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Carcinogenicity

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Carcinogenicity: via oral route

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Endpoint:
carcinogenicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2007
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)
Deviations:
yes
Remarks:
not considered to have compromised the validity or integrity of the study
Principles of method if other than guideline:
There were following deviations to the protocols:
- the temperature and relative humidity in the animal room were sometimes out of the target ranges
- the analysis of the dietary concentrations was performed in excess in week 104.
- for female D29585, only one sampled of mass was performed instead of two for masses 2110, 2118 and 1205
- for male D29335, because of a technical problem, macroscopic examination was performed after fixation with a pathologist
- rectum was not sampled for female D29626.
These deviations were not considered to have compromised the validity or integrity of the study.
GLP compliance:
yes
Specific details on test material used for the study:
- Purity: ca. 50% C12-16-benzyldimethylammonium chloride (CAS no.: 68424-85-1) in water.
- Batch no.: 667H3002
- Specification: C12-16 BKC (C12: 72.0%; C14: 27.7%; C16: 0.3%).
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Route of administration:
oral: feed
Duration of treatment / exposure:
2 year
Remarks:
Doses / Concentrations:
0, 1000, 2000, 4000 ppm of test substance (i.e., equivalent to 0, 500, 1000 and 2000 ppm of active substance)
Basis: nominal in diet
No. of animals per sex per dose:
- 20 males and 20 females of each group were used for toxicological investigations and were treated for 52 weeks.
- 50 males and 50 females of each group were used to investigate the carcinogenic potential and were treated for 104 weeks.
- A group of 60 male and 60 female rats received untreated diet under the same experimental conditions, and acted as toxicology (10 males and 10 females) and carcinogenicity (50 males and 50 females) control group.
Control animals:
yes, plain diet
Details on study design:
Post-exposure period: None
Observations and examinations performed and frequency:
- Animals were checked at least twice daily for mortality and clinical signs. In addition, detailed clinical observations were made once a week. After 6 months of treatment, all animals were palpated every 2 weeks in order to record the time of onset, location, size, appearance and progression of palpable masses. Body weights were recorded once during the pre-treatment period, on Day 1 and then once a week during the first 13 weeks of the treatment period and then once every 4 weeks until the end of the study. Food consumption was recorded once a week during the first 13 weeks of the study, and then over 7-d periods once every 3 months between weeks 14 and 25, and thereafter once per month until the end of the study.
- Haematological, blood biochemical investigations and urinalysis were performed on all surviving animals of the toxicology sub-groups in weeks 12, 26 and 52. During weeks 52, 78 and 104, differential white blood cell counts were determined for all surviving animals of the control and high-dose carcinogenicity sub-groups.
Sacrifice and pathology:
Surviving animals were killed at the end of the 52-week treatment period for the toxicology sub-groups and at the end of the 104-week treatment period for the carcinogenicity sub-groups. All animals were submitted for a full macroscopic post-mortem examination. Designated organs were weighed and selected tissue specimens were preserved. A microscopic examination was performed on all masses, and on designated tissues of animals from the control sub-groups and from the sub-groups treated at 4000 ppm of test substance sacrificed at the end of the 52 or 104-week treatment periods, and from all animals that died prematurely.
Clinical signs:
no effects observed
Description (incidence and severity):
In the toxicology sub-groups: No treatment-related clinical signs were observed during the 52-week treatment period
In the toxicology sub-groups: No test substance-related clinical signs were observed in any treated group
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Description (incidence):
In the toxicology sub-groups: No treatment-related deaths or premature sacrifices occurred during the 52-week treatment period
