Registration Dossier

Toxicological information

Carcinogenicity

Currently viewing:

Administrative data

Description of key information

Under the conditions of the 2-year dermal studies, there was no evidence of carcinogenic activity of methyl trans-styryl ketone in male or female F344/N rats or in male or female B6C3F1 mice administered 10, 30, or 90 mg/kg. Administration of methyl trans-styryl ketone resulted in nonneoplastic lesions of the skin at the site of application in male and female rats and mice. 

Key value for chemical safety assessment

Carcinogenicity: via dermal route

Link to relevant study records
Reference
Endpoint:
carcinogenicity: dermal
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: This information comes from an NTP-report (TR 572), which deals with the related substance: methyl trans-styryl ketone. The quality of this report is considered to be high.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 451 (Carcinogenicity Studies)
Deviations:
not specified
Principles of method if other than guideline:
Male and female F344/N rats and B6C3F1 mice received methyl trans-styryl ketone (98.6 % pure) in feed for 3 month and dermally for 3 month or 2 years. Two-year studies were conducted to provide data for assessment of possible toxicity due to exposure to methyl trans-styryl ketone. The dermal route was chosen since this is the route for highest human exposure and due to studies demonstrating systemic exposure following dermal application to methyl trans-styryl ketone.
GLP compliance:
not specified
Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Taconic Farms, Inc. (Germantown, NY)
- Age at study initiation: Rats and mice were 5 to 6 weeks old at the beginning of the studies.
- Housing: Rats and mice were housed individually.
- Diet (e.g. ad libitum): Feed and water were available ad libitum.
- Water (e.g. ad libitum): Feed and water were available ad libitum.
- Acclimation period: Rats and mice were quarantined for 12 days before the beginning of the studies.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 72°F +/- 3 °F
- Humidity (%): 50 % +/- 15 %
- Air changes (per hr): at least 10/hour
- Photoperiod (hrs dark / hrs light): 12 hours / day
Route of administration:
dermal
Vehicle:
ethanol
Details on exposure:
TEST SITE
- Test Area: a clipped area in the interscapular region of the back

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): All doses were administered in 95% ethanol, in volumes of 0.5 or 2.0 mL/kg for rats and mice respectively.

VEHICLE
- Justification for use and choice of vehicle (if other than water):
- Amount(s) applied (volume or weight with unit): All doses were administered in 95% ethanol, in volumes of 0.5 or 2.0 mL/kg for rats and mice respectively.
- Concentration (if solution):

Groups of 50 male and 50 female rats and mice were dermally administered 0, 10, 30, or 90 mg methyl trans-styryl ketone/kg body weight per day, 5 days per week for 105 weeks. All doses were administered in 95% ethanol, in volumes of 0.5 or 2.0 mL/kg for rats and mice respectively. Single daily doses were applied 5 days per week for at least 104 weeks to a clipped area in the interscapular region of the back using a positive displacement micropipetter.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The dose formulations were prepared three times during the 3-month studies and approximately every 4 weeks during the 2-year studies by mixing methyl trans-styryl ketone and 95% ethanol to give the required concentrations. The dose formulations for the 3-month studies were stored at refrigerator temperatures under a headspace of inert gas in sealed amber glass vials for up to 42 days. The dose formulations for the 2-year studies were stored at room temperature in sealed amber glass containers for up to 42 days. A stability study of a 50 mg/mL formulation was performed by the analytical chemistry laboratory with GC. Stability was confirmed for at least 42 days for dose formulations stored in sealed amber glass containers at room temperature or below and for at least 3 hours under simulated animal room conditions if the dose containers were kept sealed except during the brief periods of removal of simulated doses. Additional stability studies of 5 and 180 mg/mL formulations were performed using GC, and stability of dose formulations at these concentrations was confirmed for at least 42 days when stored refrigerated in sealed glass containers protected from light.
Periodic analyses of the dose formulations of methyl trans-styryl ketone were conducted by the study laboratories using GC. During the 3-month studies, the dose formulations were analyzed twice; animal room samples of these dose formulations were also analyzed. All 10 formulations for rats and mice were within 10% of the target concentrations; nine of 10 and six of eight animal room samples for rats and mice, respectively, were within 10% of the target concentrations. During the 2-year studies, the dose formulations were analyzed approximately every 2 months; animal room samples were also analyzed. All 33 formulations analyzed for rats and all 33 analyzed for mice were within 10% of the target concentrations; eight of 15 and nine of 15 animal room samples for rats and mice, respectively, were within 10% of the target concentrations. Evaporation of the ethanol vehicle during the dosing period is thought to be the reason for high animal room sample analysis results.
Duration of treatment / exposure:
105 weeks
Frequency of treatment:
single daily doses, 5 days per week for 105 weeks
Remarks:
Doses / Concentrations:
0 mg/kg bw
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
10 mg/kg bw
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
30 mg/kg bw
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
90 mg/kg bw
Basis:
nominal conc.
No. of animals per sex per dose:
50
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: see below

