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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1976
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Well documented report of a guideline study.
Cross-reference
Reason / purpose:
reference to same study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1976
Report Date:
1976

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: FIFRA guidelines
Deviations:
no
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): DADM
- Substance type: organic
- Physical state: liquid
- Analytical purity: unknown
- Impurities (identity and concentrations): unknown
- Composition of test material, percentage of components: 60% in aqueous solution
- Purity test date:
- Lot/batch No.: S11719-140
- Expiration date of the lot/batch: unknown
- Stability under test conditions: stable
- Storage condition of test material: unknown

Test animals

Species:
dog
Strain:
Beagle
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Hazelton Laboratories, Cumberland, VA, USA
- Age at study initiation: average of 3 to 4 months
- Weight at study initiation:
- Fasting period before study: no
- Housing: individual stainless-steel suspended cages with wire floors.
- Diet: 350 g/day of Respond 2000
- Water: ad libitum
- Acclimation period: yes (quarantine of unknown duration)
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22.2±1.2
- Humidity (%): 45-65
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12:12
IN-LIFE DATES: From: 22/12/1975 To: 23/03/1976

Administration / exposure

Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:
DIET PREPARATION
- Rate of preparation of diet (frequency): daily
- Mixing appropriate amounts with: Respond 2000 dog chow
- Storage temperature of food: unknown
VEHICLE
- Justification for use and choice of vehicle: none
Analytical verification of doses or concentrations:
no
Details on analytical verification of doses or concentrations:
Diets were adjusted to deliver specified doses of monomer in a 350 gram meal.
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
Daily
Doses / concentrations
Remarks:
Doses / Concentrations:
50, 200, 800 mg/kg bw/day
Basis:
nominal in diet
No. of animals per sex per dose:
4 per sex per dose
Control animals:
yes, plain diet
Positive control:
No