In the carcinogenicity sub-groups: Survival rate in animals treated with the test substance was not statistically different from to controls. Further, mortality was comparable in terms of time of occurrence and cause
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
In the toxicology sub-groups: The mean body weight was significantly lower in the males treated at 4000 ppm than in the controls from week 2 to week 50, due to a lower body weight gain over all the study (from -15% between weeks 0 and 4, to finally -21% between weeks 0 and 50). This lower body weight gain was attributable to a slightly to moderately lower food consumption (ranging from 73.3 to 94.4% of that of controls over the toxicology study), with statistically significant differences occurring during several weeks
In the carcinogenicity sub-groups: The mean body weight was significantly lower in the males and females treated at 4000 ppm than in the controls from week 2 to week 13, due to a lower body weight gain (-14% and -10% for males and females, respectively). This lower body weight gain was attributable to slightly to moderately lower food consumption compared with controls, with statistically significant differences occurring during several weeks. From week 13 to termination, the body weight of the males treated at 4000 ppm was still significantly lower than that of control animals, and this was correlated to a 18% lower body weight gain over the 104 weeks when compared with controls, while the body weight and body weight gain of all other treated animals were in the range of control values
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
In the toxicology sub-groups: Slightly to moderately lower food consumption (ranging from 73.3 to 94.4% of that of controls over the toxicology study), with statistically significant differences occurring during several weeks
In the carcinogenicity sub-groups: Slightly to moderately lower food consumption compared with controls, with statistically significant differences occurring during several weeks. F
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Description (incidence and severity):
In the toxicology sub-groups: Haematological parameters were not affected by the treatment at any dose-level
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
In the toxicology sub-groups: Blood biochemistry parameters were not affected by the treatment at any dose-level
In the carcinogenicity sub-groups: There were no significant differences in the differential white blood cell parameters of males and females treated at 4000 ppm, when compared with controls, whatever the sampling time (weeks 52, 78 and 104)
Urinalysis findings:
no effects observed
Description (incidence and severity):
In the toxicology sub-groups: Urinalysis parameters were not affected by the treatment at any dose-level
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Description (incidence and severity):
In the carcinogenicity sub-groups: There were no differences in the number and localization of palpable masses in test-treated animals and controls
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
In the toxicology sub-groups: There were no relevant histopathological findings
In the carcinogenicity sub-groups: No non-neoplastic lesions were found which were considered to represent a treatment-related effect
Histopathological findings: neoplastic:
no effects observed
Description (incidence and severity):
In the carcinogenicity sub-groups: The administration of the test substance did not induce neoplastic changes under the conditions of this study
Key result
Dose descriptor:
NOEL
Remarks:
carcinogenicity
Effect level:
4 000 ppm
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: 4000 ppm (i.e., equivalent to 97 and 119 mg a.i./kg bw/day for male and female respectively) in SD rats for two years
Dose descriptor:
NOEL
Remarks:
systemic effects
Effect level:
1 000 ppm
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: Lower body weight gain at 2000 ppm active substance (significant only in males of 52 week chronic study part; significant in males and females in 104 week carcinogenicity group)
Dose descriptor:
LOAEL
Remarks:
systemic effects
Effect level:
2 000 ppm
Based on:
act. ingr.
Sex:
male/female
Key result
Critical effects observed:
no
Treatment related:
yes
Conclusions:
Under the study conditions, the test substance was not carcinogenic following chronic dietary administration up to 4000 ppm (i.e., equivalent to 97 and 119 mg a.i./kg bw/day for male and female respectively) in SD rats for two years.
Executive summary:

