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EC number: 604-636-5 | CAS number: 148477-71-8
- 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
Carcinogenicity
Administrative data
Description of key information
A combined chronic toxicity/carcinogenicity study in the rat is available for spirodiclofen (M-026284-02-1).
A carcinogenicity study in the mouse is available for spirodiclofen (M-044116-01-1).
Key value for chemical safety assessment
Carcinogenicity: via oral route
Link to relevant study records
- Endpoint:
- carcinogenicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Reason / purpose for cross-reference:
- reference to same study
- Remarks:
- This study in the rat was performed at dietary concentrations of 0, 50, 100, 350 and 2500 ppm; the chronic toxicity phase is relevant for this endpoint.
- Qualifier:
- according to guideline
- Guideline:
- other: 88/302/EEC
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EPA OPPTS 870.4300 (Combined Chronic Toxicity / Carcinogenicity)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- other: B.67/548/EEC
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)
- Deviations:
- no
- Principles of method if other than guideline:
- Deviations from GLP:
Deviations: 1) One out of ten analytical contents check that was reevaluated after the end of the in-life phase was found to be invalid due to insufficient documentation.
2) Determination of test substance concentration in plasma samples as well as experiments for method development (telomere measurements in different tissues) were not conducted according to GLP. - GLP compliance:
- yes (incl. QA statement)
- Remarks:
- There were two deviations that were not conducted according to GLP. They are found in box above 'Principles of method if other than guideline'.
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Route of administration:
- oral: feed
- Vehicle:
- other: food
- Details on exposure:
- Exposed to test material via diet in relevant doses over a period of up to 108 weeks. Some rats that were treated with same doses were sacrificed after a treatment period of about 1 year.
- Analytical verification of doses or concentrations:
- no
- Duration of treatment / exposure:
- Up to 108 weeks.
- Frequency of treatment:
- Daily/continuous
- Dose / conc.:
- 0 ppm
- Dose / conc.:
- 50 ppm
- Dose / conc.:
- 100 ppm
- Dose / conc.:
- 350 ppm
- Dose / conc.:
- 2 500 ppm
- No. of animals per sex per dose:
- 60; 10/sex sacrificed after 12 months
- Control animals:
- yes, plain diet
- Details on study design:
- Spirodiclofen was administered via the diet to Wistar rats (50 males and 50 females per dose), in doses of 0, 50, 100, 350 and 2500 ppm over a period of up to 108 weeks. In addition, 10 rats per dose and sex, respectively, were treated with the same doses of Spirodiclofen and sacrificed after a treatment period of about 1 year. Average daily test substance intake was - in ascending order of doses 2.04, 4.11, 14.72, and 110.14 mg/kg bw per day in male rats, and 2.87, 5.93, 19.88, and 152.90 mg/kg bw per day in females, respectively.
- Observations and examinations performed and frequency:
- Detailed clinical observations, body weight, food and water consumption, ophthalmoscopic examination, hematology, urinalysis, clinical chemistry and neurobehavioral examination.
- Sacrifice and pathology:
- Gross pathology, organ weights, histopathology
- Clinical signs:
- no effects observed
- Mortality:
- mortality observed, non-treatment-related
- Description (incidence):
- Mortality was increased in 2500 ppm females, but with no statistical significance. Mortality of 2500 ppm males was decreased.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- At the highest dose the body weight-related food consumption was slightly increased in both sexes. The body weight development was slightly retarded in both sexes at 2500 ppm.
- Food consumption and compound intake (if feeding study):
- not examined
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- no effects observed
- Ophthalmological findings:
- no effects observed
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- The clinical chemical investigations revealed an increase in alkaline phosphatase activity levels at 2500 ppm, whereas the activities of ALT and AST were not affected. The cholesterol and triglyceride levels in the plasma were reduced at 2500 ppm in both sexes at most time-points. Slight changes of thyroid parameters were seen in this study at some time-points (increased thyroxine level in 2500 ppm males in week 105; increased TSH levels in 2500 ppm females in weeks 79 and 105), but there was no clear dose-response relationship and consistency over the time so that a treatment-relationship is not assumed.
- Endocrine findings:
- not examined
- Urinalysis findings:
- no effects observed
- Behaviour (functional findings):
- no effects observed
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, non-treatment-related
- Description (incidence and severity):
- No treatment-related differences in the organ weights were seen at interim or final necropsy, although some deviations occurred but these were related to the body weight retardation. Isolated kidney weight changes were regarded as incidental and unrelated to treatment.
- Gross pathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- At interim necropsy no changes were seen. At final necropsy an increased incidence of liver discoloration (females), dilation of renal pelvis (females), consistency changes of pancreas (females, only intercurrent deaths), and of uterine nodules was seen at the highest dose of 2500 ppm.
Decreased incidences of kidney findings (discoloration, surface changes in 2500 ppm males), liver findings (distinct lobulation in 2500 ppm males), and of pituitary findings (nodules in 50 and 2500 ppm females) were detected at final necropsy. - Neuropathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- At 2500 ppm in animals scheduled for interim necropsy after one year an increased incidence and/or higher severity of minimal to moderate cytoplasmic vacuolation (microvesicular and/or large vacuoles) of the adrenal zona fasciculata cells, minimal to slight diffuse adrenocorticocellular hypertrophy in three males, a minimally to moderately increased portion of ovarian stroma, and slight and perhaps spurious changes in the estrus were seen.
At final necropsy the incidences of vacuolated enterocytes in the jejunum (both sexes), diffuse
hypertrophy/vacuolation of adrenal zona fasciculata cells (males), atrophy/degeneration of the olfactory epithelium in the nasal cavity (males), and of colloidal alteration in the thyroid gland (males) were increased at 2500 ppm. At 2500 ppm the incidences of several age-dependent, non-neoplastic findings were decreased in males and/or females. Reduced incidences of arteritis/periarteritis incidences were seen in the blood vessels of various organs (males), of chronic progressive nephropathy in the kidneys (reduced severity in males; reduced incidence in females), diffuse transitional cell hyperplasia in the renal pelvis of both sexes, mineralization in the kidneys
(females), squamous cell hyperplasia of the uterine cervix (at 100 ppm and above), peliosis in the adrenal cortex (females), focal hyperplasia in the adrenal medulla (females), pigment deposits in spleen and mesenteric lymph node (both sexes), and of epithelial hyperplasia in the thymus (both sexes). - Histopathological findings: neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- The incidences of Leydig cell adenomas and focal Leydig cell hyperplasia were increased in rats treated with 2500
ppm. In addition, the number of (metastasizing) uterine adenocarcinoma, correlating with the gross pathological
finding of uterine nodules, was increased in female intercurrent deaths at 2500 ppm. This results in an increased
number of females (2500 ppm) with malignant tumors and slightly more females with both benign and malignant
neoplasms among intercurrent deaths. The number of female intercurrent deaths with neoplasms and only benign
neoplasms was comparable between the female groups. In male intercurrent deaths the number of animals with
neoplasms, malignant tumors, benign tumors and with both benign and malignant tumors was comparable in treated
and control rats. Considering all animals intended for terminal necropsy together, the number of rats with neoplasms (both sexes),
with only benign (both sexes), with both benign and malignant (both sexes) or with only malignant neoplasms
(males) was evenly distributed among the groups. Due to the high incidence of metastasising uterine
adenocarcinoma, the number of females with malignant tumors was increased at 2500 ppm.
The pancreatic consistency changes (females, several intercurrent deaths) correlated histopathologically with
metastasis of carcinoma.
A decrease was seen with regard to pituitary gland adenomas (pars distalis, both sexes) and to fibroadenomas of the
mammary gland (females) at 2500 ppm. - Details on results:
- General observations: No treatment-related clinical signs were detected by daily observation of the animals. Mortality was increased in 2500 ppm females, but with no statistical significance. Mortality of 2500 ppm males was decreased. Spirodiclofen had no effect on water consumption. At the highest dose the body weight-related food consumption was slightly increased in both sexes. The body weight development was slightly retarded in both sexes at 2500 ppm. No oculotoxic effects of the test compound were observed. The functional observational battery test performed in study week 77 and the home cage observations and observations during handling did not reveal evidence of a neurotoxic potential.