As reported in this Technical Report, subchronic studies were conducted by the dermal and oral (feed) routes of exposure. Because there were no unique lesions observed in the oral (feed) study that would not be produced by dermal exposure, the dermal route of exposure was chosen for the 2-year studies to model the major route of human exposure based on human use patterns. The dermal route was also chosen following NTP studies on the absorption, distribution, metabolism, and excretion properties of methyl trans-styryl ketone that determined that systemic exposure to methyl trans-styryl ketone and its metabolites would occur following exposure by the dermal route. Therefore, studies by the dermal route would provide data for dermal site-of-application and systemic exposures.
Positive control:
no positive control performed
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Clinical findings were recorded during study week 5 and every 4 weeks thereafter.

DERMAL IRRITATION (if dermal study): Ye
- Time schedule for examinations: Clinical findings were recorded during study week 5 and every 4 weeks thereafter.

BODY WEIGHT: Yes
- Time schedule for examinations: All animals were weighed initially, on study day 4 (males) or 5 (females), weekly for the first 13 weeks, every 4 weeks thereafter, and at the end of the studies.
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

Complete necropsies and microscopic examinations were performed on all rats and mice. At necropsy, all organs and tissues were examined for grossly visible lesions, and all major tissues were fixed and preserved in 10% neutral buffered formalin (eyes were initially fixed in Davidson’s solution), processed and trimmed, embedded in paraffin, sectioned to a thickness of 4 to 6 μm, and stained with hematoxylin and eosin for microscopic examination. For all paired organs (e.g., adrenal gland, kidney, ovary), samples from each organ were examined.

Microscopic evaluations were completed by the study laboratory pathologist, and the pathology data were entered into the Toxicology Data Management System. For the 2-year studies, a quality assessment pathologist evaluated slides from all tumors and all potential target organs, which included the skin of rats and mice and the nose of rats.
Other examinations:
none
Clinical signs:
no effects observed
Description (incidence and severity):
Survival of all dosed groups was similar to that of the vehicle controls. In the skin at the site of application, there were increased incidences of epidermal hyperplasia and hyperkeratosis in males and females administered 30 or 90 mg/kg.
Mortality:
no mortality observed
Description (incidence):
Survival of all dosed groups was similar to that of the vehicle controls. In the skin at the site of application, there were increased incidences of epidermal hyperplasia and hyperkeratosis in males and females administered 30 or 90 mg/kg.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Mean body weights of dosed groups were within 10% of those of the vehicle control groups throughout the study.
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 examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
epidermal hyperplasia and hyperkeratosis in rats and mice and chronic inflammation and melanocytic hyperplasia in mice
Details on results:
CLINICAL SIGNS AND MORTALITY
Survival of all dosed groups of males and females was similar to that of the vehicle controls.
No clinical findings related to the administration of methyl trans-styryl ketone were observed in male or female rats.
Minor clinical observations were noted including eye abnormalities in female rats and male mice and head masses in male mice.

