the product is administered per os must definitely be important.
It seems to us to be logical to think that tumours localized in the upper part of the gastrointestinal tract would be the most sensitive.
In fact, clinical experience confirms this hypothesis.
However, this confirmation does not allow generalization.
Cancer is not a localized disease, and with benzyl benzoate it is not possible to achieve control of the development of malignancy.
Only clinical experience can justify or not its use as a palliative in view of the almost complete absence of toxicity. - Executive summary:
Use of benzyl benzoate in palliative care of terminal cancer patients resulted in several systematic investigations of the cytostatic effects of benzyl benzoate therapies. In the first of these assays , two tumour types were investigated - either the solid form of the Erlich carcinoma or the Walker 256 carcinoma. In the Erlich carcinoma test, treatment was initiated 5 days after implantation of the tumour, in the form of intraperitoneal injections for 6 consecutive days. At a dose of 10 mg/kg/day, a 15% inhibition of tumour growth was noted in the treated animals. In the rat study with the Walker 256 carcinoma, treatment was initiated 3 days after subcutaneous inoculation of the tumour, in the form of intraperitoneal injections for 6 consecutive days. The maximum dose used was 100 mg/kg/day and the maximum tumour inhibition observed was 20%. The Ornellas publication describes a third and fourth assay in which the lymphotrophic and transplantable Guerin T8 tumour (rat uterus epithelioma)was grafted into rats (this virulent tumour has an almost 100% positive grafting success rate, shows an absence of tumour regression and a constancy of lymphatic metastases). In the first assay with this tumour, inoculation was achieved by implanting the graft subcutaneously on the dorsum. Oral cytostatic treatment commenced 5 days after grafting (Group I) or on the day of grafting (group II). THe doses of benzyl benzoate administered were based on human exposure (6g/day) and equated to 166 mg/kg/day. In the second assay 0.5 mL of pulverised tumour material, equating to circa 0.25g of tumour was injected under the dorsal skin rather than grafting. Oral cytostatic treatment commenced on the day of injection. Benzyl benzoate was administered at 200 mg/kg /day (Group I) or 800 mg/kg /day (Group II). The animals were retained until death occurred naturally and the tumours and metastases were excised and weighed separately. The negative animals, following completion ofte cytostatic phase were dosed daily for a period of seven months.
Cytostatic activity Inhibition of tumour growth in group I (200 mg/kg benzyl benzoate) was about 16%, relative to the controls. In the assay with a tumour graft rather than pulverised tumour material , the level of inhibition was 33%, the differences were attributed to differences in the assay techniques employed. In addition, the development of tumours from pulverized material is less influenced by external conditions: operative shock, local infections and early ulcerations. Group II (800 mg/kg /day) gave higher mean values than the control group because of two excessively high figures. The individual influence can only be removed by working with a much larger number of animals and in this case it appears the outlier results were retained in the data set.. Statistical analysis showed no significant results, even when the weight of the tumours and of the metastases of each group with the control are analysed together. Bodyweight gains Treated animals had larger weight gains than the controls. This was taken to indicate the animals' general condition was not disturbed by dosing with benzyl benzoate, and possibly that the treated animals ate more than the control animals. The weight gain curve of the control animals was compared with the weight gain curve of normal animals. There was a very slight gap between the two curves, which can be attributed to the graft itself. Survival The survival curve for rats dosed at 200 or 800 mg/kg /day showed no significant benefit for treated animals in comparison with controls. Although there was a indication of prolongation of life for group II (800 mg/kg/day), the development of tumours and of metastases was not delayed. Overall statistical analysis was not significant, when the values for each group were compared with the controls.
he cytostatic activity and general systemic toxicity of benzyl benzoate was investigated following administration of 200 or 800 mg/kg bw/day to rats over a seven month period. The primary endpoint for the investigation was potential for tumour inhibition or life prolongation, no endpoints were determined for systemic toxicity other than tolerance of repeated administration of a dose of 800 mg/kg bw.
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