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Carcinogenicity

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Description of key information

Carcinogenesis studies of Monuron were conducted in rats and mice by feeding diets lasting for 103-104 weeks. In rats, target concentrations were 0, 750, or 1500 ppm and effective concentrations were 0, 747 and 1514 ppm , corresponding with 60 and 121 mg/kg bw. There was clear evidence of carcinogenicity for male rats showing increased incidences of tubular cell adenocarcinomas of the kidney, tubular cell adenomas of the kidney, and neoplastic nodules or carcinomas (combined) of the liver. Monuron induced cytomegaly of the renal tubular epithelial cells in both male and female rats. There was no evidence of carcinogenicity for female rats. In mice target concentrations were 0, 5000, or 10000 ppm and effective concentrations were 4965 and 10004 ppm, corresponding to 993 and 2001 mg/kg bw. There was no evidence of carcinogenicity for male or female B6C3F1 mice.

The Carcinogenicity Potency Database (CPDB) reports a TD50(dose that is tumorigenic in 50% of rats) of 131 mg/kg bw, with kidney and liver as target organs (as explained above). This corresponds with a T25 of 65 mg/kg bw.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records
Reference
Endpoint:
carcinogenicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1979-1981
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
test procedure in accordance with generally accepted scientific standards and described in sufficient detail
GLP compliance:
not specified
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: Lot no. D-A330 obtained from the Hopkins Chemical Co. (Madison, WI) in one lot
- Expiration date of the lot/batch: The purity and identity determinations were made three times per year at the Study Laboratory and showed that the chemical maintained its identity and purity throughout the studies.
- Purity test date: Not provided.

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: A heat stability study performed by the analytical chemistry laboratory indicated that the compound was stable in storage. After receiving the study chemical from the analytical chemistry laboratory, the study laboratory stored it at 0° ± 5° C. Periodic characterization of the chemical at EG&G Mason Research Institute by infrared spectroscopy and thin-layer chromatography indicated that no detectable decomposition occurred during the studies.
- Stability under test conditions: Monuron was stable in feed when stored for 2 weeks at 25°C or below.
- Solubility and stability of the test substance in the solvent/vehicle: Monuron was stable in feed when stored for 2 weeks at 25°C or below.
The mixture of monuron in stock rodent feed at the 0.5% (5000 ppm) concentration was more homogenous after 15 minutes than after 10 minutes mixing in a 4-qt Patterson-Kelly Twin-Shell® blender with intensifier bar. The variations in the samples of the 15-minute mixture are within 10% of the target concentration of chemical in the feed.

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: After receiving the study chemical from the analytical chemistry laboratory, the study laboratory stored it at 0° ± 5° C.
- Final preparation of a solid: The study laboratory prepared formulated diets by layering a dry premix between portions of feed and blending the mixture for 15 minutes.
1.Premix: Monuron (7.54 g ± 0.01 g) was added directly to 100 g of Wayne Lab Blox® rodent feed.
This premixture was homogenized in a 1-qt large-mouth glass jar rotated for 15 minutes on a ball-mill type tumbler apparatus, with manual end-over-end tumbling every 5 minutes.
2.Bulk mixing: The above premix and 1400 g more feed were mixed in a Patterson-Kelly Twin-Shell® blender for 15 minutes. The blender was loaded from the top of the shells as follows: 700 g of feed was poured in and allowed to settle and level at the bottom (vertex of the "V"); then the dried premix was poured in on top of the feed from each side; this layer was covered with the remaining 700 g of feed poured in from each side. After 10-and 15minute mixing times, duplicate 5-g samples were removed from the top of each shell and the bottom trap of blender for subsequent analysis.
Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals and environmental conditions:
- Source: Charles River Breeding Laboratories (Portage, Ml)
- Age at study initiation (when placed on study): 7 wk
- Housing: Polycarbonate cages (Lab Products, Inc., Rochelle Park, NJ) with Nonwoven fiber cage filters (Lab Products, Inc., Rochelle Park, NJ, and Snow Filtration, Cincinnati, OH) and Aspen Bed® hardwood chips (American Excelsior Co., Baltimore, MD) as bedding material; 5 animals per cage
- Diet (e.g. ad libitum): Wayne Lab Blox® (Allied Mills, Inc., Chicago, IL); ad libitum
- Water (e.g. ad libitum): Tap, available ad libitum via automatic watering system (Edstrom Industries, Waterford, WI)
- Acclimation period: 16 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 24° C average, range 18°-33° C
- Humidity (%): 51.3% average relative humidty; range 8%-80%
- Air changes (per hr): 10 changes room air/h
- Photoperiod (hrs dark / hrs light): fluorescent light 12 h/d