BODY WEIGHT AND WEIGHT GAIN
Mean body weights of dosed groups of rats were within 10% of those of the vehicle controls throughout the study

ORGAN WEIGHTS

GROSS PATHOLOGY AND HISTOPATHOLOGY
This section describes the statistically significant or biologically noteworthy changes in the incidences of neoplasms of the pancreatic islets, thymus, thyroid gland, and uterus and nonneoplastic lesions of the skin, lung, nose, mediastinal and mesenteric lymph nodes, adrenal gland, and pancreas.
Pancreatic Islets: In male rats, the incidences of pancreatic islet adenoma (vehicle control, 5/49; 10 mg/kg, 16/50; 30 mg/kg, 7/49; 90 mg/kg, 12/50) and pancreatic islet adenoma or carcinoma (combined) (8/49, 17/50, 9/49, 14/50) were increased in all dosed groups relative to the vehicle control group. However, the increased incidences of these lesions were not considered treatment related because of the lack of a dose response (only the increased incidence in the 10 mg/kg group was significant, and the trend was not significant), and because the incidences in all dosed groups were within the historical control range for studies by all routes (0% to 36%;). Also, the incidences of hyperplasia and carcinoma in the dosed groups were not significantly different from those in the vehicle control group.
Pancreatic islet adenomas were discrete, well-circum-scribed masses of islet cells that were 1 mm in diameter or larger and compressed the surrounding acinar tissue. Occasionally, a fibrous connective tissue capsule surrounded adenomas. Pancreatic islet carcinomas were characterized by neoplastic cells with varying degrees of atypia and typically invaded the surrounding fibrous capsule. Hyperplastic islets were enlarged (greater than 500 μm and less than 1,000 μm) but did not compress the adjacent parenchyma and the cells showed no evidence of atypia. There was no dose-related trend for this observed lesion, and it was not considered related to chemical administration.
Thymus: In male rats, two benign thymomas occurred in the 30 mg/kg group and one in the 90 mg/kg group; these increases were not statistically significant (0/50, 0/50, 2/46, 1/49). The benign thymomas were characterized by islands and cords of proliferating epithelial cells with varying amounts of connective tissue stroma, adipose tissue, and lymphocytes. The epithelial cells had distinct cell margins, round to oval nuclei, often with prominent nucleoli, and basophilic cytoplasm. Benign thymoma has not been seen in historical controls from dermal studies using 95% ethanol as the vehicle, and the incidence in the 30 mg/kg group exceeded the historical control range for studies by all routes (0% to 2%). However, they were not considered to be treatment related in this study for several reasons: 1) the incidence in the 30 mg/kg group exceeded the historical control range by only a single animal, 2) the increased incidence was not statistically significant, 3) the increased incidence was not dose related, and 4) benign thymomas were not seen in female rats or in mice.
Thyroid Gland: In male rats, an increased incidence of C-cell adenomas in the 90 mg/kg group resulted in a significantly positive trend test (vehicle control, 6/46; 10 mg/kg, 6/45; 30 mg/kg, 6/43; 90 mg/kg, 13/49). C-cell adenomas were well-demarcated masses of proliferating C-cells that exceeded the diameter of five contiguous follicles and compressed the adjacent parenchyma. Although not significantly increased, the incidence in 90 mg/kg males exceeded the historical control range for studies by all routes (2% to 24%); however, the incidence in the vehicle controls was below the historical control range for studies using 95% ethanol as the vehicle (18% to 20%). Furthermore, there was no evidence of carcinogenic activity in the thyroid gland of female rats or in mice, and there were no increased incidences of C-cell hyperplasia in dosed male groups compared to the vehicle control group. Consequently, the increased incidence of C-cell adenoma in the 90 mg/kg males was not consid-ered to be related to treatment.
Uterus: There was a significantly increased incidence of stromal polyps in 30 mg/kg females (10/50, 8/50, 18/50, 7/50). The increased incidence in the 30 mg/kg group was not considered treatment related for several reasons: 1) the incidence exceeded the historical control range for studies by all routes (4% to 34%) by only a single animal, 2) there was no dose-related increased incidence and the inci-dence in the 90 mg/kg group was below that of the vehicle control group, and 3) there were no similar lesions in female mice.