A study was conducted to determine the carcinogenicity of the test substance (ca. 50% purity) according to OECD Guideline 453, in compliance with GLP. The substance was administered daily to Sprague-Dawley rats by dietary admixture at the concentrations of 1000, 2000 and 4000 ppm (equivalent to 500, 1000 and 2000 ppm a.i.) for 52 weeks (toxicology sub-group) and for 104 weeks (carcinogenicity sub-group; corresponding to 24, 48 or 97 mg a.i./kg bw/day for males and 29, 58 or 119 mg a.i./kg bw/day for females). No treatment-related tumorigenic effects were observed. Under the study conditions, the test substance was not carcinogenic following chronic dietary administration up to 4000 ppm (equivalent to 97 and 119 mg a.i./kg bw/day for males and females, respectively) in SD rats for two years (Appelqvist, 2007).

Endpoint:
carcinogenicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From March 22, 1988 to July 08, 1991
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 870.4300 (Combined Chronic Toxicity / Carcinogenicity)
Deviations:
no
GLP compliance:
yes
Specific details on test material used for the study:
- Name of test material (as cited in study report): Alkyldimethylbenzylammonium chloride (ADBAC)
- Physical state: Pale yellow viscous liquid
- Analytical purity: 81.09% active substance in aqueous/ethanol solution.
- Lot/batch No.: 7293K
- Stability under test conditions: The test substance is hydrolytically and photolytically stable under the conditions of this study and has been shown to be stable in aqueous, alcohol and alcohol/aqueous solutions for extended periods, e.g. at least five years under standard laboratory conditions.
- Storage condition of test material: Room temperature
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
Test animals:
- Source: Sprague-Dawley CD rats were obtained from Charles River Breeding Laboratories, Portage MI USA
- Age at study initiation: 8 weeks
- Weight at study initiation: 246.9-308.7 g (males) and 161.8-215.1 g (females)
- Housing: The animals were housed one animal/cage in divided stainless steel cages (solid sides with three mesh floors) mounted in a stainless steel Maxi-Rack (Hazleton Systems, Inc., Aberdeen, MD).
- Diet: Ground Purina Certified Rodent Chow # 5002 (Ralstor Purina Co., St. Louis, MO), ad libitum
- Water: Municipal water, ad libitum. Water was provided by an automatic watering system with demand control valves mounted on each rack.
- Acclimation period: One week

Environmental conditions
- Temperature: 66-77 °F
- Humidity: 40-70%
- Air changes: 8/h
- Photoperiod: Fluorescent lighting was provided 12 h/d using an automatic timer.

In-life dates: From: 22 March 1988 to: 27 March 1990
Route of administration:
oral: feed
Vehicle:
ethanol
Details on exposure:
Diet preparation: Test diets were prepared by direct addition of the test substance to ground rodent feed. A concentrated premix was prepared to ensure maximal loss of the ethanol (approximately 12% by weight) from the test substance during the original mixing time of 1h. Test diets were prepared by appropriate dilutions of the concentrated premix or higher diet concentrations.
- Rate of preparation of diet (frequency): Fresh diet was prepared and offered to the animals each week.
- Mixing appropriate amounts with (Type of food): Ground Purina Certified Rodent Chow # 5002
- Storage temperature of food: Diets were stored in polypropylene containers at room temperature.

Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Experimental diets were analyzed for stability, homogeneity and concentration of test substance in the diet by using liquid chromatography.
- Homogeneity studies performed on samples from all dietary concentrations indicated that test substance was uniformly distributed in the diet.
- Stability studies were conducted on diets (300 and 200 ppm) stored at room temperature in closed polypropylene containers and in glass jars. These analyses indicated that the test substance was stable in the diets for at least 14d in glass jars and stable for at least 21 d in closed polyethylene containers.
- Concentration verification analyses of 87 samples (mean of duplicate assays) for the diets revealed that the test substance concentration ranged from 92.4 to 110.0% of nominal for all 3 concentrations.
Duration of treatment / exposure:
24 months (104 weeks)
Frequency of treatment:
Daily
Post exposure period:
No
Remarks:
Doses / Concentrations:
0, 300, 1000 or 2000 ppm test substance (equivalent to mean intake levels of 0, 13, 44, and 88 mg/kg bw/day (males) and 0, 17, 57 and 116 mg/kg bw/day (females).
Basis: nominal in diet
No. of animals per sex per dose:
60
Control animals:
yes, plain diet
Details on study design:
Rationale for animal assignment: Animals considered suitable for study on the basis of pretest health screen. Evaluations for fecal parasites, clinical pathology, gross pathology, histology and serology conducted during the pretest period indicated that the animals were free of infectious disease and parasites. Animals were assigned to test groups, based on body weight, by a computer generated, weight stratified randomization procedure. Only rats with body weights within ± 20% of the population mean for each sex were used in the study.

