Registration Dossier

Administrative data

Description of key information

Repeated dose toxicity: oral

Based on all the available data, it was observed that the test chemical did not induce any systemic and local toxicity in the tested animals. Therefore, the test chemical is not likely to be 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 test chemical, which is reported as 0.00268 mm Hg. Also considering the particle size distribution of the substance, the majority of the particles were found to be in the size of 105.0 micrometer which is much larger size range compared to the inhalable particulate matter. Thus, exposure to inhalable dust, mist and vapour of the test chemical is highly unlikely. Therefore this study is considered for waiver.

Repeated Dose Toxicity: Dermal

The acute toxicity value for the test chemical (as provided in section 7.2.3) is >5000 mg/kg body weight. Also, given the use of the chemical as flavour and fragrance agents; repeated exposure by the dermal route is unlikely. Thus, it is expected that the test chemical shall not exhibit 28 day repeated dose toxicity by the dermal route. In addition, there is no data available that suggests that the test chemical shall exhibit repeated dose toxicity by the dermal route. Hence this end point was considered for waiver.

Key value for chemical safety assessment

Toxic effect type:
dose-dependent

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
secondary literature
Justification for type of information:
Data is from secondary source
Qualifier:
no guideline available
Principles of method if other than guideline:
The objective of this study was to evaluate the chronic toxicity of repeated administration of the test chemical in rats.
GLP compliance:
not specified
Specific details on test material used for the study:
- Name of test material (as cited in study report): Cinnamyl alcohol
- IUPAC name : 3-Phenylprop-2-en-1-ol
- Molecular Formula: C9H10O
- Molecular Weight: 134.177 g/mol
- Smiles: c1(ccccc1)/C=C/CO
- InChI: 1S/C9H10O/c10-8-4-7-9-5-2-1-3-6-9/h1-7,10H,8H2/b7-4+
- Substance type: Organic
- Physical state: Crystalline solid
Species:
rat
Strain:
not specified
Details on species / strain selection:
No Data Available
Sex:
not specified
Details on test animals and environmental conditions:
No Data Available
Route of administration:
oral: unspecified
Details on route of administration:
No Data Available
Vehicle:
not specified
Details on oral exposure:
No Data Available
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
No Data Available
Duration of treatment / exposure:
17 weeks
Frequency of treatment:
Intermittent
Dose / conc.:
6 366 mg/kg bw/day (nominal)
Remarks:
Dose Group
No. of animals per sex per dose:
No data available
Control animals:
not specified
Details on study design:
No Data Available
Positive control:
No Data Available
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: Not specified
- Time schedule: Not specified

BODY WEIGHT: Not specified
- Time schedule for examinations: Not specified

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Not specified
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Not specified
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Not specified

FOOD EFFICIENCY: Not specified
- 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: No data available
- Anaesthetic used for blood collection: Not specified
- Animals fasted: Not specified
- How many animals: Not specified
- Parameters checked in table [No.?] were examined.: TP, bilirubin, cholesterol

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Not specified
- Animals fasted: Not specified
- How many animals: Not specified
- Parameters checked in table [No.?] were examined.: Enzyme inhibition, induction, or change in blood or tissue levels - other Enzymes

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: Not specified
Sacrifice and pathology:
GROSS PATHOLOGY: Not specified

HISTOPATHOLOGY: Not specified
Other examinations:
No Data Available
Statistics:
No Data Available
Clinical signs:
not specified
Mortality:
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:
effects observed, treatment-related
Description (incidence and severity):
changes in serum composition (e.g. TP, bilirubin, cholesterol) was observed.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
Enzyme inhibition, induction, or change in blood or tissue levels was observed.
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:
not specified
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Details on results:
No Data Available
Dose descriptor:
LOAEL
Effect level:
6 366 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
not specified
Basis for effect level:
haematology
clinical biochemistry
Remarks on result:
not determinable due to absence of adverse toxic effects
Critical effects observed:
not specified
Conclusions:
Based on all the observations and results, it was concluded that under the condition of the study, LOAEL for the test chemical was considered to be 6366 mg/kg.
Executive summary:

A chronic repeated dose oral toxicity study was conducted using rat species to evaluate the effects after long term exposure of the test chemical. The test chemical was administered orally to rats intermittently for 17 weeks. The animals used in the study were examined with respect to clinical pathology (viz. haematology and clinical chemistry). It was observed that there were changes in serum composition (e.g. TP, bilirubin, cholesterol), biochemical - enzyme inhibition, induction, or change in blood or tissue levels. The compromised biochemical parameters were attributed to the administration of the test chemical. Therefore, based on all the above observations and results, it was concluded that under the condition of the study, LOAEL for the test chemical was considered to be 6366 mg/kg.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
The data is from a Klimisch 1 datasource and provides a robust study summary.