Hematology, clinical chemistry, urinalysis: The results of the hematological examinations did not provide evidence of damage to the blood, the coagulation and the blood-forming tissues. The clinical chemical investigations revealed an increase in alkaline phosphatase activity levels at 2500 ppm, whereas the activities of ALT and AST were not affected. The cholesterol and triglyceride levels in the plasma were reduced at 2500 ppm in both sexes at most time-points. Slight changes of thyroid parameters were seen in this study at some time-points (increased
thyroxine level in 2500 ppm males in week 105; increased TSH levels in 2500 ppm females in weeks 79 and 105), but there was no clear dose-response relationship and consistency over the time so that a treatment-relationship is not assumed. Urinalysis did not reveal any compound-related effect.
Gross pathology, organ weights, histopathology: At interim necropsy no changes were seen. At final necropsy an increased incidence of liver discoloration (females), dilation of renal pelvis (females), consistency changes ofpancreas (females, only intercurrent deaths), and of uterine nodules was seen at the highest dose of 2500 ppm.
Decreased incidences of kidney findings (discoloration, surface changes in 2500 ppm males), liver findings (distinct lobulation in 2500 ppm males), and of pituitary findings (nodules in 50 and 2500 ppm females) were detected at final necropsy. No treatment-related differences in the organ weights were seen at interim or final necropsy, although some deviations occurred but these were related to the body weight retardation. Isolated kidney weight changes were
regarded as incidental and unrelated to treatment.
Non-neoplastic findings:
Histopathological examination after one year of dietary exposure to Spirodiclofen did not reveal treatment-related findings in both sexes up to and including 350 ppm. At 2500 ppm in animals scheduled for interim necropsy after one year an increased incidence and/or higher severity of minimal to moderate cytoplasmic vacuolation (microvesicular and/or large vacuoles) of the adrenal zona fasciculata cells, minimal to slight diffuse adrenocorticocellular hypertrophy in three males, a minimally to moderately increased portion of ovarian stroma, and
slight and perhaps spurious changes in the estrus were seen.
Other degenerative and inflammatory changes typical for this strain and age when kept under conventional conditions were also observed, but were not regarded as treatment-related due the type, number and distribution of the findings in the individual treatment groups.
At final necropsy the incidences of vacuolated enterocytes in the jejunum (both sexes), diffuse
hypertrophy/vacuolation of adrenal zona fasciculata cells (males), atrophy/degeneration of the olfactory epithelium in the nasal cavity (males), and of colloidal alteration in the thyroid gland (males) were increased at 2500 ppm.
At 2500 ppm the incidences of several age-dependent, non-neoplastic findings were decreased in males and/or females. Reduced incidences of arteritis/periarteritis incidences were seen in the blood vessels of various organs (males), of chronic progressive nephropathy in the kidneys (reduced severity in males; reduced incidence in females), diffuse transitional cell hyperplasia in the renal pelvis of both sexes, mineralization in the kidneys (females), squamous cell hyperplasia of the uterine cervix (at 100 ppm and above), peliosis in the adrenal cortex (females), focal hyperplasia in the adrenal medulla (females), pigment deposits in spleen and mesenteric lymph node
(both sexes), and of epithelial hyperplasia in the thymus (both sexes).
Degenerative and inflammatory changes not related to the treatment were also observed in control and treatment
groups.
Neoplastic findings:
No substance-related neoplastic changes were observed in animals scheduled for interim necropsy.
The incidences of Leydig cell adenomas and focal Leydig cell hyperplasia were increased in rats treated with 2500
ppm. In addition, the number of (metastasizing) uterine adenocarcinoma, correlating with the gross pathological
finding of uterine nodules, was increased in female intercurrent deaths at 2500 ppm. This results in an increased
number of females (2500 ppm) with malignant tumors and slightly more females with both benign and malignant
neoplasms among intercurrent deaths. The number of female intercurrent deaths with neoplasms and only benign
neoplasms was comparable between the female groups. In male intercurrent deaths the number of animals with
neoplasms, malignant tumors, benign tumors and with both benign and malignant tumors was comparable in treated
and control rats.
At terminal necropsy no difference between treated and control rats (both sexes) was seen with regard to the number
of animals with neoplasms, with only malignant or with both malignant and benign tumors. At 350 ppm the number
of females with only benign neoplasms was increased as compared to the other female groups (terminal necropsy).
Since this was not dose-related (26 females at 350 ppm versus 13 at 2500 ppm) or based on the increase of a specific
tumor type, this is considered to be incidental. The number of males with only benign tumors was similar in treated
and control rats.
Considering all animals intended for terminal necropsy together, the number of rats with neoplasms (both sexes),
with only benign (both sexes), with both benign and malignant (both sexes) or with only malignant neoplasms
(males) was evenly distributed among the groups. Due to the high incidence of metastasising uterine
adenocarcinoma, the number of females with malignant tumors was increased at 2500 ppm.
The pancreatic consistency changes (females, several intercurrent deaths) correlated histopathologically with
metastasis of carcinoma.
A decrease was seen with regard to pituitary gland adenomas (pars distalis, both sexes) and to fibroadenomas of the
mammary gland (females) at 2500 ppm. With the exception of the tumors discussed in the text above all neoplasms listed in the Table 5.5.1g were evenly
distributed among the groups and were found at incidences known from previous studies with this strain. Considering the time-dependent occurrence of tumor bearing animals no dose correlated effect is obvious (see Tables 5.5.1j and 5.5.1k). - Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 350 ppm
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- gross pathology
- histopathology: neoplastic
- histopathology: non-neoplastic
- Key result
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 2 500 ppm
- System:
- male reproductive system
- Organ:
- testes
- Treatment related:
- yes
- Dose response relationship:
- yes
- Relevant for humans:
- yes
- Key result
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 2 500 ppm
- System:
- female reproductive system
- Organ:
- uterus
- Treatment related:
- yes
- Dose response relationship:
- yes
- Relevant for humans:
- yes
- Conclusions:
- There was some evidence of carcinogenicity in this study; the incidences of uterine adenocarcinoma in females and Leydig cell adenoma in males were increased at the highest dietary concentration of 2500 ppm.
