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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
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1985
Report Date:
1985

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: OECD Guidelines of May 1981
Principles of method if other than guideline:
At the end of the study, an additional 10 male and 10 female animals per test group were given the standard diet for a period of 30 days. This was to assess whether any observed effects were reversible or any late effects could occur.
GLP compliance:
no
Remarks:
Study predates GLP
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: particulate/powder
Specific details on test material used for the study:
- Test material: Simazine Technical
- Description: White powder

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Winkelmann, Borchen, Germany
- Females (if applicable) nulliparous and non-pregnant: [yes/no]
- Weight at study initiation: 137 g (mean bodyweight)
- Housing: conventional single cages (Makrolon type 2)
- Diet (e.g. ad libitum): laboratory standard diet
- Water: available ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22°C ± 2°C
- Humidity (%): 50 - 60%
- Photoperiod (hrs dark / hrs light): 12 hours light / 12 hours dark

Administration / exposure

Route of administration:
oral: feed
Duration of treatment / exposure:
3 months
Frequency of treatment:
Treated feed was available ad libitum.
Doses / concentrationsopen allclose all
Dose / conc.:
100 ppm
Remarks:
Group I
Dose / conc.:
500 ppm
Remarks:
Group II
Dose / conc.:
2 500 ppm
Remarks:
Group III
No. of animals per sex per dose:
30 animals per sex per dose
Control animals:
yes, concurrent no treatment

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Daily

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

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: Yes

HAEMATOLOGY: Yes
- Time schedule for collection of blood: 50, 90 and 120 days
- Parameters examined: Leucocytes, haematocrit, haemoglobin, erythrocytes, differential haemogram

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: 50, 90 and 120 days
- Parameters examined: Glucose, total albumin, GOT, GPT, γ-GT, LDH, alkaline phosphatase

URINALYSIS: Yes
- Time schedule for collection of urine: 50, 90 and 120 days
- Parameters examined: specific gravity, pH, urobilinogen, erythrocytes, bilirubin, ketone, glucose, nitrite and protein

NEUROBEHAVIOURAL EXAMINATION: No

IMMUNOLOGY: No
Sacrifice and pathology:
10 animals per sex per dose group were narcotised and autopsied after 50 and 90 days of treatment. After 120 days the remaining animals (10 animals per sex per dose group) were autopsied.

The following organ weights were measured: brain, heart, liver, kidneys (left and right), adrenal glands (left and right), spleen, ovaries (left and right), testicles and epididymis (left and right).

Histology was performed on the following organs of control and Group III animals after 90 days: liver, heart, kidneys (left and right), spleen, brain (cerebrum, cerebellum, medulla oblongata), thyroid glands (left and right), stomach, duodenum, colon, pancreas, hypophysis, testicles (left and right), epididymis (left and right), uterus and ovaries (left and right), adrenal glands (left and right), lung, N. ischiadicus, urinary bladder.

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):
After intervals (50, 90 and 120 days) means of weight changes showed clear dose related decreases during the exposure period and increased gains during the reversal period.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
After intervals (50, 90 and 120 days) means of total feed consumption showed clear dose related decreases during the exposure period.
Food efficiency:
effects observed, treatment-related
Description (incidence and severity):
During the exposure period, feed efficacy of the highest dosage group was clearly diminished.
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
effects observed, non-treatment-related
Description (incidence and severity):
At 90 days, male animals of Groups II and III and female animals of Group III showed significantly higher values of total albumin. This was not observed at 50 and 120 days.
At 90 days, male and female animals of Group III showed significantly higher values of alkaline phosphatase. This was not observed at 50 and 120 days.
Urinalysis findings:
no effects observed
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Female animals treated with 500 ppm showed increased organ weights of liver and kidney at 50 and 90 days.

In animals treated with 2500 ppm the following alterations occurred:
- in females, increased organ weights of liver and kidneys at 90 days and increased liver organ weights at 120 days
- males showed significantly decreased weights of testicles in the 50 and 90 days interim autopsy and in the 120 days final autopsy.
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Degeneration of the germinal epithelium occurred in the testes of all male animals in Group III. In five cases, the lesions were so severe that regeneration was not possible as total atrophy had occurred.

Effect levels

Key result
Dose descriptor:
NOEL
Effect level:
100 ppm
Based on:
test mat.
Sex:
male/female
Remarks on result:
other: equivalent to 8.0 mg/kg bw

Target system / organ toxicity

Key result
Critical effects observed:
no

Applicant's summary and conclusion

Conclusions:
At 100 ppm in all evaluated parameters during the treatment period of 90 days, no test specific alterations occurred. The 90 day NOEL in rats for Simazine Technical is therefore 100 ppm, which corresponds to 8.0 mg/kg bw.