IN-LIFE DATES:
From: First dosing: 12 July 1979
To: 13 July 1981-22 July 1981 (killed at 111-113 wks old)
Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Duration of treatment / exposure:
103 weeks
Frequency of treatment:
continuous exposure in the food
Post exposure period:
1 week
Dose / conc.:
0 ppm
Remarks:
target concentration; 0 ppm experimental mean concentration
Dose / conc.:
750 ppm
Remarks:
target concentration; 747 ppm experimental mean concentration
Dose / conc.:
1 500 ppm
Remarks:
target concentration; 1514 ppm experimental mean concentration
No. of animals per sex per dose:
50
Control animals:
yes, concurrent no treatment
Details on study design:
- Rationale for animal assignment: Distributed to cages and then to groups according to two separate tables of random numbers.
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
All animals were observed two times per day. Animals found moribund were humanely killed.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Clinical signs were recorded once per week.

BODY WEIGHT: Yes
- Time schedule for examinations: Body weights by cage were recorded once per week for the first 13 weeks of the study and once per month thereafter. Mean body weights were calculated for each group.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
The average feed consumption per animal was calculated by dividing the total feed consumption for all cages in the dose groups by the number of surviving animals in the group.
Sacrifice and pathology:
GROSS PATHOLOGY: Yes. A necropsy was performed on all animals, including those found dead,unless they were excessively autolyzed or cannibalized, missexed, or found missing. Thus, the number of animals from which particular organs or tissues were examined microscopically varies and is not necessarily equal to the number of animals that were placed on study.
Examinations for grossly visible lesions were performed on major tissues or organs. The following t issues were examined in all groups: tissue masses, abnormal lymph nodes, skin, mandibular lymph nodes, mammary gland, thigh muscle, sciatic nerve, bone marrow, costochondral junction, thymus, larynx, trachea, lungs and bronchi, heart, thyroid gland, parathyroids, esophagus, stomach, duodenum, jejunum, colon, mesenteric lymph nodes, liver, gallbladder (mice), pancreas, spleen, kidneys, adrenal glands, urinary bladder, seminal vesicles/prostate/testes or ovaries/uterus, brain, pituitary gland, eyes, external and middle ear, stomach, ileum, salivary glands, nasal cavity, and spinal cord.