- Executive summary:
In this combined chronic toxicity/carcinogenicity study performed to OECD 453, spirodiclofen was administered in the diet to groups of Wistar rats (50/sex) at concentrations of 0 (controls), 50, 100, 350 and 2500 ppm over a period of up to 108 weeks. In addition, 10 rats/se/group were treated with the same dietary concentrations and sacrificed after a treatment period of about 1 year. Mean achieved intakes over the entire study period were 0, 2.04, 4.11, 14.72 and 110.14 mg/kg bw/d in males; 0, 2.87, 5.93, 19.88 and 152.90 mg/kg bw/d in females, respectively. No treatment-related clinical signs were detected by daily observation of the animals. Mortality was increased in 2500 ppm females, but with no statistical significance; mortality of 2500 ppm males was decreased. There was no effect of treatment on water consumption. At the highest dose level, food consumption was slightly increased in both sexes. Body weight development was slightly retarded in both sexes at 2500 ppm. Ophthalmoscopy did not reveal any treatment-related findings. FOB did not reveal evidence of neurotoxic potential. The results of the haematological examinations did not provide evidence of adverse effects. Clinical chemistry revealed an increase in alkaline phosphatase activity at 2500 ppm; ALT and AST activities were not affected. Cholesterol and triglyceride levels were reduced at 2500 ppm in both sexes at most timepoints. Slight changes in thyroid parameters were seen in this study at some time-points (increased thyroxine level in 2500 ppm males at Week 105; increased TSH levels in 2500 ppm females at Weeks 79 and 105), but there was no clear dose-response relationship and consistency over the time so that a treatment-relationship is not assumed. Urinalysis did not reveal any treatment-related effect. At interim necropsy no changes were seen. At terminal necropsy, an increased incidence of liver discoloration (females), dilation of renal pelvis (females), consistency changes of pancreas (females, only intercurrent deaths), and of uterine nodules was seen at the highest dose of 2500 ppm. Decreased incidences of kidney findings (discoloration, surface changes in 2500 ppm males), liver findings (distinct lobulation in 2500 ppm males), and of pituitary findings (nodules in 50 and 2500 ppm females) were detected at final necropsy. No treatment-related differences in the organ weights were seen at interim or final necropsy; some deviations occurred but these were related to the body weight retardation. Isolated kidney weight changes were regarded as incidental and unrelated to treatment. Histopathological examination after one year did not reveal treatment-related findings in either sex up to and including 350 ppm. At 2500 ppm in animals scheduled for interim necropsy after one year an increased incidence and/or higher severity of minimal to moderate cytoplasmic vacuolation (microvesicular and/or large vacuoles) of the adrenal zona fasciculata cells, minimal to slight diffuse adrenocorticocellular hypertrophy in three males, a minimally to moderately increased portion of ovarian stroma, and slight and perhaps spurious changes in the estrus were seen. Other degenerative and inflammatory changes typical for this strain and age when kept under conventional conditions were also observed, but were not regarded as treatment-related due the type, number and distribution of the findings in the individual treatment groups. At final necropsy the incidences of vacuolated enterocytes in the jejunum (both sexes), diffuse hypertrophy/ vacuolation of adrenal zona fasciculata cells (males), atrophy/ degeneration of the olfactory epithelium in the nasal cavity (males), and of colloidal alteration in the thyroid gland (males) were increased at 2500 ppm. At 2500 ppm the incidences of several age-dependent, non-neoplastic findings were decreased in males and/or females. Reduced incidences of arteritis/periarteritis incidences were seen in the blood vessels of various organs (males), of chronic progressive nephropathy in the kidneys (reduced severity in males; reduced incidence in females), diffuse transitional cell hyperplasia in the renal pelvis of both sexes, mineralization in the kidneys (females), squamous cell hyperplasia of the uterine cervix (at 100 ppm and above), peliosis in the adrenal cortex
(females), focal hyperplasia in the adrenal medulla (females), pigment deposits in spleen and mesenteric lymph node (both sexes), and of epithelial hyperplasia in the thymus (both sexes). Degenerative and inflammatory changes not related to the treatment were also observed in control and treatment groups. No substance-related neoplastic changes were observed in animals scheduled for interim necropsy. The incidences of Leydig cell adenomas and focal Leydig cell hyperplasia were increased in rats treated with 2500 ppm. In addition, the number of (metastasizing) uterine adenocarcinoma, correlating with the gross pathological finding of uterine nodules, was increased in female intercurrent deaths at 2500 ppm. This results in an increased number of females (2500 ppm) with malignant tumours and slightly more females with both benign and malignant neoplasms among intercurrent deaths. The number of female intercurrent deaths with neoplasms and only benign neoplasms was comparable between the female groups. In male intercurrent deaths the number of animals with neoplasms, malignant tumours, benign tumours and with both benign and malignant tumours was comparable in treated and control rats. At terminal necropsy no difference between treated and control rats (both sexes) was seen with regard to the number of animals with neoplasms, with only malignant or with both malignant and benign tumours. At 350 ppm the number of females with only benign neoplasms was increased as compared to the other female groups (terminal necropsy). Since this was not dose-related (26 females at 350 ppm versus 13 at 2500 ppm) or based on the increase of a specific tumour type, this is considered to be incidental. The number of males with only benign tumours was similar in treated and control rats. Considering all animals intended for terminal necropsy together, the number of rats with neoplasms (both sexes), with only benign (both sexes), with both benign and malignant (both sexes) or with only malignant neoplasms (males) was evenly distributed among the groups. Due to the high incidence of metastasising uterine adenocarcinoma, the number of females with malignant tumours was increased at 2500 ppm. The pancreatic consistency changes (females, several intercurrent deaths) correlated histopathologically with metastasis of carcinoma. A decrease was seen with regard to pituitary gland adenomas (pars distalis, both sexes) and to fibroadenomas of the mammary gland (females) at 2500 ppm. With the exception of the tumours discussed above, all neoplasms were evenly distributed among the groups and were found at incidences known from previous studies with this strain. Considering the time-dependent occurrence of tumour bearing animals no dose correlated effect is obvious. The NOAEL of this study was 350 ppm (equivalent to 14.72 mg/kg bw/d in males; 19.88 mg/kg bw/d) in females. This was based on effects on the adrenals (vacuolation) and on some neoplastic (uterine adenocarcinomas, Leydig cell adenomas) and non-neoplastic findings at the highest dose of 2500 ppm. Due to these findings, the body weight effects and the changes of clinical chemistry parameters, the highest dose of 2500 ppm has to be regarded as an MTD.
- Endpoint:
- carcinogenicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 451 (Carcinogenicity Studies)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EPA OPP 83-2 (Carcinogenicity)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- other: TSCA 798.3300
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- other: Japan MAFF: Oncogenicity Study.
- Deviations:
- no
- GLP compliance:
- yes
- Remarks:
- Deviations: The INSTEM Computer Systems version C8 does not retain old and new feeder weights used to calculate food consumption during the feeder top-up procedure (FILLUP).
- Species:
- mouse
- Strain:
- CD-1
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- spirodiclofen was administered to CD-1 mice (50 males and 50 females per dose), at dose levels of 0, 25, 3500 and 7000 ppm in the diet over a period of approximately 18 months. The mean daily test compound intake was 0, 4.1, 610, and 1216 mg/kg bw in males and 0, 5.1, 722, and 1495 mg/kg bw in females, respectively. The dose levels for this study were established based on a range-finding study in which CD-1 mice were administered doses of spirodiclofen of 25, 50, 500, 2500 and 7000 ppm for 6 weeks via the diet.
- Route of administration:
- oral: feed
- Vehicle:
- unchanged (no vehicle)
- Analytical verification of doses or concentrations:
- not specified
- Duration of treatment / exposure:
- 18 months
- Frequency of treatment:
- Test substance was administered within the diet, which was available ad libitum. The frequency of treatment is not applicable as food was replenished as the test animals consumed it. Due to this, the frequency of treatment can be considered daily as the test subjects were exposed to the test substance at every meal.
- Dose / conc.:
- 0 ppm
- Remarks:
- No test substance - diet only
- Dose / conc.:
- 25 ppm
- Dose / conc.:
- 3 500 ppm
- Dose / conc.:
- 7 000 ppm
- No. of animals per sex per dose:
- 50 males and 50 females per dose. 100 total at each dose level.
- Control animals:
- yes, plain diet
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- No clinical signs or a treatment-related increase in mortality were noted. Food intake and
body weight gain were also not affected at any dose. - Haematological findings:
- no effects observed
- Description (incidence and severity):
- No treatment-related changes were detected at 12 and 18 months.
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- The adrenal and liver weights were increased and the kidney weights decreased at 3500 and 7000 ppm in both sexes. The testes weights were increased in males at 3500 and 7000 ppm. Histopathological examination revealed pigmentation and vacuolation in the adrenals at 3500 and 7000 ppm. Interstitial cell hypertrophy and hyperplasia was seen in the testes of 3500 and 7000 ppm males. Hepatocytomegaly was observed in 3500 and 7000 ppm males, and liver adenoma and liver carcinoma incidences were increased in 3500 ppm males and females and in 7000 ppm males.
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- Final necropsy did not reveal any treatment-related findings.
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- effects observed, non-treatment-related
- Description (incidence and severity):
- The total rate of the animals with benign tumors was slightly increased in the 7000 ppm males, which is due to the increased incidence of liver adenomas in this group. However, the total tumor incidence was not affected by the treatment. In the animals, which were found dead or were sacrificed in moribund, no increased tumor incidences were seen so that the time of tumor occurrence was not increased.