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: inhalation
Data waiving:
exposure considerations
Justification for data waiving:
a short-term toxicity study does not need to be conducted because exposure of humans via inhalation in production and/or use is not likely as based on the provided thorough and rigorous exposure assessment
Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: inhalation
Data waiving:
exposure considerations
Justification for data waiving:
a short-term toxicity study does not need to be conducted because exposure of humans via inhalation in production and/or use is not likely as based on the provided thorough and rigorous exposure assessment
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

Data summarized for the repeated dose toxicity studies of the test chemical is as follows:

Study 1:

A 28 days repeated dose toxicity study was performed under GLP conditions in accordance with the OECD TG 407 using male and female Wistar rats. In this study, the animals of age 6 -7 weeks were used. 5 animals per sex per dose were used in the study. A total of 6 dose groups were selected for the study viz. 0 mg/kg bw/day (control group), 250 mg/kg bw (Low Dose Group), 500 mg/kg bw (Intermediate Dose Group) and 1000 mg/kg bw (High Dose Group). Further, two recovery groups were also included in the study in order to check the reversibility of the effects that are observed due to the administration of the test chemical, namely, Control Group Recovery (0 mg/kg bw/day) and High Dose Recovery (1000 mg/kg bw/day). 5 animals per sex per dose were used in the study. The animals were treated daily once via oral gavage route. The vehicle used for the study was distilled water. The parameters that were checked in the study were clincal signs, clinical observations (behavioral parameters), body weight and feed consumption, hematological and clinical biochemistry parameters, urinalysis, absolute and relative organ weights, gross pathology and histopathology. The animals of main groups were dosed consecutively for 28 days and on day 29, they were sacrificed. The animals were kept in metabolic cages a day prior to sacrifice in order to collect urine for urinalysis. Before sacrifice, blood was collected from all the animals from all the dose groups, using isofluorane anesthesia for hematological and biochemistry parameters. The same procedure was followed for recovery group animals before sacrifice on day 43. The in-life observations showed that No clinical signs were observed in any of the vehicle control(G1), low(G2), intermediate (G3), high dose(G4), vehicle control recovery (G1R) and recovery high dose (G4R) group animals. No mortality was observed in vehicle control (G1), low (G2), intermediate (G3), high dose (G4), recovery control (G1R) and recovery high dose (G4R) group animals. No adverse effect on body weight was observed for treated groups when compared with control group. No significant and toxicologically relevant changes in the body weight between treated and control group were observed. No significant changes related to the test chemical in the feed consumption was observed in any of the treated and recovery groups when compared with vehicle control (G1) group. No adverse effects on opthalmological findings were observed during the study. In hematological parameters, males in high dose group (G4) were showed decrease in WBC count when compared with control group. However, no changes in the females were observed. Treatment with the test chemical had no effects on both male and female animals with respect to hematological parameters viz RBC, Hb, MCV, MCHC, PCV, PLT, PT and APTT. In males, when compared with control group, bilirubin levels increased in low dose group (G2), ALT levels decreased in high dose, total protein levels decreased in low dose and intermediate dose compared to control, albumin levels increased in low, intermediate and high dose, Globulin levels decreased in low dose, intermediate and high dose, cholesterol levels increased in low dose and high dose. In females, when compared with control group, creatinine levels decreased in intermediate dose group (G3), bilirubin levels decreased in high dose (G4), triglyceride levels increased in intermediate dose (G3). All the recovery group male and female animals showed no effect on biochemical parameters. This change in the biochemical parameters is considered to have arisen by chance or caused by slightly higher/lower control values and not to represent a change of any biological significance. No significant changes in any of the treated groups and recovery groups were observed in urinalysis findings. No significant and test chemical related findings were observed during functional observation battery. There were no test chemical related changes in the in absolute and relative organ weights in both sexes in main group and recovery group animals. No test chemical related effects were observed during the necropsy of the animals in any organs in main groups or also in the recovery group. No test chemical related changes in the histopathology was observed in the animals of all dose groups in main groups or also in the recovery group. Therefore, based on all the available data, it was observed that the test chemical did not induce any systemic and local toxicity in the tested animals in main groups and recovery groups, respectively. Thus, on the basis of all the observations and results, it was concluded that the NOAEL for the test chemical was 1000 mg/kg bw/day.