HISTOPATHOLOGY: Yes. Tissues were preserved in 10% neutral buffered formalin, embedded in paraffin, sectioned, and stained with hematoxylin and eosin. Tissues examined microscopically were:
tissue masses, abnormal lymph nodes, skin, mandibular lymph nodes, mammary gland, bone marrow, costochondral junction, thymus, larynx, trachea, lungs and bronchi, heart, thyroid gland, parathyroids, esophagus, stomach, duodenum, jejunum, colon, mesenteric lymph nodes, liver, gallbladder (mice), pancreas, spleen, kidneys, adrenal glands, urinary bladder, seminal vesicles/prostate/testes or ovaries/uterus, brain, pituitary gland, stomach, ileum, salivary glands.
Description (incidence and severity):
After 6 months on study, one male and one female sentinel rat showed positive titers to rat coronavirus (RCV); by 12 months, virtually all animals were infected. An infection by pneumonia virus of mice (PVM) was detected in all male and female sentinel rats during the 18th month of the test.
Description (incidence):
In groups of male rats, 28/50 (56%) control, 45/50 (90%) low dose, and 41/50 (82%) high dose rats lived to the termination of the study at 105-106 weeks. The death of 11 control male rats at week 93 of the study was due to a malfunction in a thermostat, which allowed the animal room to overheat. Cages housing control animals were at the top of the racks where temperatures may have been higher.
Survival of low dose female rats was significantly greater than that of the control group (P=0.034). In groups of female rats, 38/50 (76%) control, 44/50 (88%) low dose, and 42/50 (84%) high dose rats lived to the termination of the study at 105-106 weeks.
The survival incidences include two control males, one low dose male, and four control females that died during the termination period of the study. For statistical purposes, these animals have been pooled with those killed at the end of the study.
Description (incidence and severity):
Mean body weights of dosed males and females were lower than those of the controls throughout most of the study.The mean body weights were inversely related to dose.
The weight gain decrement was established by the 8th week. This decrement was relatively steady for male rats throughout the study. The weight gain decrement increased slowly during the study for female rats.
Description (incidence and severity):
Low dose male and female rats consumed about as much feed as did the controls.
The average daily feed consumption per rat by low dose and high dose rats was 88% and 83% that by the controls for males and 87% and 72% for females. These daily intake amounts are actually measurements of amounts of feed removed from the feed containers; they cannot be considered as measurements of feed (and compound) intake because they have not been corrected for scattering and waste.
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Immunological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Non-neoplastic changes associated with the long-term administration of monuron to rats included renal tubular cell cytomegaly, mainly involving the proximal convoluted tubules in male and female rats, and dose-related hepatic cytoplasmic changes in male rats.
In the 104-week study, the kidneys and liver of male rats were the primary tissues affected.
No exceptional microscopic changes were found in the lymphocytic and hematopoietic tissues.
Histopathological findings: neoplastic:
effects observed, treatment-related
Description (incidence and severity):
There was clear evidence of carcinogenicity for male F344/N rats in that monuron caused increased incidences of tubular cell adenocarcinomas of the kidney, tubular cell adenomas of the kidney, and neoplastic nodules or carcinomas (combined) of the liver. Monuron induced cytomegaly of
the renal tubular epithelial cells in both male and female F344/N rats. There was no evidence of carcinogenicity for female F344/N rats.
Critical effects observed:
yes
Organ:
kidney
Treatment related:
yes
Critical effects observed:
yes
Organ:
liver
Treatment related:
yes
Conclusions:
In the two-year studies, renal tubular epithelial hypertrophy was noted at high incidence in rats (48/50 low-dose males and 50/50 high-dose males; 12/50 low-dose females and 49/50 high-dose females).
The nuclei of these cells were greatly enlarged, had anaplastic features and were sometimes multiple.
Dose-dependent hepatocytic changes and degeneration observed in males (but not females) and splenic haemosiderosis in female rats were the only other toxic effects clearly related to treatment in the two-year studies.
Under the conditions of these 2-year feed studies, there was clear evidence of carcinogenicity for male F344/N rats in that monuron caused increased incidences of tubular cell adenocarcinomas of the kidney, tubular cell adenomas of the kidney, and neoplastic nodules or carcinomas (combined) of the
liver. There was no evidence of carcinogenicity for female F344/N rats.
Executive summary:

Carcinogenesis studies of monuron (greater than 99% pure), a substituted urea herbicide, were conducted by feeding diets containing 0, 750, or 1500 ppm monuron to groups of 50 F344/N rats of each sex for 103 weeks. Survivors then were fed a control diet for 1 week, killed, and examined.

Throughout most of the studies, mean body weights of dosed rats of each sex were lower than those of the controls. Survival rates of low dose female rats were increased relative to those of the controls.

In 13-week toxicity studies, the lympho/hematopoietic system of rats was the primary site affected. The lymphoid depletion found in these animals was not seen in rats surviving to the end of the 104-week studies.

Non-neoplastic changes associated with the long-term administration of monuron to rats included renal tubular cell cytomegaly, mainly involving the proximal convoluted tubules in male and female rats, and dose-related hepatic cytoplasmic changes in male rats.

In the 104-week study, the kidneys and liver of male rats were the primary tissues affected. Longterm

administration of monuron was associated with an increase in renal tubular cell adenomas (control, 0/50; low dose, 2/50; high dose, 7/50) and renal tubular cell adenocarcinomas (0/50; 1/50; 8/50).

Administration of monuron to male rats was associated with increased incidences of neoplastic nodules of the liver (1/50; 6/49; 7/50) and of neoplastic nodules or carcinomas (combined) of the liver (1/50; 6/49; 9/50).

Dosed male and female rats had decreased incidences of mononuclear cell leukemia; dosed male rats had lower incidences of pheochromocytomas of the adrenal glands and C-cell carcinomas of the thyroid gland; dosed female rats had reduced incidences of mammary gland fibroadenomas.

Under the conditions of these 2-year feed studies, there was clear evidence of carcinogenicity for male F344/N rats in that monuron caused increased incidences of tubular cell adenocarcinomas of the kidney, tubular cell adenomas of the kidney, and neoplastic nodules or carcinomas (combined) of the liver.