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 25 ppm
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- histopathology: non-neoplastic
- Key result
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 3 500 ppm
- System:
- hepatobiliary
- Organ:
- liver
- Treatment related:
- yes
- Dose response relationship:
- yes
- Relevant for humans:
- yes
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 3 500 ppm
- System:
- endocrine system
- Organ:
- adrenal glands
- Treatment related:
- yes
- Dose response relationship:
- yes
- Relevant for humans:
- yes
- Conclusions:
- A NOAEL was established at 25 ppm for both sexes which is equivalent to 4.1 and 5.1 mg/kg bw
in males and females, respectively. This was based on liver (hepatocytomegaly, hepatocellular
adenomas and carcinomas) and adrenal effects (vacuolization) at 3500 ppm. The total tumour
incidence and the time of occurrence and type of tumours observed in this study do not indicate a
primary oncogenic potential of spirodiclofen. - Executive summary:
In a carcinogenicity study performed to OECD 451, spirodiclofen was administered to groups of CD-1 mice (50/sex) at dietary concentrations of 0, 25, 3500 and 7000 ppm for up to 18 months. The mean achieved intake was 0, 4.1, 610 and 1216 mg/kg bw in males; 0, 5.1, 722, and 1495 mg/kg bw/d in females, respectively. No clinical signs or a treatment-related increase in mortality were noted. Food intake and body weight gain were not affected at any dose. No treatment-related haematological changes were detected at 12 and 18 months. Final necropsy did not reveal any treatment-related findings. The adrenal and liver weights were increased and the kidney weights decreased at 3500 and 7000 ppm in both sexes. The testes weights were increased in males at 3500 and 7000 ppm. Histopathological examination revealed pigmentation and vacuolation in the adrenals at 3500 and 7000 ppm. Interstitial cell hypertrophy and hyperplasia was seen in the testes of 3500 and 7000 ppm males. Hepatocytomegaly was observed in 3500 and 7000 ppm males, and liver adenoma and liver carcinoma incidences were increased in 3500 ppm males and females and in 7000 ppm males. The total rate of the animals with benign tumours was slightly increased in the 7000 ppm males, which is due to the increased incidence of liver adenomas in this group. However, the total tumour incidence was not affected by the treatment. In the animals, which were found dead or had to be sacrificed moribundly, no increased tumour incidences were seen so that the time of tumour occurrence was not increased. A NOAEL was established at 25 ppm for both sexes which is equivalent to 4.1 and 5.1 mg/kg bw/d in males and females, respectively. This was based on liver (hepatocytomegaly, hepatocellular adenomas and carcinomas) and adrenal effects (vacuolization) at 3500 ppm. The total tumour incidence and the time of occurrence and type of tumours observed in this study do not indicate a primary oncogenic potential.
Referenceopen allclose all
Chronic toxicity and carcinogenicity study in rats: Clinical chemistry (males)
Dose (ppm)
| APh (U/L) | CHOL [MMOL/L] | Trigl [mmol/L] |
Week 27 | |||
0 | 175 | 4.44 | 4.31 |
50 | 196 | 2.72 | 1.91 |
100 | 186 | 2.20 | 2.18 |
350 | 201 | 2.57 | 1.75 |
2500 | 305** | 1.90 | 1.36 |
Week 53 | |||
0 | 203 | 3.15 | 1.73 |
50 | 199 | 3.90 | 2.13 |
100 | 180 | 2.91 | 2.10 |
350 | 213 | 3.81 | 2.09 |
2500 | 279** | 2.78 | 1.81 |
Week 79 | |||
0 | 171 | 3.59 | 2.70 |
50 | 178 | 4.25 | 2.45 |
100 | 163 | 3.07 | 2.39 |
350 | 192 | 4.44 | 2.42 |
2500 | 277** | 2.89 | 1.84 |
Week 105 | |||
0 | 176 | 4.11 | 2.39 |
50 | 167 | 4.41 | 2.16 |
100 | 212 | 3.88 | 2.42 |
350 | 197 | 3.77 | 2.15 |
2500 | 265** | 3.29 | 1.57 |
* p 0.05, ** p 0.01
Chronic toxicity and carcinogenicity study in rats: Clinical chemistry (females)
Dose (ppm)
| APh (U/L) | CHOL [MMOL/L] | Trigl [mmol/L] |
Week 27 | |||
0 | 122 | 2.17 | 2.00 |
50 | 128 | 2.46 | 2.13 |
100 | 134 | 2.04 | 1.82 |
350 | 150 | 2.21 | 1.66 |
2500 | 226** | 2.07 | 1.16* |
Week 53 | |||
0 | 123 | 2.32 | 1.69 |
50 | 112 | 2.79 | 2.38 |
100 | 115 | 2.54 | 1.89 |
350 | 135 | 2.11 | 1.82 |
2500 | 183 | 2.06 | 1.31 |
Week 79 | |||
0 | 122 | 2.25 | 2.12 |
50 | 100 | 3.71 | 6.30 |
100 | 105 | 2.47 | 2.73 |
350 | 120 | 2.24 | 2.06 |
2500 | 226** | 2.06 | 1.91 |
Week 105 | |||
0 | 117 | 2.25 | 2.26 |
50 | 110 | 3.71 | 2.66 |
100 | 112 | 2.47 | 2.70 |
350 | 135 | 2.24 | 2.43 |
2500 | 188** | 2.06 | 2.06 |
* p 0.05, ** p 0.01
Treatment-Related Necropsy Findings - Terminal Necropsy
Dose (ppm) | 0 |
| 50 |
| 100 |
| 350 |
| 2500 |
| 0 |
| 50 |
| 100 |
| 350 |
| 2500 |
Sex | m |
| m |
| m |
| m |
| m |
| f |
| f |
| f |
| f |
| f |
No. investigated | 50 |
| 50 |
| 50 |
| 50 |
| 50 |
| 50 |
| 50 |
| 50 |
| 50 |
| 50 |
UTERUS |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Nodules | - |
| - |
| - |
| - |
| - |
| 8 |
| 7 |
| 9 |
| 9 |
| 17 |
PANCREAS |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Consistency Change/s | 1* |
| 2* |
| 0 |
| 0 |
| 0 |
| 1* |
| 1* |
| 0 |
| 0 |
| 5* |
KIDNEYS |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Surfac Change/s PITUITARY GLAND Nodules | 12
4 |
| 11
5 |
| 11
0 |
| 13
2 |
| 1
3 |
| 1*
11 |
| 4
6 |
| 6
13 |
| 4
13 |
| 0
4* |
Non-Neoplastic Changes in Animals Scheduled for Interim Sacrifice
Dose (ppm) | 0 | 50 | 100 | 350 | 2500 |
Sex | m | m | m | m | m |
No. of animals | 10 | 10 | 10 | 10 | 10 |
Adrenal glands | 10 | 10 | 10 | 10 | 10 |
Cytoplasmic vacuoles/small | 6 | 7 | 5 | 3 | 9 |
Average Grading | 1.3 | 1.0 | 1.0 | 1.0 | 2.2 |
Cytoplasmic vacuoles/large | 6 | 5 | 4 | 5 | 10 |
Average Grading | 1.5 | 1.4 | 1.3 | 1.2 | 1.5 |
Cortical Hypertrophy/diffuse | - | - | - | - | 3 |
Average Grading | 0 | 0 | 0 | 0 | 1.7 |
Non-Neoplastic Changes in Animals Scheduled for Interim Sacrifice
Dose (ppm) |
| 50 | 100 | 350 | 2500 |
Sex |
| f | f | f | f |