 

Study 2:

The chronic toxicity study was conducted to evaluate the toxicity effect of the test chemical in rats. Daily doses of 53.5 mg/kg bw of the test chemical, equivalent to 2% of the LD50 for the respective substance, were each administered in a sunflower oil solution (0.2 ml/100 g bw) to white rats (12 males/group, strain not identified) by oral intubation once daily for 4 months. Liver function tests were performed on animals at days 40 and 140. Increased (26%) blood serum fructose diphosphate aldolase activity was observed in the test chemical at day 140. Activity of serum cholinesterase and alanine aminotransferase, as well as levels of blood serum SH groups, exhibited no change compared to controls. It was concluded that the test chemical did not caused any significant pathological changes in the liver of rats. Thus, under the condition of the study, the no observed adverse effect level (NOAEL) from a 4 month rat study was considered to be 53.5 mg/kg bw.

Study 3:

A chronic repeated dose oral toxicity study was conducted using rat species to evaluate the effects after long term exposure of the test chemical. The test chemical was administered orally to rats intermittently for 17 weeks. The animals used in the study were examined with respect to clinical pathology (viz. haematology and clinical chemistry). It was observed that there were changes in serum composition (e.g. TP, bilirubin, cholesterol), biochemical - enzyme inhibition, induction, or change in blood or tissue levels. The compromised biochemical parameters were attributed to the administration of the test chemical. Therefore, based on all the above observations and results, it was concluded that under the condition of the study, LOAEL for the test chemical was considered to be 6366 mg/kg.

Study 4:

In a chronic toxicity oral study, the test chemical was evaluated in male and female Osborne-Mendel rats where the test chemical was administered by diet at concentration of 0, 1000, 2500 or 10000 ppm (0, 5, 125 or 500 mg/kg body weight). No effects were noted when the rats were exposed to 2500 ppm (125 mg/kg body weight) while treatment with 10000 ppm (500 mg/kg body weight) resulted in slight hepatic cell swelling and slight hyperkeratosis of squamous portion of the stomach.No other microscopic effects were observed on any other organs at all the doses. No effects on subsequent lower doses were observed.Therefore,Based on all the observations and results, it was concluded that the No Observed Adverse Effect Level (NOAEL) was considered to be 125 mg/kg when Osborne-Mendel rats were exposed to the test chemical for 16 weeks.

Study 4:

A combined repeated dose chronic and carcinogenicity study of the test chemical inF344/N male and female rats was performed to evaluate the effect of the long term exposure of the test chemical. In this chronic study, the vehicle control treated and dietary doses equivalent to 50, 100 and 200mg/kg/bw/day was exposed to male and female F344/N rats. The exposure of test chemical to the animals was performed for105 (Male) and 106 (females) weeks. The animals were observed throughout the study duration for mortality, change in body weight, food consumption, clinical signs and urinalysis, gross and histopathology at the end of the study.Mortality of 200 mg/kg males was greater than that of the vehicle control group but not significantly however mortality in other exposed groups of males and of exposed females was similar to that of the vehicle control groups. No clinical signs of toxicity observed in any animals exposed to test chemical. In the body weight study mean body weights of 200mg/kg males were less than those of the vehicle controls throughout the study however in 200mg/kg females body weight were significantly less after week 18 as compared to control treated group.Mean body weights of 100mg/kg males were less afterweek 94 compared to control treated group. At the beginning and end of the study feed consumption by 100mg/kg and 200mg/kg males and 200mg/kg females was less than that by the vehicle controls.In urinalysis Hippuric acid excretion in urine expressed as the hippuric acid to creatinine ratio was proportional to dose indicating that neither absorption, metabolism, nor excretion was saturated in either male or female rats exposed to dosed feed containing 50mg/kg to 200mg/kg of test chemical. No visible lesions were observed in gross pathology However in histopathology The incidences of adenoma of the preputial gland (vehicle control, 5/50; 50mg/kg, 1/49; 100mg/kg, 2/50; 200 mg/kg, 0/50) and prostate gland (4/50, 0/49, 0/49, 0/50) in 200 mg/kg males were significantly decreased compared to those in the vehicle controls. The incidence of mononuclear cell leukemia in 200mg/kg males was significantly decreased (18/50, 15/50, 21/50, 9/50), was considered not related to test chemical exposure.Therefore, based on all the available observations and results, it was concluded that the NOAEL for chronic study (2 years) of test chemical in F344/N male and female rats was considered to be 100 mg/kg.

