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Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
1978

Data source

Referenceopen allclose all

Reference Type:
publication
Title:
Toxicology and Carcinogenesis Studies of Monuron (CAS No.150-68-5) in F344/N Rats and B6C3F1 Mice (Feed Studies)
Author:
US National Toxicology Program, U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES, Public Health Service National Institutes of Health
Year:
1988
Bibliographic source:
US National Toxicology Program Technical Report Series No. 26 (1988)
Reference Type:
review article or handbook
Title:
IARC Monographs on the evaluation of carcinogenic risks to humans, Volume 53, Occupational Exposures in Insecticide Application, and Some Pesticides
Author:
International Agency for Research on Cancer (IARC)
Year:
1991
Bibliographic source:
IARC Monographs Volume 53 Sup 7 (1991) p.467-480

Materials and methods

Test material

Constituent 1
Test material form:
solid: crystalline
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.

Test animals

Species:
rat
Strain:
Fischer 344
Remarks:
F344/N
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Harlan Industries, Inc. (Indianapolis, IN)
- Age at study initiation (when placed on study): 7-8 wk
- Housing: Polycarbonate cages (Lab Products, Inc., Rochelle Park, NJ) with Nonwoven fiber cage filters (Lab Products, Inc., Rochelle Park, NJ) 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: 18 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22° C average, range 19°-26° C
- Humidity (%): 23.9% average relative humidty; range 7%-55%
- 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: 25 September 1978
To: 26 December 1978 – 29 December 1978 (killed at 20-21 wks old)

Administration / exposure

Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
DIET PREPARATION
- Rate of preparation of diet (frequency): Maximum Storage Time: 14 days.
- Mixing appropriate amounts with (Type of food): Wayne Lab Blox® (Allied Mills, Inc., Chicago, IL).
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.
- Storage temperature of food: The mixture was held at 5°C until use and was used within 13 days after being mixed.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The analytical chemistry laboratory demonstrated the homogeneity of a formulated diet mixture. Further studies showed that monuron was stable in feed when stored for 2 weeks at 25°C or below.
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
continuous exposure in the food
Doses / concentrationsopen allclose all
Dose / conc.:
0 ppm
Remarks:
target concentration
Dose / conc.:
750 ppm
Remarks:
target concentration
Dose / conc.:
1 500 ppm
Remarks:
target concentration
Dose / conc.:
3 000 ppm
Remarks:
target concentration
Dose / conc.:
6 000 ppm
Remarks:
target concentration
Dose / conc.:
12 000 ppm
Remarks:
target concentration
Dose / conc.:
0 ppm
Remarks:
experimental mean concentration
Dose / conc.:
900 ppm
Remarks:
experimental mean concentration
Dose / conc.:
1 800 ppm
Remarks:
experimental mean concentration
Dose / conc.:
3 200 ppm
Remarks:
experimental mean concentration
Dose / conc.:
7 200 ppm
Remarks:
experimental mean concentration
Dose / conc.:
12 400 ppm
Remarks:
experimental mean concentration
No. of animals per sex per dose:
10
Control animals:
yes, concurrent no treatment
Details on study design:
- Rationale for animal assignment: Distributed to groups so that average group weights approximately equal

Examinations

Observations and examinations performed and frequency:
CLINICAL SIGNS AND MORTALITY
Animals were checked two times per day; moribund animals were killed, and necropsies were performed.

BODY WEIGHT AND WEIGHT GAIN
Individual animal weights were recorded once per week.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
Feed consumption was measured once per week. One day before the animals were killed, formulated diets were replaced with control feed.

GROSS PATHOLOGY
At the end of the 13-week studies, survivors were killed. A necropsy was performed on all animals, except those excessively autolyzed or cannibalized.
Sacrifice and pathology:
GROSS PATHOLOGY: Yes. At the end of the 13-week studies, survivors were killed. A necropsy was performed on all animals, except those excessively autolyzed or cannibalized.

HISTOPATHOLOGY: Yes. Histologic exam performed on control, 6000-, and 12000-ppm groups and early death rats: gross lesions and tissue masses, mandibular lymph nodes, mammary gland,
salivary glands, thyroid gland, parathyroids, sternebrae, liver, colon, small intestine, prostate/testes or ovaries/uterus, urinary bladder, lungs and bronchi, heart, esophagus, stomach, brain, thymus, trachea, pancreas, spleen, kidneys, adrenal glands, pituitary gland, spinal cord and eyes.
Partial histologic exam on 3000-ppm group: thymus, bone marrow, spleen, mesenteric and mandibular lymph nodes.