| 10 | 10 | 10 | 10 | 10 |
OVARIES | 10 | 10 | 10 | 10 | 10 |
- Portion/Ovarian Stroma | 6 | 7 | 6 | 9 | 9 |
Average Grading | 1.8 | 1.6 | 1.5 | 1.7 | 2.3 |
ESTRUS CYCLE | 10 | 10 | 10 | 10 | 10 |
- Metestrus/ Diestrus | 3 | 2 | 2 | 2 | 0 |
Non-Neoplastic Changes in animals scheduled for terminal necropsy
Sex Dose (ppm) Organ/ Findings |
0 |
50 | Males 100 |
350 |
2500 |
0 |
50 | Females 100 |
350 |
2500 | |
NASAL CAVITY | No.Examined | 50 | 50 | 50 | 50 | 50 | 50 | 50 | 50 | 50 | 50 |
Atrophy/degeneration olfactory epithelium | 13 | 19 | 15 | 16 | 25 | 13 | 19 | 14 | 13 | 17 | |
TONGUE | No.Examined | 50 | 50 | 50 | 50 | 50 | 50 | 50 | 50 | 50 | 50 |
Arteritis/Periarteritis | 3 | 2 | 2 | 1 | 0 | 0 | 3 | 2 | 1 | 3 | |
GLANDULAR STOMACH No.Examined | 50 | 50 | 50 | 50 | 50 | 50 | 50 | 50 | 50 | 50 | |
Arteritis/Periarteritis | 3 | 4 | 4 | 2 | 0 | 0 | 0 | 1 | 1 | 0 | |
JEJUNUM | No.Examined | 50 | 50 | 50 | 50 | 50 | 50 | 49 | 50 | 50 | 50 |
Vacuoles enterocytes | 3 | 0 | 4 | 3 | 18 | 5 | 0 | 0 | 1 | 17 | |
PANCREAS | No.Examined | 50 | 50 | 50 | 50 | 50 | 50 | 50 | 50 | 50 | 50 |
Arteritis/Periarteritis | 6 | 9 | 3 | 3 | 0 | 2 | 2 | 4 | 4 | 1 | |
KIDNEYS | No.Examined | 50 | 50 | 50 | 50 | 50 | 50 | 50 | 50 | 50 | 50 |
Diffuse transitional cell hyperplasia | 3 | 2 | 3 | 3 | 0 | 7 | 10 | 5 | 4 | 4 | |
Chronic progressive nephropathy | 46 | 47 | 46 | 48 | 45 | 44 | 44 | 40 | 41 | 37 | |
Grading | 2.8 | 2.7 | 2.9 | 2.8 | 2.2 | 2.4 | 2.2 | 2.4 | 2.2 | 2.3 | |
Mineralization | 1 | 1 | 1 | 1 | 1 | 13 | 15 | 19 | 13 | 3 | |
URINARY BLADDER | No.Examined | 50 | 50 | 50 | 50 | 50 | 50 | 50 | 49 | 50 | 50 |
Diffuse transitional cell hyperplasia | 2 | 0 | 1 | 1 | 0 | 0 | 0 | 1 | 1 | 0 | |
TESTES | No.Examined | 50 | 50 | 50 | 50 | 50 | - | - | - | - | - |
Arteritis/Periarteritis | 13 | 16 | 17 | 17 | 8 |
|
|
|
|
| |
UTERINE CERVIX | No.Examined | - | - | - | - | - | 50 | 50 | 50 | 50 | 50 |
Squamous cell hyperplasia |
|
|
|
|
| 8 | 9 | 2 | 3 | 2 | |
THYROID GLAND | No.Examined | 50 | 50 | 50 | 50 | 50 | 50 | 50 | 50 | 50 | 50 |
Colloidal alteration | 23 | 23 | 28 | 28 | 35 | 2 | 5 | 2 | 5 | 3 | |
ADRENAL CORTICES | No.Examined | 50 | 50 | 50 | 50 | 50 | 50 | 50 | 50 | 50 | 50 |
Diffuse hypertrophy and vacuolization | 3 | 1 | 5 | 5 | 25 | 0 | 0 | 0 | 0 | 0 | |
Peliosis | 2 | 1 | 0 | 0 | 1 | 35 | 38 | 39 | 34 | 28 | |
ADRENAL MEDULLAS | No.Examined | 50 | 50 | 50 | 50 | 50 | 50 | 49 | 50 | 50 | 50 |
Focal hyperplasia | 13 | 16 | 16 | 17 | 6 | 6 | 6 | 9 | 7 | 2 | |
SPLEEN | No.Examined | 50 | 50 | 50 | 50 | 50 | 50 | 50 | 50 | 50 | 50 |
Pigment deposits | 7 | 9 | 8 | 9 | 0 | 21 | 24 | 26 | 23 | 6 | |
THYMUS | No.Examined | 48 | 50 | 48 | 50 | 50 | 49 | 50 | 49 | 50 | 48 |
Epithelial glandular hyperplasia | 8 | 6 | 3 | 4 | 2 | 26 | 24 | 26 | 27 | 18 | |
MESENT. LYMPH NODE | No.Examined | 50 | 50 | 50 | 49 | 49 | 49 | 50 | 50 | 50 | 50 |
Pigment deposits | 33 | 30 | 24 | 24 | 9 | 32 | 31 | 33 | 36 | 13 |
- = not available
Incidence of Neoplasms (including Intercurrent Deaths)
Sex Dose (ppm) Organ/ Findings |
0 |
50 | Males 100 |
350 |
2500 |
0 | Females 50 100 |
350 |
2500 | ||
BRAIN | No. Examined | 50 | 50 | 50 | 50 | 50 | 50 | 50 | 50 | 50 | 50 |
- Astrocytoma (b) | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | |
- Malignant astrocytoma (m) | 0 | 0 | 0 | 1 | 1 | 0 | 0 | 0 | 0 | 0 | |
- Oligodendroglioma (m) | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | |
- Granular cell tumor (b) | 2 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 2 | 0 | |
SPINAL CORD | No. Examined | 50 | 50 | 50 | 50 | 49 | 50 | 50 | 50 | 50 | 50 |
- Astrocytoma Benign (b) | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | |
- Neurilemmoma (b) | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | |
HEART | No. Examined | 50 | 50 | 50 | 50 | 50 | 50 | 50 | 50 | 50 | 50 |
- Malignant atriocaval mesothelioma (m) | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | |
- Malignant endocardial schwannoma (m) | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | |
PHARYNX | No. Examined | 50 | 50 | 50 | 50 | 50 | 50 | 50 | 50 | 50 | 50 |
- Malignant Schwannoma (m) |
|
|
|
|
| 0 | 1 | 0 | 0 | 0 | |
GLANDULAR STOMACH No. Examined | 50 | 50 | 50 | 50 | 50 | 50 | 50 | 50 | 50 | 50 | |
- Leiomyosarcoma (m) | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | |
JEJUNUM | No. Examined | 50 | 50 | 50 | 50 | 50 | 50 | 49 | 50 | 50 | 50 |
- Leiomyoma (b) | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | |
- Leiomyosarcoma (m) | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 1 | |
ILEUM | No. Examined | 50 | 50 | 50 | 50 | 49 | 50 | 50 | 50 | 50 | 50 |
- Adenoma (b) | 0 | 0 | 1 | 0 | 0 |
|
|
|
|
| |
LIVER | No. Examined | 50 | 50 | 50 | 50 | 50 | 50 | 50 | 50 | 50 | 50 |
- Cholangioma (b) | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | |
- Hepatocellular carcinoma (m) | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | |
- Hepatocellular adenoma (b) | 2 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | |
PANCREAS | No. Examined | 50 | 50 | 50 | 50 | 50 | 50 | 50 | 50 | 50 | 50 |
- Mixed acinar-islet cell adenoma (b) | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | |
- Islet cell carcinoma (m) | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | |
- Islet cell adenoma (b) | 0 | 0 | 2 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | |
KIDNEYS | No. Examined | 50 | 50 | 50 | 50 | 50 | 50 | 50 | 50 | 50 | 50 |
- Liposarcoma (m) | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | |
TESTES | No. Examined | 50 | 50 | 50 | 50 | 50 | - | - | - | - | - |
- Benign Leydig cell tumor (b) | 2 | 1 | 0 | 4 | 10 |
|
|
|
|
| |
OVARIES | No. Examined | - | - | - | - | - | 50 | 50 | 50 | 50 | 50 |
- Benign luteoma (b) |
|
|
|
|
| 1 | 0 | 0 | 0 | 0 | |
- Benign sex cord stromal tumor (b) |
|
|
|
|
| 0 | 0 | 2 | 0 | 0 | |
- Benign thecoma (b) |
|
|
|
|
| 1 | 2 | 1 | 0 | 0 | |
- Malignant thecoma (m) |