Monuron induced cytomegaly of the renal tubular epithelial cells in both male and female F344/N rats.

There was no evidence of carcinogenicity for female F344/N rats.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
T25
65 mg/kg bw/day
Study duration:
chronic
Species:
rat
Quality of whole database:
Reliable
System:
other: renal and hepatobiliary
Organ:
kidney
liver

Carcinogenicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Carcinogenicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Carcinogenesis studies of Monuron were conducted by feeding diets containing target concentration of 0, 750, or 1500 ppm and effective concentrations of 0, 747 and 1514 ppm Monuron to groups of 50 F344/N rats of each sex for 103 weeks (NTP, 1988; IARC, 1991). Taking into account a mean body weight of 250 g and daily food consumption of 20 g in adult rats, these dose levels approximated 60 and 121 mg/kg bw. Throughout most of the studies, mean body weights of dosed rats of each sex were lower than those of the controls. Survival rates of low dose female rats were increased relative to those of the controls.

In 13-week toxicity studies, the lympho/hematopoietic system of rats was the primary site affected. The lymphoid depletion found in these animals was not seen in rats surviving to the end of the 104-week studies. Non-neoplastic changes associated with the long-term administration of monuron to rats included renal tubular cell cytomegaly, mainly involving the proximal convoluted tubules in male and female rats, and dose-related hepatic cytoplasmic changes in male rats. In the 104-week study, the kidneys and liver of male rats were the primary tissues affected. An increase in renal tubular cell adenomas (control, 0/50; low dose, 2/50; high dose, 7/50) and renal tubular cell adenocarcinomas (0/50; 1/50; 8/50), as well as neoplastic nodules of the liver (1/50; 6/49; 7/50) and neoplastic nodules or carcinomas (combined) of the liver (1/50; 6/49; 9/50) were observed. Dosed male and female rats had decreased incidences of mononuclear cell leukemia; dosed male rats had lower incidences of pheochromocytomas of the adrenal glands and C-cell carcinomas of the thyroid gland; dosed female rats had reduced incidences of mammary gland fibroadenomas. Under the conditions of these 2-year feed studies, there was clear evidence of carcinogenicity for male F344/N rats in that monuron caused increased incidences of tubular cell adenocarcinomas of the kidney, tubular cell adenomas of the kidney, and neoplastic nodules or carcinomas (combined) of the liver. Monuron induced cytomegaly of the renal tubular epithelial cells in both male and female F344/N rats. There was no evidence of carcinogenicity for female F344/N rats (NTP, 1988; IARC, 1991). The Carcinogenicity Potency Database (CPDB) reports a TD50 (dose that is tumorigenic in 50% of rats) of 131 mg/kg bw, with kidney and liver as target organs (as explained above). This would correspond with a T25 of 65 mg/kg bw.

 

Carcinogenesis studies of Monuron, were conducted by feeding diets containing target concentrations of 0, 5000, or 10000 ppm and effective concentrations of 4965 and 10004 Monuron to groups of 50 B6C3F1 mice of each sex for 103 weeks (NTP, 1988; IARC, 1991). Taking into account a mean body weight of 25 g and daily food consumption of 5 g in adult mice, these dose levels approximated 993 and 2001 mg/kg bw. Throughout most of the studies, mean body weights of dosed rats and mice of each sex were lower than those of the controls. Survival rates of high dose male and female mice were increased relative to those of the controls. In 13-week toxicity studies, the lympho/hematopoietic system of mice was the primary site affected. The lymphoid depletion found in these animals was not seen in mice surviving to the end of the 104-week studies. In the 104-week study, in male mice, dose-related decreases occurred in the incidences of hepatocellular carcinomas (6/50; 5/49; 2/50) and hepatocellular adenomas or carcinomas (12/50; 8/49; 6/50); incidences of hepatocellular tumors in low dose female mice were reduced, but the decreases were not dose related. The incidences of malignant lymphomas were reduced in dosed female mice (16/50; 8/50; 7/50). Under the conditions of these 2-year feed studies, there was no evidence of carcinogenicity for male or female B6C3F1 mice (NTP, 1988; IARC, 1991).

Justification for classification or non-classification

Monuron has a harmonised classification according to Annex VI of Regulation (EC) No 1272/2008 (CLP Regulation) for carcinogenicity as Carc. 2, H351 (suspected of causing cancer).