Study 5:

In a combined repeated and reproductive developmental toxicity study, wistar male and female rats were treated with the test chemical in the concentration of 0, 308, 556 and 1000 mg/kg bw orally by gavage in Corn oil for 63 days. No mortality or morbidity and apparent treatment related clinical signs were observed any of the groups of animals throughout the study period. Detailed clinical examinations like Home cage observation, Handling observation and Open field observation of all animals were observed to be normal during study period. Number of rear, urine pools, fecal bolus in animals of all the test groups of both the sexes was comparable and did not show any treatment related significant difference as compared to the respective control groups. Body weight, percent body weight changes and feed consumption in animals of all the test groups of both the sexes was comparable and did not show any treatment related significant difference as compared to the respective control groups. The sensory reactivity measurements, Foot splay, fore limb and hind limb grip strength parameters and Motor activity were comparable and no treatment related changes were revealed in any of the animals of all treated groups as compare to the repective control groups. Similarly,No treatment related changes were observed inhematological and clinical chemistry parameters of treated male and female rats as compared to control.No test item related changes in estrous cyclicity and precoital interval were observed. There was statistically significant decrease in G3 (556 mg/kg body weight) as compared to control G1 (0 mg/kg body weight). This is not dose dependent hence not considered as treatment related. There was no statistically significant difference between the control and treatment groups in the maternal and pups parameters, except markedly decreased pregnancy index / fertility index in G4 (1000 mg/kg body weight), which was considered to be treatment related.In addition, no significant change in organ weight,External and visceral examination of treated and recovery groups as compared to control.Focal to multifocal minimal lymphocytic infiltration of male and female and focal minimal necrosis in male in liver, focal minimal lymphocytic infiltration of male and female and focal mild mineralization in female in kidney, multifocal minimal lymphocytic infiltration in male and female andfocal minimal histiocyte infiltration in female lungs, focal minimal lymphocytic infiltration in heart of male, focal minimal aneurysm in aorta of male, focal moderate cystic dilationof cortex of Mandibular Lymph Node in female,focal mildsquamous epitheliumhyperplasia stomach of female, focal moderate cystic dilation of cortex in Mesenteric lymph node, focalto diffuse minimal to mild extramedullary hematopoesis in spleen and mild to moderate atrophy in Thymus of female, focal to multifocal minimal to moderate Neutrophilic/lymphocytic infiltration of Trachea of male and female, unilateral accessory adrenocortical tissue of Adrenals and focal to multifocal minimal to mildretention of mature sperm,focal minimal to milddegeneration of seminiferous tubules,focal to multifocal minimalsloughing of Pachytene Spermatocyte,focal minimalsloughing of round spermatid andfocal mildinfiltration of multinucleated giant cells of Testes,multifocal mildneutrophilic/lymphocytic infiltration of Seminal Vesicles and focal moderate necrotic debris in lumen of Prostate observed in male rats, multifocal to diffuse mild reduction of stromal cells, focal moderate necrosis, multifocal mild to moderate nodular hyperplasia of Uterus and focal minimal lymphocytic infiltration of Cervix in female rats were observed. Lesions observed in liver, kidneys, lungs, heart, aorta, stomach, lymph nodes, spleen, thymus, trachea, adrenal gland and reproductive organs of high dose treated group rats are well comparable with respective control group rats and exhibited no dose relationship Therefore, No Observed Adverse Effect Level (NOAEL) is considered to be 1000 mg / kg body weight when Wistar male and female rats were orally treated with the test chemical.

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 test chemical, which is reported as 0.00268 mm Hg. Also considering the particle size distribution of the substance, the majority of the particles were found to be in the size of 105.0 micrometer which is much larger size range compared to the inhalable particulate matter. Thus, exposure to inhalable dust, mist and vapour of the test chemical is highly unlikely. Therefore this study is considered for waiver.

Repeated Dose Toxicity: Dermal

The acute toxicity value for the test chemical (as provided in section 7.2.3) is >5000 mg/kg body weight. Also, given the use of the chemical as flavour and fragrance agents; repeated exposure by the dermal route is unlikely. Thus, it is expected that the test chemical shall not exhibit 28 day repeated dose toxicity by the dermal route. In addition, there is no data available that suggests that the test chemical 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 test chemical is not likely to be classified as a toxicant after repeated exposure.