Results and discussion

Results of examinations

Mortality:
mortality observed, treatment-related
Description (incidence):
8/10 male rats and 9/10 female rats fed diets containing 12000 ppm monuron died during the first 2 weeks of the studies.
5/10 male rats and 6/10 female rats fed diets containing 6000 ppm monuron died during the first 4 weeks of the studies.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
The final weights of the rats were inversely related to the concentration of monuron in the feed.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Female rats fed 750-12000 ppm ate less than did the controls.
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Discoloration and mottling of the lungs, smoothing and thinning of the stomach, and enlargement and discoloration of the adrenal glands were noted at necropsy and appeared to be compound related.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
A generalized atrophy of lymphocytic and hematopoietic tissues was observed in male and female rats fed diets containing 12000 ppm monuron. These changes included lymphoid depletion and
congestion of the splenic white pulp, lymphoid depletion with overall reduction in size of the thymus, myeloid depletion of bone marrow, and lymphoid depletion of B-and T-cell areas of lymph nodes
causing a marked reduction in the size of all examined lymph nodes. Similar but less severe changes were seen in male and female rats fed diets containing 6000 ppm monuron; changes seen in the l
ymphocytic and hematopoietic tissues of rats fed monuron at lower concentrations were considered to be slight or equivocal.

Effect levels

Key result
Dose descriptor:
LOAEL
Effect level:
5 mg/kg diet

Target system / organ toxicity

open allclose all
Critical effects observed:
yes
System:
haematopoietic
Treatment related:
yes
Critical effects observed:
yes
Organ:
kidney
Treatment related:
yes
Critical effects observed:
yes
Organ:
liver
Treatment related:
yes

Applicant's summary and conclusion

Conclusions:
In a 13 weeks feeding study, dietary uptake of monuron (>99% pure) of up to 12000 ppm in Fischer 344 rats, the kidney, liver and lympho/haematopoietic systems were targets for toxicity. The lympho/hematopoietic system of rats was the primary site affected. The Iymphocytic and haematopoietic tissue atrophy seen in rats at high doses in the 13-week studies was not seen in the two-year feeding studies.
Because of weight gain depression and histopathologic changes observed at higher dose levels, doses selected for the 2-year studies in rats were 750 and 1500 ppm monuron in feed.
Executive summary:

Thirteen-week studies were conducted to evaluate the toxicity associated with repeated ingestion of monuron and to determine the concentrations to be used in the 2-year studies.

Groups of 10 F344/N rats of each sex were fed diets containing 0, 750, 1500, 3000, 6000, or 12000 ppm monuron. All diets were available ad libitum. Formulated diets were first offered to each group on September 25, 1978. Necropsies were performed between December 26 and December 29, 1978.

Animals were checked two times per day, moribund animals were killed and necropsies were performed. Feed consumption was measured once per week. One day before the animals were killed, formulated diets were replaced with control feed. Individual animal weights were recorded once per week. At the end of the 13 week studies, survivors were killed. A necropsy was performed on all animals, except those excessively autolyzed or cannibalized.

Eight of 10 male rats and 9/10 female rats fed diets containing 12000 ppm monuron died during the first 2 weeks of the studies. Five of 10 male rats and 6/10 female rats fed diets containing 6000 ppm monuron died during the first 4 weeks of the studies. The final weights of the rats were inversely related to the concentration of monuron in the feed. Female rats fed 750-12000 ppm ate less than did the controls.

Discoloration and mottling of the lungs, smoothing and thinning of the stomach, and enlargement and discoloration of the adrenal glands were noted at necropsy and appeared to be compound related.

A generalized atrophy of lymphocytic and hematopoietic tissues was observed in male and female rats fed diets containing 12000 ppm monuron. These changes included lymphoid depletion and congestion of the splenic white pulp, lymphoid depletion with overall reduction in size of the thymus, myeloid depletion of bone marrow, and lymphoid depletion of B-and T-cell areas of lymph nodes causing a marked reduction in the size of all examined lymph nodes. Similar but less severe changes were seen in male and female rats fed diets containing 6000 ppm monuron; changes seen in the lymphocytic and hematopoietic tissues of rats fed monuron at lower concentrations were considered to be slight or equivocal.

Because of weight gain depression and histopathologic changes observed at higher dose levels, doses selected for the 2-year studies in rats were 750 and 1500 ppm monuron in feed.