Assignment of animals: The animals were assigned into following groups in the study:
- Group 1(Diet control): Plain diet
- Group 2 (Low dose): 300 ppm test substance in diet
- Group 3 (Mid dose): 1000 ppm test substance in diet
- Group 4(High dose): 2000 ppm test substance in diet
- Group 5 (Diet control): Plain diet
Observations and examinations performed and frequency:
MORTALITY/MORBIDITY and CLINICAL SIGNS: Yes
Time schedule: Twice daily

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Detailed clinical observations were performed once each week. Observations for overt clinical signs were made once daily on days when detailed observations were not conducted.

BODY WEIGHT: Yes
- Time schedule for examinations: Body weight data were collected weekly for the first 14 weeks and every other week thereafter.

FOOD CONSUMPTION: Yes
- Time schedule: Food consumption data were collected weekly for the first 14 weeks and every other week thereafter.

WATER CONSUMPTION AND COMPOUND INTAKE: No

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: Ophthalmologicic examinations were performed prior to study initiation and prior to final sacrifice.
- Dose groups that were examined: All animals

HAEMATOLOGY: Yes
- Time schedule for collection of blood: At 26, 52, 78, and 104 weeks of study
- Animals fasted: Yes (overnight)
- How many animals: 15 animals/sex/group at 26, 52, 78, and 104 weeks of study and on all animals prior to necropsy.
- Parameters checked: Hemoglobin, hematocrit, erythrocyte count, erythrocyte indices, platelet count, total leukocyte count, differential leukocyte count, reticulocyte count

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: At 26, 52, 78, and 104 weeks of study
- Animals fasted: Yes (overnight)
- How many animals: 15 animals/sex/group at 26, 52, 78, and 104 weeks of study and on all animals prior to necropsy.
- Parameters checked: Glucose, urea nitrogen, creatinine, AST (SGPT), ALT (SGOT), creatine kinase, gamma glutamyl transpeptidase, alkaline phosphatase, total protein, total cholesterol, albumin, globulin, A/G ratio, total bilirubin, direct bilirubin, indirect bilirubin, calcium, phosphorous, sodium, potassium, chloride.

URINALYSIS: Yes
- Time schedule for collection of urine: At 25, 51, 77, and 103 weeks of study.
- How many animals: 15 animals/sex/group at 25, 51, 77, and 103 weeks of study.
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes
- Parameters checked: Color, appearance, specific gravity, total volume, pH, protein, glucose, ketone, bilirubin, blood, urobilirubinogen, microscopic elements.