Skin (site of application): Significantly increased incidences of epidermal hyperplasia and hyperkeratosis occurred at the site of application in 90 mg/kg males and females; hyperkeratosis was also significantly increased in 30 mg/kg rats. The severity of epidermal hyperkeratosis was increased in the 90 mg/kg groups.
Epidermal hyperplasia was characterized by thickening of the epidermis due to increased layers of epidermal cells with three to four layers defining minimal hyperplasia and five to six layers defining mild hyperplasia. Hyperkeratosis was characterized by the relative increase in the number of layers of the stratum corneum and density of the lamellar keratin resulting in a thicker keratin layer.
Lung: There were increased incidences of alveolar epithelial hyperplasia in 30 and 90 mg/kg male rats [0/50, 0/50, 4/50 (average severity, 2.0), 8/50 (average severity, 1.8)]. Alveolar epithelial hyperplasia was characterized by increased numbers of Type II pneumocytes lining alveoli that maintained their normal architecture. The lesions were considered minimal to mild in severity. The biological significance of this lesion is unclear.
Other Organs: There were significantly increased incidences of fungal hyphae of the nasal cavity in all dosed male groups and squamous metaplasia of the respiratory epithelium in 30 and 90 mg/kg males. There were also increased incidences of chronic inflammation in 30 and 90 mg/kg males, respiratory epithelial hyperplasia in 90 mg/kg males, and respira-tory metaplasia of the olfactory epithelium in 10 and 90 mg/kg males, though the increases were not significant. The morphology of the fungal hyphae was consistent with Aspergillus sp., a common environmental contaminant. Fungal hyphae are sometimes seen in the nasal cavity in NTP studies and are not generally considered a direct effect of exposure to the test article. In this study, the fungal organisms are considered to be an opportunistic invader and secondary to the nasal epithelial damage (evidenced by the nasal epithelial lesions). The dose-responsive incidence pattern of the fungal hyphae seen in this study supports this conclusion.
There were statistically significant increased incidences of lymphoid hyperplasia of the mediastinal lymph node in 30 mg/kg males (2/25; 8/30, 7/21, 6/26). There were also significantly increased incidences of lymphoid hyperplasia of the mesenteric lymph node in 10 and 90 mg/kg males (3/50, 12/50, 7/50, 11/50). In females, there was a significantly increased incidence of lymphoid hyperplasia of the mesenteric lymph node in the 90 mg/kg group (11/50, 12/49, 13/50, 19/50). Lymphoid hyperplasia of the mesenteric lymph nodes is a common lesion in laboratory rodents in NTP studies and, therefore, is considered a background lesion that is not related to treat-ment. Furthermore, because collection and examination of the mediastinal lymph nodes are required only in NTP inhalation studies, they were serendipitously pre-sent in some sections of lung but were not present in all lung sections and therefore were not evaluated for all animals in the study. Additionally, the frequency with which lymphoid hyperplasia occurs in the mediastinal lymph nodes is unknown. As a consequence, the data for the mediastinal lymph nodes cannot be reliably interpreted in this study.
In female rats, there were increased incidences of accessory adrenal cortical nodules, which reached significance in the 10 and 90 mg/kg groups (vehicle control, 10/50; 10 mg/kg, 19/50; 30 mg/kg, 16/50; 90 mg/kg, 24/50). These lesions consist of an architec-turally normal focus (or nodule) of adrenocortical tissue and typically include a capsule and one or more adrenocortical zones. They may be located within or adjacent to the adrenal capsule, or in the periadrenal or perirenal adipose tissue. These lesions are common in F344/N rats and are not considered to be related to methyl trans-styryl ketone administration.
In female rats, there were increased incidences of pancreatic cysts in all dosed groups but only the increase in the 90 mg/kg group was significant (13/49, 16/50, 15/50, 30/49). Pancreatic cysts were characterized by dilated clusters of pancreatic ducts. These were typically associated with pancreatic atrophy and were not considered a treatment-related finding.
Relevance of carcinogenic effects / potential:
Under the conditions of these 2-year dermal studies, there was no evidence of carcinogenic activity* of methyl trans-styryl ketone in male or female F344/N rats or in male or female B6C3F1 mice administered 10, 30, or 90 mg/kg. Administration of methyl trans-styryl ketone resulted in nonneoplastic lesions of the skin at the site of application in male and female rats and mice.
Dose descriptor:
NOAEL
Remarks on result:
not determinable
Remarks:
no NOAEL identified. Effect type:carcinogenicity (migrated information)