|
|
|
|
| 1 | 0 | 0 | 0 | 0 |
Incidence of Neoplasms (including Intercurrent Deaths) (continued)
Sex Dose (ppm) Organ/ Findings |
0 |
50 | Males 100 |
350 |
2500 |
0 | Females 50 100 |
350 |
2500 | ||
UTERUS | No. Examined | - | - | - | - | - | 50 | 50 | 50 | 50 | 50 |
- Adenocarcinoma (m) |
|
|
|
|
| 4 | 5 | 3 | 2 | 14 | |
- Adenoma (b) |
|
|
|
|
| 0 | 0 | 0 | 1 | 0 | |
- Adenosquamous carcinoma (m) |
|
|
|
|
| 0 | 0 | 0 | 0 | 1 | |
- Glandular polyp (b) |
|
|
|
|
| 1 | 2 | 0 | 0 | 2 | |
- Granular cell tumor (b) |
|
|
|
|
| 0 | 2 | 1 | 0 | 0 | |
- Malignant mixed Muellerian tumor (m) |
|
|
|
|
| 0 | 0 | 1 | 0 | 0 | |
- Malignant Schwannoma (m) |
|
|
|
|
| 1 | 0 | 0 | 1 | 0 | |
- Squamous cell carcinoma (m) |
|
|
|
|
| 1 | 0 | 0 | 0 | 1 | |
- Stromal cell sarcoma (m) |
|
|
|
|
| 1 | 0 | 0 | 0 | 0 | |
- Stromal polyp (b) |
|
|
|
|
| 9 | 8 | 7 | 11 | 10 | |
CERVIX | No. Examined | - | - | - | - | - | 50 | 50 | 50 | 50 | 50 |
- Granular cell tumor (b) |
|
|
|
|
| 0 | 2 | 0 | 0 | 0 | |
VAGINA | No. Examined | - | - | - | - | - | 49 | 50 | 50 | 50 | 49 |
- Squamous cell carcinoma (m) |
|
|
|
|
| 0 | 1 | 0 | 0 | 0 | |
PITUITARY GLAND | No. Examined | 50 | 50 | 50 | 50 | 50 | 50 | 50 | 50 | 50 | 50 |
- Adenoma of pars distalis (b) | 11 | 13 | 13 | 12 | 5 | 19 | 21 | 25 | 25 | 16 | |
THYROID GLAND | No. Examined | 50 | 50 | 50 | 50 | 50 | 50 | 50 | 50 | 50 | 50 |
- C-cell adenoma (b) | 4 | 6 | 5 | 4 | 7 | 2 | 2 | 3 | 5 | 6 | |
- C-cell carcinoma (m) | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | |
- Follicular cell adenoma (b) | 1 | 1 | 2 | 2 | 1 | 0 | 0 | 0 | 0 | 1 | |
ADRENAL CORTICES | No. Examined | 50 | 50 | 50 | 50 | 50 | 50 | 50 | 50 | 50 | 50 |
- Adenoma (b) | 0 | 1 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | |
ADRENAL MEDULLAS | No. Examined | 50 | 50 | 50 | 50 | 50 | 50 | 49 | 50 | 50 | 50 |
- Benign medullary tumor (b) | 6 | 10 | 6 | 9 | 5 | 2 | 0 | 0 | 0 | 2 | |
- Malignant medullary tumor (m) | 0 | 0 | 2 | 1 | 1 | 0 | 0 | 0 | 0 | 0 | |
- Tumor/NOS (b) | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | |
HEMOLYMPHORETICULAR SYSTEM | 50 | 50 | 50 | 50 | 50 | 50 | 50 | 50 | 50 | 50 | |
No. Examined |
|
|
|
|
|
|
|
|
|
| |
- Granulocytic leukemia (m) | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 2 | |
- Histiocytic sarcoma (m) | 0 | 2 | 0 | 3 | 1 | 0 | 0 | 0 | 0 | 1 | |
- Malignant fibrous histiocytoma (m) | 0 | 1 | 1 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | |
- Malignant lymphoma (m) | 0 | 1 | 0 | 0 | 1 | 1 | 1 | 1 | 1 | 0 | |
SPLEEN | No. Examined | 50 | 50 | 50 | 50 | 50 | 50 | 50 | 50 | 50 | 50 |
- Hemangiosarcoma (m) | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | |
THYMUS | No. Examined | 48 | 50 | 48 | 50 | 50 | 49 | 50 | 49 | 50 | 48 |
- Hibernoma (m) | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | |
- Malignant thymoma (m) | 1 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | |
- Benign thymoma (b) | 0 | 0 | 3 | 2 | 0 | 4 | 1 | 1 | 2 | 3 |
Incidence of Neoplasms (including Intercurrent Deaths) (continued)
Sex Dose (ppm) Organ/ Findings |
0 |
50 | Males 100 |
350 |
2500 |
0 | Females 50 100 |
350 |
2500 | ||
MESENTERIC LYMPH NODE No. Examined | 50 | 50 | 50 | 49 | 49 | 49 | 50 | 50 | 50 | 50 | |
- Hemangioma (b) | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | |
MAMMARY GLAND | No. Examined | 50 | 50 | 50 | 49 | 50 | 50 | 50 | 50 | 50 | 50 |
- Adenocarcinoma arising in fibroadenoma (m) |
|
|
|
|
| 1 | 0 | 0 | 0 | 0 | |
- Adenocarcinoma (m) |
|
|
|
|
| 1 | 1 | 2 | 0 | 2 | |
- Adenoma (b) |
|
|
|
|
| 0 | 0 | 1 | 0 | 0 | |
- Fibroadenoma (b) |
|
|
|
|
| 9 | 6 | 9 | 7 | 4 | |
SKIN/OTHER | No. Examined | 7 | 4 | 6 | 4 | 2 | 2 | 3 | 5 | 2 | 2 |
- Basal cell carcinoma (m) | 1 | 1 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | |
- Fibrosarcoma (m) | 1 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | |
- Hair follicle tumor (b) | 0 | 0 | 1 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | |
- Keratoacanthoma (b) | 1 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | |
- Maligant schwannoma (m) | 1 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | |
- Fibroma (b) | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 | |
BODY CAVITIES | No. Examined | 1 | 1 | 1 | 1 | 1 | 5 | 1 | 3 | 2 | 5 |
- Malignant mesothelioma (m) | 1 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | |
ORAL CAVITY | No. Examined | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 |
- Squamous carcinoma (m) | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 |
- = not available (m) = malignant (b) = benign NOS = not otherwise specified
Incidence of Neoplasms (Intercurrent Deaths)
Sex Males Dose (ppm) Organ/ Findings |
0 |
50 | Males 100 |
350 |
2500 |
0 | Females 50 100 |
350 |
2500 | ||
BRAIN | No. Examined | 19 | 20 | 14 | 19 | 9 | 21 | 18 | 19 | 15 | 24 |
- Malignant astrocytoma (m) | 0 | 0 | 0 | 1 | 1 | 0 | 0 | 0 | 0 | 0 | |
- Granular cell tumor (b) | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 1 | 0 | |
HEART | No. Examined | 19 | 20 | 14 | 19 | 9 | 21 | 18 | 19 | 15 | 24 |
- Malignant endocardial schwannoma (m) | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | |
- Malignant atriocaval mesothelioma (m) | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | |
PHARYNX | No. Examined | 19 | 20 | 14 | 19 | 9 | 21 | 18 | 19 | 15 | 24 |
- Malignant Schwannoma (m) | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | |
JEJUNUM | No. Examined | 19 | 20 | 14 | 19 | 9 | 21 | 17 | 19 | 15 | 24 |
- Leiomyosarcoma (m) | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | |
LIVER | No. Examined | 19 | 20 | 14 | 19 | 9 | 21 | 18 | 19 | 15 | 24 |
- Cholangioma (b) | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | |
- Hepatocellular adenoma (b) | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | |
PANCREAS | No. Examined | 19 | 20 | 14 | 19 | 9 | 21 | 18 | 19 | 15 | 24 |