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
SACRIFICE: Animals were anesthetized with methoxyflurane and exsanguinated by severing the brachial vessel. 
GROSS PATHOLOGY: Yes, complete gross postmortem examination was performed on all animals.
HISTOPATHOLOGY: Yes, microscopic examination was performed on all tissues from the two controls and high dose animals as well as lungs, liver, kidneys, and gross lesions in the mid and low dose groups. In addition to gross lesions and tissue masses, the following tissues were examined: spinal cord, brain, pituitary, thyroid, thymic region, trachea, lungs, heart, salivary gland, liver, spleen, kidneys, adrenals, pancreas, testes, epididymis, prostate, seminal vesicles, ovaries, uterus, vagina, mammary gland, skin, esophagus, stomach, duodenum, jejunum, ileum, cecum, colon, rectum, urinary bladder, representative lymph nodes, peripheral nerve, sternum, femur, thigh musculature, eyes and aorta. Apart from treatment-related lesions, observations were also made for any presence of neoplasm or various tumour types in different tissues.
Other examinations:
ORGAN WEIGHT: The liver, kidneys, adrenals, spleen, brain with stem, heart, testes and ovaries were weighed for all animals sacrificed at termination.
Statistics:
Parametric variables were compared between the test and control groups using Leven’s test for homogeneity of variances, by analysis of variance and by pooled variance t-tests. Non-parametric data were analyzed by the Kruskal-Wallis test or by the Wilcoxon rank sum test as modified by Mann-Whitney. Frequency data were compared using Fisher’s exact tests. Mortality and mean days to first palpable mass were analysed using life-table analyses. The two control groups were treated as independent entities for statistical or other interpretative purposes.
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
An increased incidence of loose faeces was noted in the male rats in all groups treated with the test substance. Based upon previous 14-day and 90-day dietary studies with the test substance, the increased incidence of loose faeces in this study was considered potentially treatment-related; however, the lack of a dose response relationship in incidence and the sporadic nature of the observation throughout all dose groups limited the importance of this finding. There were no other clinical signs observed in male rats considered to be treatment-related. No clinical signs observed in the female rats were considered to be related to treatment with test substance.
Dermal irritation (if dermal study):
not examined
Mortality:
mortality observed, non-treatment-related
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
The mean absolute body weights of the 2000 ppm group male and female rats were statistically significantly decreased at most measurement periods from Week 1 to Week 26 (male) and Week 1 to 60 (female) and, while not consistently statistically significant, remained decreased throughout the study. No treatment related changes were observed in the other groups.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
A transient food consumption decrease was reported in the male rats in the 1000 ppm treatment group during the first few months of the study. Mean food consumption values for the 2000 ppm dose group were generally depressed 2 to 12 % throughout the study.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
No treatment-related effects were observed in any of the tissues examined.
Histopathological findings: neoplastic:
no effects observed
Description (incidence and severity):
No treatment-related effects were observed in any of the tissues examined. The tumour type or incidence in any tissues or organs were also not affected by the treatment.
Relevance of carcinogenic effects / potential:
No treatment-related neoplasm or increase in tumor incidence was observed in treated males and females.
Key result
Dose descriptor:
NOAEL
Remarks:
carcinogenicity
Effect level:
> 2 000 ppm (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: see 'Remark'
Key result
Dose descriptor:
NOAEL
Remarks:
systemic toxicity
Effect level:
1 000 ppm (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain
food consumption and compound intake
Key result
Critical effects observed:
no
Conclusions:
Under the test conditions, there was no evidence of carcinogenic activity of the test substance in rats administered at dietary dose levels up to 88 mg/kg bw/day or 71.3 mg a.i./kg bw/day in males and 116 mg/kg bw/day or 93.9 mg a.i./kg bw/day in females.
Executive summary:

A study was conducted to determine the carcinogenicity of the test substance (ca. 81% purity) according to OECD Guideline 453 and US EPA OPPTS 870.4300, in compliance with GLP. The experiment was performed as a two-year oral feeding study in Sprague-Dawley CD rats. The test substance was orally administered to rats (60/sex/group) at dose levels of 0, 300, 1000 or 2000 ppm (equivalent to mean intake levels of 0, 13, 44, and 88 mg/kg bw/day in males and 0, 17, 57 and 116 mg/kg bw/day in females) in the diet daily for 104 weeks. There were two control groups of 60/sex/group each. The animals were observed twice daily, body weights and clinical findings were recorded periodically. Clinical pathology measurements (haematology, clinical chemistry and urine analysis) were made at 6, 12, 18 and 24 months. At termination, a thorough post-mortem examination was conducted on all animals. Histopathology was conducted on a full set of tissues and organs from all animals in the control and high dose groups as well as on selected organs from animals in the low and mid dose groups. Further, examinations were also performed to evaluate any treatment-related effect on tumour type or incidence in various organs. An increased incidence of loose faeces in male rats was observed which was considered to be potentially treatment-related, however, was not of biological significance. A reduction in mean absolute bodyweights and food consumption was observed in males and females in the high dose group. No treatment related effects were observed in the type or incidence of clinical signs, survival, the type or incidence of palpable masses, clinical pathology, organ weights, gross and microscopic anatomic pathology or ophthalmology. Under the test conditions, there was no evidence of carcinogenic activity of the test substance in rats administered at dietary dose levels up to 88 mg/kg bw/day or 71.3 mg a.i./kg bw/day in males and 116 mg/kg bw/day or 93.9 mg a.i./kg bw/day in females (Gill, 1991).