Groups of 50 male and 50 female rats were dermally administered 0, 10, 30, or 90 mg methyl trans-styryl ketone/kg body weight in 95% ethanol, 5 days per week for 105 weeks. Survival of all dosed groups was similar to that of the vehicle controls. Mean body weights of dosed groups were within 10% of those of the vehicle control groups throughout the study. In the skin at the site of application, there were increased incidences of epidermal hyperplasia and hyperkeratosis in males and females administered 30 or 90 mg/kg.

Under the conditions of these 2-year dermal studies, there was no evidence of carcinogenic activity of methyl trans-styryl ketone in male or female F344/N rats or in male or female B6C3F1 mice administered 10, 30, or 90 mg/kg. Administration of methyl trans-styryl ketone resulted in nonneoplastic lesions of the skin at the site of application in male and female rats and mice.

The 2-year studies showed that the primary site of toxicity was the skin at the site of application. The principal effects of dermal administration of methyl trans-styryl ketone were epidermal hyperplasia and hyperkeratosis in rats and mice and chronic inflammation and melanocytic hyperplasia in mice. Sustained cell proliferation resulting in epidermal hyperplasia has been associated with tumor formation in skin and other tissues. Methyl trans-styryl ketone is a mutagen in the Ames/Salmonella assay, and in the presence of chronic cell proliferation, mutagenic compounds often induce carcinogenesis. However, even in the presence of chronic hyperplasia, methyl trans-styryl ketone did not induce skin neoplasms. Other chemicals that produced chronic skin toxicity and compensatory cell proliferation but did not elicit a tumorigenic response include 1,2-dibromo-2,4-dicyanobutane (NTP, 2010), benzethonium chloride (NTP, 1995), and sodium xylenesulfonate (NTP, 1998). Overall, even though methyl trans-styryl ketone was mutagenic and produced compensatory cell proliferation following dermal administration, no neoplasms were observed at the site of application. Because methyl trans-styryl ketone was eliminated more rapidly than it was absorbed, mass balance studies indicated no bioaccumulation is likely, and systemic neoplasms were not produced in a dose-related fashion, any systemic neoplasms observed in the current study were considered spontaneous and not treatment related.