- Mixed acinar-islet cell adenoma (b) | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | |
- Islet cell carcinoma (m) | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | |
KIDNEYS | No. Examined | 19 | 20 | 14 | 19 | 9 | 21 | 18 | 19 | 15 | 24 |
- Liposarcoma (m) | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | |
TESTES | No. Examined | 19 | 20 | 14 | 19 | 9 | - | - | - | - | - |
- Benign Leydig cell tumor (b) | 0 | 0 | 0 | 0 | 1 |
|
|
|
|
| |
OVARIES | No. Examined | - | - | - | - | - | 21 | 18 | 19 | 15 | 24 |
- Benign luteoma (b) |
|
|
|
|
| 1 | 0 | 0 | 0 | 0 | |
- Benign sex cord stromal tumor (b) |
|
|
|
|
| 0 | 0 | 1 | 0 | 0 | |
- Benign thecoma (b) |
|
|
|
|
| 0 | 0 | 1 | 0 | 0 | |
UTERUS | No. Examined | - | - | - | - | - | 21 | 18 | 19 | 15 | 24 |
- Adenocarcinoma (m) |
|
|
|
|
| 2 | 2 | 1 | 2 | 11 | |
- Adenosquamous carcinoma (m) |
|
|
|
|
| 0 | 0 | 0 | 0 | 1 | |
- Glandular polyp (b) |
|
|
|
|
| 1 | 1 | 0 | 0 | 0 | |
- Granular cell tumor (b) |
|
|
|
|
| 0 | 1 | 1 | 0 | 0 | |
- Malignant Schwannoma (m) |
|
|
|
|
| 1 | 0 | 0 | 1 | 0 | |
- Squamous cell carcinoma (m) |
|
|
|
|
| 1 | 0 | 0 | 0 | 1 | |
- Stromal cell sarcoma (m) |
|
|
|
|
| 1 | 0 | 0 | 0 | 0 | |
- Stromal polyp (b) |
|
|
|
|
| 5 | 3 | 2 | 4 | 3 | |
CERVIX | No. Examined | - | - | - | - | - | 21 | 18 | 19 | 15 | 24 |
- Granular cell tumor (b) |
|
|
|
|
| 0 | 1 | 0 | 0 | 0 | |
VAGINA | No. Examined | - | - | - | - | - | 20 | 18 | 19 | 15 | 23 |
- Squamous cell carcinoma (m) |
|
|
|
|
| 0 | 1 | 0 | 0 | 0 | |
PITUITARY GLAND | No. Examined | 19 | 20 | 14 | 19 | 9 | 21 | 18 | 19 | 15 | 24 |
- Adenoma of pars distalis (b) | 4 | 4 | 2 | 2 | 2 | 10 | 9 | 9 | 7 | 7 |
Incidence of Neoplasms (Intercurrent Deaths) (continued)
Sex Males Dose (ppm) Organ/ Findings |
0 |
50 | Males 100 |
350 |
2500 |
0 | Females 50 100 |
350 |
2500 | ||
THYROID GLAND | No. Examined | 19 | 20 | 14 | 19 | 9 | 21 | 18 | 19 | 15 | 24 |
- C-cell adenoma (b) | 0 | 2 | 1 | 0 | 0 | 1 | 0 | 0 | 1 | 2 | |
- C-cell carcinoma (m) | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | |
- Follicular cell adenoma (b) | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | |
ADRENAL CORTICES | No. Examined | 19 | 20 | 14 | 19 | 9 | 21 | 18 | 19 | 15 | 24 |
- Adenoma (b) | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | |
ADRENAL MEDULLAS | No. Examined | 19 | 20 | 14 | 19 | 9 | 21 | 18 | 19 | 15 | 24 |
- Benign medullary tumor (b) | 1 | 3 | 3 | 5 | 1 | 0 | 0 | 0 | 0 | 2 | |
- Malignant medullary tumor (m) | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | |
- Tumor/N0S (b) | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | |
HEMOLYMPHORETICULAR SYSTEM | 19 | 20 | 14 | 19 | 9 | 21 | 18 | 19 | 15 | 24 | |
No. Examined |
|
|
|
|
|
|
|
|
|
| |
- Granulocytic leukemia (m) | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 2 | |
- Histiocytic sarcoma (m) | 0 | 1 | 0 | 2 | 1 | 0 | 0 | 0 | 0 | 1 | |
- Malignant fibrous histiocytoma (m) | 0 | 1 | 1 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | |
- Malignant lymphoma (m) | 0 | 1 | 0 | 0 | 1 | 1 | 1 | 1 | 1 | 0 | |
THYMUS | No. Examined | 18 | 20 | 13 | 19 | 9 | 21 | 18 | 18 | 15 | 22 |
- Hibernoma (m) | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | |
- Benign thymoma (b) | 0 | 0 | 1 | 1 | 0 | 3 | 0 | 0 | 0 | 2 | |
MESENTERIC LYMPH NODE No. Examined | 19 | 20 | 14 | 19 | 9 | 21 | 18 | 19 | 15 | 24 | |
- Hemangioma (b) | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | |
MAMMARY GLAND | No. Examined | 19 | 20 | 14 | 18 | 9 | 21 | 18 | 19 | 15 | 24 |
- Adenocarcinoma (m) | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 2 | |
- Fibroadenoma (b) | 0 | 0 | 0 | 0 | 0 | 3 | 3 | 7 | 1 | 2 | |
SKIN/OTHER | No. Examined | 4 | 3 | 3 | 2 | 1 | 2 | 1 | 4 | 0 | 1 |
- Basal cell carcinoma (m) | 1 | 1 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | |
- Fibrosarcoma (m) | 1 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | |
- Fibroma (b) | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | |
- Maligant schwannoma (m) | 1 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | |
BODY CAVITIES | No. Examined | 1 | 0 | 1 | 1 | 0 | 5 | 1 | 1 | 2 | 5 |
- Malignant mesothelioma (m) | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | |
ORAL CAVITY | No. Examined | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 |
- Squamous carcinoma (m) | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 |
ne = not examined (m) = malignant(b) = benign NOS = not otherwise specified ot available
Table 5.5.1i: Rats Intended for Terminal Necropsy with Benign and/or Malignant Tumors
Sex | Males | Females |
Dose (ppm) | 0 50 100 350 2500 | 0 50 100 350 2500 |
n | 50 50 50 50 50 | 50 50 50 50 50 |
| Animals Deceased During Treatment | |
Number of Animals Examined | 19 20 14 19 9 | 21 18 19 15 24 |
Animals with Neoplasms | 8 11 9 12 6 | 19 16 14 14 22 |
Animals with only Benign Neoplasms | 3 5 6 7 2 | 11 9 9 9 6 |
Animals with only Malignant Neoplasms | 2 3 2 5 3 | 2 1 1 2 7 |
Animals with both Neoplasms | 3 3 1 0 1 | 6 6 4 3 9 |
| Terminal Necropsy | |
Number of Animals Examined | 31 30 36 31 41 | 29 32 31 35 26 |
Animals with Neoplasms | 17 16 24 18 21 | 17 20 22 28 17 |
Animals with only Benign Neoplasms | 15 15 21 15 19 | 12 17 17 26 13 |
Animals with only Malignant Neoplasms | 1 0 2 1 1 | 0 1 2 1 1 |
Animals with both Neoplasms | 1 1 1 2 1 | 5 2 3 1 3 |
| All Animals Intended for Terminal Necropsy | |
Number of Animals Examined | 50 50 50 50 50 | 50 50 50 50 50 |
Animals with Neoplasms | 25 27 33 30 27 | 36 36 36 42 39 |
Animals with only Benign Neoplasms | 18 20 27 22 21 | 23 26 26 35 19 |
Animals with only Malignant Neoplasms | 3 3 4 6 4 | 2 2 3 3 8 |
Animals with both Neoplasms | 4 4 2 2 2 | 11 8 7 4 12 |
Table 5.5.1j: Tumor Bearing Animals Scheduled for Interim Necropsy
Dose (ppm) | 0 | 50 | 100 | 350 | 2500 | 0 | 50 | 100 | 350 | 2500 | |
Sex | m | m | m | m | m | f | f | f | f | f | |
n | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | |
Weeks |
|
|
|
|
|
|
|
|
|
| |
1 - 13 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | |
14 - 26 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | |
27 - 39 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | |
40 - 52 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | |
53 - 54 | 0 | 0 | 0 | 0 | 0 | 2 | 1 | 0 | 1 | 1 | |
1 - | 54 | 0 | 0 | 0 | 0 | 1 | 2 | 1 | 0 | 1 | 1 |
Table 5.5.1k: Tumor Bearing Animals Scheduled for Terminal Necropsy
Dose (ppm) | 0 | 50 | 100 | 350 | 2500 | 0 | 50 | 100 | 350 | 2500 | |
Sex | m | m | m | m | m | f | f | f | f | f | |
n | 50 | 50 | 50 | 50 | 50 | 50 | 50 | 50 | 50 | 50 | |
Weeks |
|
|
|
|
|
|
|
|
|
| |
1 - 13 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | |
14 - 26 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | |
27 - 39 | 1 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | |
40 - 52 | 1 | 0 | 0 | 0 | 1 | 1 | 0 | 0 | 1 | 0 | |
53 - 65 | 2 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 2 | |
66 - 78 | 1 | 1 | 0 | 1 | 2 | 1 | 1 | 3 | 1 | 3 | |
79 - 91 | 1 | 1 | 2 | 5 | 2 | 4 | 9 | 3 | 3 | 7 | |
92 - 104 | 2 | 6 | 6 | 3 | 1 | 12 | 5 | 8 | 7 | 9 | |
105 - 109 | 17 | 18 | 25 | 21 | 21 | 18 | 21 | 22 | 28 | 18 | |
1 | - 109 | 25 | 27 | 33 | 30 | 27 | 36 | 36 | 36 | 42 | 39 |
Table 1 - Oncogenicity study in male mice: Absolute Organ Weights (mg)
Dose (ppm) | 0 | 25 | 3500 | 7000 |
Liver | 2303 | 2421 | 2593* | 2720* |
Adrenals | 8 | 8 | 12* | 15* |
Kidneys | 937 | 960 | 787* | 711* |
Testes | 203 | 204 | 225 | 242* |
* p ≤ 0.05, ** p ≤ 0.01
Table 2 - Oncogenicity study in female mice: Absolute Organ Weights (mg)
Dose (ppm) | 0 | 25 | 3500 | 7000 |
Liver | 2254 | 2149 | 2315 | 2566* |
Adrenals | 13 | 13 | 19* | 23* |
Kidneys | 679 | 658 | 558* | 530* |
* p ≤ 0.05, ** p ≤ 0.01
Table 3 - Oncogenicity study in male mice: Relative Organ Weights (mg/100 g)
Dose (ppm) | 0 | 25 | 3500 | 7000 |
Liver | 5797 | 6051 | 6818* | 7108* |
Adrenals | 22 | 21 | 31* | 40* |
Kidneys | 2365 | 2402 | 2062* | 1861* |
Testes | 515 | 513 | 593* | 636* |
* p ≤ 0.05, ** p ≤ 0.01
Table 4 - Oncogenicity study in female mice: Relative Organ Weights (mg/100 g)
Dose (ppm) | 0 | 25 | 3500 | 7000 |
Liver | 6179 | 6063 | 6704 | 7454* |
Adrenals | 36 | 38 | 54* | 66* |
Kidneys | 1864 | 1858 | 1627* | 1542* |
* p ≤ 0.05, ** p ≤ 0.01
Table 5 - Oncogenicity study in mice: Non-neoplastic changes in animals scheduled for final necropsy
Dose (ppm) | 0 | 25 | 3500 | 7000 | 0 | 25 | 3500 | 7000 |
Gender | M | M | M | M | F | F | F | F |
LIVER (n) | 50 | 50 | 50 | 50 | 50 | 50 | 50 | 50 |
Hepatocytomegaly | 2 | 6 | 17* | 21* | 0 | 0 | 0 | 1 |
ADRENALS (n) | 50 | 49 | 50 | 49 | 50 | 49 | 50 | 50 |
Vacuolization | 0 | 0 | 31* | 37* | 1 | 6 | 49* | 48* |
Pigmentation | 7 | 5 | 11 | 27* | 11 | 20* | 45* | 42* |
* p ≤ 0.05, ** p ≤ 0.01
Table 6 - Oncogenicity study in mice: Neoplastic changes in animals scheduled for final necropsy
Dose (ppm) | 0 | 25 | 3500 | 7000 | 0 | 25 | 3500 | 7000 |
Gender | M | M | M | M | F | F | F | F |
LIVER (n) | 50 | 50 | 50 | 50 | 50 | 50 | 50 | 50 |
hepatocell. adenoma (b) | 0 | 0 | 5 | 6 | 0 | 0 | 3 | 1 |
hepatocell. carcinoma (m) | 1 | 1 | 3 | 5 | 0 | 0 | 2 | 2 |
m = malign, b = benign
Table 7 - Oncogenicity study in mice: Number of animals (unscheduled sacrifice + found dead) with tumors
Dose (ppm) | 0 | 25 | 3500 | 7000 | 0 | 25 | 3500 | 7000 |
Gender | M | M | M | M | F | F | F | F |
n | 12 | 11 | 10 | 14 | 12 | 12 | 12 | 14 |
benign tumour | 3 | 0 | 0 | 2 | 2 | 0 | 0 | 4 |
malignant tumour | 2 | 5 | 1 | 2 | 9 | 7 | 6 | 5 |
total no. any type | 5 | 5 | 1 | 4 | 9 | 7 | 6 | 9 |
Table 8 - Oncogenicity study in mice: Number of animals (unscheduled + terminal) with tumors
Dose (ppm) | 0 | 25 | 3500 | 7000 | 0 | 25 | 3500 | 7000 |
Gender | M | M | M | M | F | F | F | F |
n | 50 | 50 | 50 | 50 | 50 | 50 | 50 | 50 |
benign tumour | 11 | 16 | 9 | 10 | 12 | 13 | 10 | 13 |
malignant tumour | 10 | 12 | 5 | 9 | 21 | 20 | 17 | 17 |
total no. any type | 19 | 25 | 13 | 17 | 27 | 30 | 27 | 26 |
Table 9 - Oncogenicity study in mice: Number of tumors
Dose (ppm) | 0 | 25 | 3500 | 7000 | 0 | 25 | 3500 | 7000 |
Gender | M | M | M | M | F | F | F | F |
n | 50 | 50 | 50 | 50 | 50 | 50 | 50 | 50 |
benign tumour | 11 | 17 | 11 | 10 | 16 | 15 | 12 | 15 |
malignant tumour | 11 | 13 | 5 | 9 | 21 | 23 | 19 | 18 |
Endpoint conclusion
- Endpoint conclusion:
- adverse effect observed
- Dose descriptor:
- LOAEL
- Study duration:
- chronic
- Species:
- mouse
- Quality of whole database:
- GLP- and guideline-compliant studies of chronic toxicity/carcinogenicity in the rat and mouse are available for spirodiclofen.
- System:
- endocrine system
- Organ:
- liver
- testes
- uterus
Carcinogenicity: via inhalation route
Endpoint conclusion
- Endpoint conclusion:
- no study available
Carcinogenicity: via dermal route
Endpoint conclusion
- Endpoint conclusion:
- no study available
Justification for classification or non-classification
Spirodiclofen has a harmonised classification for carcinogenicity in Category 1B. Based on the available mutagenicity tests, RAC concluded that the mechanism(s) for the carcinogenic effect of spirodiclofen was probably non-genotoxic. In the mouse study, RAC concluded that the combined frequency of hepatocellular tumours (hepatocellular adenoma and carcinoma) was significantly increased over controls in 3500 and 7000 ppm males and in 3500 ppm females. In the rat study, RAC concluded that the frequency of benign Leydig cell tumours was markedly increased at 2500 ppm. In the uterus of female rats, adenocarcinomas were increased at 2500 ppm. RAC concluded that classification for carcinogenicity in Cat 1B was appropriate on the basis of a combination of benign and malignant metastatic neoplasms in two or more species.
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