Endpoint:
carcinogenicity
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
1970, 1977 and 1989
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
secondary literature
Principles of method if other than guideline:
No guideline followed
Details on results:
Result (carcinogenicity): negative
Conclusions:
In the reported studies, the test substance did not reveal carcinogenic potential in studies conducted in mice, rats, rabbits or guinea pigs following dermal or oral administration.
Executive summary:

In published reports, the tumorigenic potential of the test substance was evaluated in a dermal study involving 100 female Swiss mice and ten New Zealand rabbits (both males and females). Half of the mice and rabbits were treated with 8.5% test substance and the remaining half with 17% for about 80 weeks. An untreated group consisting of 100 mice and 19 rabbits served as controls. The solutions were applied uncovered twice a week (0.02 mL) on shaved dorsal skin (mice) or ear (rabbit). Complete necropsy was performed on each animal. Skin samples, grossly observed tumours, and other lesions in the lung, liver, kidneys were examined microscopically. Neither local skin tumour nor systemic tumours were induced. Further, in a 2-year study in rat dosed up to 250 mg/kg bw/d via the diet, the incidence of neoplasm among the treated groups was not significantly different from that observed in the control group. Only a limited number of organs were examined. Another 1-year study in guinea pigs (10 male and 10 female/group) dosed up to 25 mg/kg bw/d by stomach tube did not reveal treatment related tumours. Under the studies conditions, the test substance did not reveal carcinogenic potential in studies conducted in mice, rats, rabbits or guinea pigs following dermal or oral administration (Cutler, 970, Stenback, 1977 and BIBRA, 1989).

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Study duration:
chronic
Species:
rat
Quality of whole database:
Exceeds the information requirements for this tonnage band.

Carcinogenicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Carcinogenicity: via dermal route

Link to relevant study records
Reference
Endpoint:
carcinogenicity
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
1970, 1977 and 1989
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
secondary literature
Principles of method if other than guideline:
No guideline followed
Details on results:
Result (carcinogenicity): negative
Conclusions:
In the reported studies, the test substance did not reveal carcinogenic potential in studies conducted in mice, rats, rabbits or guinea pigs following dermal or oral administration.
Executive summary:

In published reports, the tumorigenic potential of the test substance was evaluated in a dermal study involving 100 female Swiss mice and ten New Zealand rabbits (both males and females). Half of the mice and rabbits were treated with 8.5% test substance and the remaining half with 17% for about 80 weeks. An untreated group consisting of 100 mice and 19 rabbits served as controls. The solutions were applied uncovered twice a week (0.02 mL) on shaved dorsal skin (mice) or ear (rabbit). Complete necropsy was performed on each animal. Skin samples, grossly observed tumours, and other lesions in the lung, liver, kidneys were examined microscopically. Neither local skin tumour nor systemic tumours were induced. Further, in a 2-year study in rat dosed up to 250 mg/kg bw/d via the diet, the incidence of neoplasm among the treated groups was not significantly different from that observed in the control group. Only a limited number of organs were examined. Another 1-year study in guinea pigs (10 male and 10 female/group) dosed up to 25 mg/kg bw/d by stomach tube did not reveal treatment related tumours. Under the studies conditions, the test substance did not reveal carcinogenic potential in studies conducted in mice, rats, rabbits or guinea pigs following dermal or oral administration (Cutler, 970, Stenback, 1977 and BIBRA, 1989).

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Study duration:
chronic
Species:
other: Swiss mice and New Zealand rabbits
Quality of whole database:
Literature data; supporting the absence of tumorigenic potential of the test substance following chronic dermal application in Swiss mice and New Zealand rabbits. Exceeds the information requirements for this tonnage band.