Table 2 - Summary of the 2-Year Carcinogenesis and Genetic Toxicology Studies of Methyl trans-Styryl Ketone
  Male F344/N Rats Female F344/N Rats Male B6C3F1 Mice Female B6C3F1 Mice
Doses in 95% ethanol by dermal application 0, 10, 30, or 90 mg/kg 0, 10, 30, or 90 mg/kg 0, 10, 30, or 90 mg/kg 0, 10, 30, or 90 mg/kg
Body weights Dosed groups were within 10% of the vehicle control group Dosed groups were within 10% of the vehicle control group Dosed groups were within 10% of the vehicle control group Dosed groups were within 10% of the vehicle control group
Survival rates 27/50, 30/50, 22/50, 30/50 30/50, 24/50, 27/50, 26/50 34/50, 35/50, 35/50, 38/50 37/50, 39/50, 31/50, 37/50
Nonneoplastic effects Skin: site of application, epidermis, hyperplasia (0/50, 3/50, 3/50, 29/50); site of application, hyperkeratosis (20/50, 13/50, 33/50, 47/50) Skin: site of application, epidermis, hyperplasia (1/50, 1/50, 5/50, 39/50); site of application, hyperkeratosis (9/50, 11/50, 20/50, 47/50) Skin: site of application, epidermis, hyperplasia (7/50, 13/50, 29/50, 37/50); site of application, hyperkeratosis (17/50, 19/50, 26/50, 40/50); site of application, inflammation, chronic (1/50, 8/50, 15/50, 43/50); site of application, hyperplasia, melanocyte (0/50, 1/50, 23/50, 44/50) Skin: site of application, epidermis, hyperplasia (7/50, 11/50, 31/50, 33/50); site of application, hyperkeratosis (9/50, 16/50, 37/50, 36/50); site of application, inflammation, chronic (7/50, 11/50, 33/50, 38/50); site of application, hyperplasia, melanocyte (3/50, 3/50, 33/50, 36/50)
Neoplastic effects None None None None
Level of evidence of carcinogenic activity No evidence No evidence No evidence No evidence
Genetic toxicology
Bacterial gene mutations: Positive inS. typhimuriumstrain TA100 with S9, negative without S9; negative in strain TA98 with or without S9 and inE.colistrain WP2 uvr4/pKM101 without S9. Inconsistent responses inE.coliwith S9.
Micronucleated erythrocytes
Mouse peripheral blood in vivo(feed exposure): Negative
Mouse peripheral blood in vivo(dermal exposure): Negative

Table 3
Survival of Rats in the 2-Year Dermal Study of Methyl trans-Styryl Ketone
  Vehicle Control 10 mg/kg 30 mg/kg 90mg/kg
Male        
Animals initially in study 50 50 50 50
Moribund 15 14 19 17
Natural deaths 8 6 9 3
Animals surviving to study termination 27 30d 22 30d
Percent probability of survival at end of studya 54 60 44 60
Mean survival (days)b 683 678 672 691
Survival analysisc P=0.654N P=0.719N P=0.369 P=0.632N
Female
Animals initially in study 50 50 50 50
Moribund 10 14 13 16
Natural deaths 10 12 10 8
Animals surviving to study termination 30 24 27 26
Percent probability of survival at end of study 60 48 54 52
Mean survival (days) 683 669 675 663
Survival analysis P=0.745 P=0.240 P=0.654 P=0.463
a  Kaplan-Meier determinations
b  Mean of all deaths (uncensored, censored, and terminal sacrifice).
c  The result of the life table trend test (Tarone, 1975) is in the vehicle control column, and the results of the life table pairwise comparisons (Cox, 1972) with the vehicle controls are in the dosed group columns. A negative trend or lower mortality in a dose group is indicated byN.
d  Includes one animal that died during the last week of the study

Table 4
Incidences of Nonneoplastic Lesions of the Skin (Site of Application) in Rats in the 2-Year Dermal Study of Methyltrans-Styryl Ketone
  Vehicle Control 10 mg/kg 30mg/kg 90 mg/kg
Male        
Number Examined Microscopically 50 50 50 50
Epidermis, Hyperplasiaa 0 3 (1.0)b 3 (1.0) 29** (1.0)
Hyperkeratosis 20 (1.1) 13 (1.0) 33** (1.2) 47** (2.4)
Female
Number Examined Microscopically 50 50 50 50
Epidermis, Hyperplasia 1 (1.0) 1 (1.0) 5 (1.0) 39** (1.2)
Hyperkeratosis 9 (1.1) 11 (1.0) 20* (1.0) 47** (2.3)
*  Significantly different (P<0.05) from the vehicle control group by the Poly-3 test
** P<0.01
a  Number of animals with lesion
b  Average severity grade of lesions in affected animals: 1=minimal, 2=mild, 3=moderate, 4=marked