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: No data
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: No data
BODY WEIGHT: Yes
- Time schedule for examinations: Weekly
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No
FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Yes
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: Yes
- Time schedule for collection of blood: Prior to initial feeding, at 45 days and at end of study.
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: All animals
- Parameters checked in tables 7-13 were examined.
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Prior to initial feeding, at 45 days and at end of study.
- Animals fasted: No data
- How many animals: All animals
- Parameters checked in table 14-19 were examined.
URINALYSIS: Yes
- Time schedule for collection of urine: Prior to initial feeding, at 45 days and at end of study.
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- Parameters checked in tables20-25 were examined.
NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
All dogs were necropsied and histopathology performed.
Internal organs were carefully inspected and representative blocks from the following ones were saved: skin, eyes, ears, tongue, fat, skeletal muscle, salivary glands, thyroids*, trachea, esophagus, lungs, heart*, gallbladder, liver*, stomach, small intestine, large intestine, adrenals*, kidneys*, urinary bladder, gonads*, prostate, vagina, pituitary*, brain*, spinal cord, bone and marrow. The asterisked tissues were also weighted and organ-to-body weight as well as organ-to-brain weight ratios were calculated.
Representative sections from the above organs and tissues from all dogs were stained with routine hematoxylin and eosin and examined with ordinary light microscopy.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
only at highest dose
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY
BODY WEIGHT AND WEIGHT GAIN
The terminal body weights of the 800 mg/kg male dogs were significantly lower than the terminal body weights of the control group. Otherwise there were no treatment related effects in this study.
FOOD CONSUMPTION AND COMPOUND INTAKE
Only an occasional test group had a significantly different average daily feed consumption as compared to the control.
FOOD EFFICIENCY
- The mean feed efficiency of the control group ranged from 0.047 to 0.257 with an average feed efficiency of 0.142. The corresponding mean weekly body weight gain ranged from 0 to 600 g. over the duration of the experiment with a net average gain of 4,100 g.
- The mean feed efficiency for the 50 mg/kg DADMAC group ranged from o to 0.217, with an average feed efficiency of 0.107. The corresponding mean weekly body weight gain ranged from 0 to 500 g with a net average weight gain of 3,300 g.
-The mean feed efficiency for the 200 mg/kg DADMAC group ranged from o to 0.258, with an average feed efficiency of 0.130. The corresponding mean weekly body weight gain ranged from 0 to 600 g. with a net average weight gain of 3,900 g.
- The mean feed efficiency for the 800 mg/kg DADMAC test group ranged from 0.045 to 0.275 with an average feed efficiency of 0.121. The corresponding mean weekly body weight gain ranged from 100 to 500 g with a net average weight gain of 3.200 g.
HAEMATOLOGY
- The lowest hematocrit at 0 weeks was 33% in one control dog.
- The lowest haemoglobin at 0 weeks was 10.8 gms% (in one control dog and one 800 mg/kg dog ). By three months all dogs had normal haemoglobin values.
- White cell differential counts of all dogs, both male and female, remained within normal limits for the duration of the study.
CLINICAL CHEMISTRY
- Although some of dogs at 0 week had a blood glucose concentration between 129 and 150 mg%, at six and 13 weeks all blood glucose values fell within normal limits.
All BUN, SGOT, SGPT, and CGTP values were within the normal values at termination of the study.
URINALYSIS
All dogs except one had normal urinalysis findings at the beginning, at 45 days and at the conclusion of the experiment. One Dog (800 mg/kg group) at six weeks had 8-10 RBC/h.p.f. By thirteen weeks, however, its urinalysis results were normal.
ORGAN WEIGHTS
The mean terminal body weight for the male control group was 9.0 kg, for the 50 mg/kg group, 8.1 kg., for the 200 mg/kg group, 8.5 kg and for the 800 mg/kg group 7.8 kg. The corresponding mean terminal body weight for the female control group was 8.1 kg., for the 50 mg/kg group, 7.9 kg., for the 200 mg/kg group 8.6 kg and for the 800 mg/kg group, 7.8 kg.
The mean thyroid weight for the male control group was 0.70 gram, for the 50 mg/kg test group 0.78 gram, for the 200 mg/kg group 0.71 gram and for the 800 mg/kg group 0.78 gram. The corresponding mean thyroid weight for the female control group was 0.71 gram, for the 50 mg/kg group 0.81 gram, for the 200 mg/kg group 0.64 gram and for the 800 mg/kg group 0.78 gram
The mean heart weight for the male control group was 72.50 grams, for the 50 mg/kg group 66.30 grams, for the 200 mg/kg group 68.80 grams and for the 800 mg/kg group 57.50. The corresponding mean heart weight for the female control group was 63.80 grams, for the 50 mg/kg group 65.00 grams, for the 200 mg/kg group 63.80 grams and for the 800 mg/kg group 72.50 grams
The mean liver weight for the male control group was 231.3 grams, for the 50 mg/kg group 208.8 grams, for the 200 mg/kg group 265.0 grams and for the 800 mg/kg group 252.5 grams. The corresponding liver weight for the female control group was 202.5 grams, for the 50 mg/kg group 218.8 grams, for the 200 mg/kg group 212.5 grams and for the 800 mg/kg group 221.3 grams.
The mean adrenal weight for the male control group was 0.85 gram, for the 50 mg/kg group 0.95 gram, for the 200 mg/kg group 0.94 gram and for the 800 mg/kg group 0.93 gram. The corresponding mean adrenal weight for the female control group was 0.80 gram, for the 50 mg/kg group 0.92 gram, for the 200 mg/kg group 0.85 gram and for the 800 mg/kg group 0.95 gram.
The mean kidney weight for the male control group was 50.00 grams, for the 50 mg/kg group 45.00 grams, for the 200 mg/kg group 55.00 grams and for the 800 mg/kg group 50.00 grams. The corresponding mean kidney weight for the female control group was 40.00 grams, for the 50 mg/kg group 43.80 grams, for the 200 mg/kg group 41.30 grams and for the 800 mg/kg group 45.00.
The mean testicular weight for the male control group was 6.55 grams, for the 50 mg/kg group 6.94 grams, for the 200 mg/kg group 4.48 grams and for the 800 mg/kg DADM group 8.02 grams. The corresponding ovarian weight for the female control group was 0.69 gram, for the 50 mg/kg group 0.75 gram, for the 200 mg/kg DADM group 0.56 gram and for the 800 mg/kg DADM group 0.80 gram.
The mean pituitary weight for the male control group was 0.07 gram, for the 50 mg/kg group 0.06 gram, for the 200 mg/kg group 0.07 gram and for the 800 mg/kg group 0.01 gram The corresponding pituitary weight for the female control group was 0.06 gram, for the 50 mg/kg group 0.06 gram, for the 200 mg/kg DADM group 0.05 gram and for the 800 mg/kg group 0.06 gram.
The mean brain weight for the male control group was 72.00 grams, for the 50 mg/kg group 76.30 grams, for the 200 mg/kg group 76.00 grams and for the 800 mg/kg group 79.00. The corresponding brain weight for the female control group was 69.30 grams, for the 50 mg/kg DADM group 71.30 grams, for the 200 mg/kg DADM group 73.50 grams and for the 800 mg/kg DADM group 73.80 grams.
HISTOPATHOLOGY: NON-NEOPLASTIC
Two male dogs (one of the 50 mg/kg group and one of the 200 mg/kg group) had small testes macroscopically. Microscopically the seminiferous tubules appeared underdeveloped . It was not believed to be compound-related but rather of congenital origin. One additional dog (of the 200 mg/kg group) had small pulmonary granulomata compatible with pulmonary ascariasis but neither larva could be demonstrated in the granulomata nor worms in the intestine. All remaining dogs had normal histology.

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
200 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: overall effects
Dose descriptor:
LOAEL
Effect level:
800 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: decrease in body weight gain.

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
The NOAEL for DADMAC was 200 mg/kg/day and the LOAEL was 800 mg/kg/day (based on body weight loss). These values are valid for the registered substance based on their close structural relationship.