Additional information

Oral and dermal

Study 1. A study was conducted to determine the carcinogenicity of the test substance (ca. 50% purity) according to OECD Guideline 453, in compliance with GLP. The substance was administered daily to Sprague-Dawley rats by dietary admixture at the concentrations of 1000, 2000 and 4000 ppm (equivalent to 500, 1000 and 2000 ppm a.i.) for 52 weeks (toxicology sub-group) and for 104 weeks (carcinogenicity sub-group; corresponding to 24, 48 or 97 mg a.i./kg bw/day for males and 29, 58 or 119 mg a.i./kg bw/day for females). No treatment-related tumorigenic effects were observed. Under the study conditions, the test substance was not carcinogenic following chronic dietary administration up to 4000 ppm (equivalent to 97 and 119 mg a.i./kg bw/day for males and females, respectively) in SD rats for two years (Appelqvist, 2007).

Study 2. A study was conducted to determine the carcinogenicity of the test substance (ca. 81% purity) according to OECD Guideline 453 and US EPA OPPTS 870.4300, in compliance with GLP. The experiment was performed as a two-year oral feeding study in Sprague-Dawley CD rats. The test substance was orally administered to rats (60/sex/group) at dose levels of 0, 300, 1000 or 2000 ppm (equivalent to mean intake levels of 0, 13, 44, and 88 mg/kg bw/day in males and 0, 17, 57 and 116 mg/kg bw/day in females) in the diet daily for 104 weeks. There were two control groups of 60/sex/group each. The animals were observed twice daily, body weights and clinical findings were recorded periodically. Clinical pathology measurements (haematology, clinical chemistry and urine analysis) were made at 6, 12, 18 and 24 months. At termination, a thorough post-mortem examination was conducted on all animals. Histopathology was conducted on a full set of tissues and organs from all animals in the control and high dose groups as well as on selected organs from animals in the low and mid dose groups. Further, examinations were also performed to evaluate any treatment-related effect on tumour type or incidence in various organs. An increased incidence of loose faeces in male rats was observed which was considered to be potentially treatment-related, however, was not of biological significance. A reduction in mean absolute bodyweights and food consumption was observed in males and females in the high dose group. No treatment related effects were observed in the type or incidence of clinical signs, survival, the type or incidence of palpable masses, clinical pathology, organ weights, gross and microscopic anatomic pathology or ophthalmology. Under the test conditions, there was no evidence of carcinogenic activity of the test substance in rats administered at dietary dose levels up to 88 mg/kg bw/day or 71.3 mg a.i./kg bw/day in males and 116 mg/kg bw/day or 93.9 mg a.i./kg bw/day in females (Gill, 1991).

Study 3. In published reports, the tumorigenic potential of the test substance was evaluated in a dermal study involving 100 female Swiss mice and ten New Zealand rabbits (both males and females). Half of the mice and rabbits were treated with 8.5% test substance and the remaining half with 17% for about 80 weeks. An untreated group consisting of 100 mice and 19 rabbits served as controls. The solutions were applied uncovered twice a week (0.02 mL) on shaved dorsal skin (mice) or ear (rabbit). Complete necropsy was performed on each animal. Skin samples, grossly observed tumours, and other lesions in the lung, liver, kidneys were examined microscopically. Neither local skin tumour nor systemic tumours were induced. Further, in a 2-year study in rat dosed up to 250 mg/kg bw/d via the diet, the incidence of neoplasm among the treated groups was not significantly different from that observed in the control group. Only a limited number of organs were examined. Another 1-year study in guinea pigs (10 male and 10 female/group) dosed up to 25 mg/kg bw/d by stomach tube did not reveal treatment related tumours. Under the studies conditions, the test substance did not reveal carcinogenic potential in studies conducted in mice, rats, rabbits or guinea pigs following dermal or oral administration (Cutler, 970, Stenback, 1977 and BIBRA, 1989).

 

Justification for classification or non-classification

The available oral and dermal data suggest that the test substance is not a carcinogen. Therefore, the substance does not require classification for this endpoint according to CLP (EC 1272/2008) criteria.