Table 5
Incidences of Nonneoplastic Lesions of the Nose in Male Rats in the 2-Year Dermal Study of Methyltrans-Styryl Ketone
  Vehicle Control 10mg/kg 30mg/kg 90mg/kg
Number Examined Microscopically 50 49 50 50
Fungusa 2 9* 11** 12**
Inflammation, Chronic 25(1.6)b 24 (2.0) 31 (1.7) 30 (2.1)
Olfactory Epithelium, Metaplasia,
Respiratory 7 (1.3) 13 (1.3) 6 (1.8) 12 (1.5)
Respiratory Epithelium, Hyperplasia 19 (1.4) 18 (1.9) 18 (1.7) 23 (2.0)
Respiratory Epithelium, Metaplasia,
Squamous 3 (2.3) 7 (2.1) 15** (2.3) 13** (2.1)
*  Significantly different (P<0.05) from the vehicle control group by the Poly-3 test
** P<0.01
a  Number of animals with lesion
b  Average severity grade of lesions in affected animals: 1=minimal, 2=mild, 3=moderate, 4=marked
Conclusions:
Under the conditions of these 2-year dermal studies, there was no evidence of carcinogenic activity of methyl trans-styryl ketone in male or female F344/N rats or in male or female B6C3F1 mice administered 10, 30, or 90 mg/kg.
Administration of methyl trans-styryl ketone resulted in nonneoplastic lesions of the skin at the site of application in male and female rats and mice.
Executive summary:

Methyl trans-styryl ketone was studied for its effects on male and female rats and mice to identify potential toxic or cancer-related hazards. The solutions containing methyl trans-styryl ketone in ethanol were applied on the backs of male and female rats. Groups of 50 male and female rats received 10, 30, or 90 milligrams of methyl trans-styryl ketone per kilogram of body weight 5 days per week for 2 years. Groups of animals receiving ethanol alone served as the control groups. At the end of the study tissues from more than 40 sites were examined for every animal. The only effects observed were in the skin at the site where the chemical was applied. Occurrences of epidermal hyperplasia and hyperkeratosis were greatly increased in all animal groups receiving 90 mg/kg methyl trans-styryl ketone. It is concluded that while exposure to methyl trans-styryl ketone caused skin lesions including hyperplasia, hyperkeratosis, and inflammation at the site of application, the chemical did not cause cancer in male or female rats.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Study duration:
chronic
Species:
other: rat/mouse
Quality of whole database:
This information comes from an NTP-report (TR 572), which deals with the related substance: methyl trans-styryl ketone.

Additional information

Methyl trans-styryl ketone was studied for its effects on male and female rats and mice to identify potential toxic or cancer-related hazards. The solutions containing methyl trans-styryl ketone in ethanol were applied on the backs of male and female animals. Groups of 50 animals of each sex received 10, 30, or 90 milligrams of methyl trans-styryl ketone per kilogram of body weight 5 days per week for 2 years. Groups of animals receiving ethanol alone served as the control groups. At the end of the study tissues from more than 40 sites were examined for every animal. The only effects observed were in the skin at the site where the chemical was applied. Occurrences of epidermal hyperplasia and hyperkeratosis were greatly increased in all animal groups receiving 90 mg/kg methyl trans-styryl ketone. Chronic inflammation was also seen in the skin of male and female mice receiving methyl trans-styryl ketone.

It is concluded that while exposure to methyl trans-styryl ketone caused skin lesions including hyperplasia, hyperkeratosis, and inflammation at the site of application, the chemical did not cause cancer in male or female rats or mice.

Justification for selection of carcinogenicity via dermal route endpoint:
Only one study is available.

Justification for classification or non-classification

According to the European regulation (EC) No. 1272/2008 the test material does not meet the criteria for classification and will not require labelling.