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Toxicological information

Repeated dose toxicity: oral

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Administrative data

chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
12th January 1988 to 28th February 1990
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference Type:
study report
Report date:

Materials and methods

Test guidelineopen allclose all
equivalent or similar to guideline
EPA OTS 798.3260 (Chronic Toxicity)
equivalent or similar to guideline
OECD Guideline 452 (Chronic Toxicity Studies)
GLP compliance:
Limit test:

Test material

Constituent 1
Chemical structure
Reference substance name:
EC Number:
EC Name:
Cas Number:
Molecular formula:
Test material form:
Details on test material:
- Name of test material (as cited in study report): Omite® Technical
- Storage condition of test material: in a dry location

Test animals

Details on test animals or test system and environmental conditions:
- Source: Marshall Research Animals, Inc., North Rose, New York, USA
- Age at study initiation: 5-7 months old
- Weight at study initiation: 7.2-10.6 kg (males); 6.3-9.1 kg (females)
- Housing: individually in elevated metal grid cages
- Diet: 400 g Purina® Certified Canine Diet #5007 presented fresh daily for 4.5 hours
- Water: ad libitum
- Acclimation period: 39 days

- Temperature: 60-85 ºF
- Humidity: 13-90 %
- Photoperiod: 12 hours light/12 hours dark

Administration / exposure

Route of administration:
oral: feed
unchanged (no vehicle)
Analytical verification of doses or concentrations:
Details on analytical verification of doses or concentrations:
Samples of the diet containing the test material were homogenised and analysed by GC.
Duration of treatment / exposure:
One year
Frequency of treatment:
Daily for approximately 4.5 hours/day.
Doses / concentrationsopen allclose all
Dose / conc.:
160 mg/kg diet
5.0 mg/kg bw/day
Dose / conc.:
1 250 mg/kg diet
38.0 mg/kg bw/day
Dose / conc.:
1 875 mg/kg diet
Weeks 9 to 13; 44.0 mg/kg bw/day
Dose / conc.:
2 500 mg/kg diet
Weeks 1 to 8
No. of animals per sex per dose:
Control animals:
yes, plain diet
Details on study design:
- Dose selection rationale: based upon results in previous dog chronic and subchronic studies


Observations and examinations performed and frequency:
- Time schedule: twice daily

- Time schedule: pretest and weekly thereafter

- Time schedule for examinations: pretest, weekly to week 13 and monthly thereafter. High-dose animals were weighed weekly from week 38 to study termination.

- Time schedule for examinations: pretest, weekly to week 13 and monthly thereafter.


- Time schedule for examinations: pretest and study termination

- Time schedule for collection of blood: pretest, months 3 and 6 and study termination
- Anaesthetic used for blood collection: No
- Animals fasted: Yes
- Parameters checked: hemoglobin concentration, haematocrit, erythrocyte count, reticulocyte count, platelet count, mean corpuscular volume/hemoglobin/haemoglobin concentration, total and differential leukocyte counts, erythrocyte morphology.

- Time schedule for collection of blood: pretest, months 3 and 6 and study termination
- Parameters checked: aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, blood urea nitrogen, creatinine, fasting glucose, cholesterol, total protein, albumin, A/G ratio, total bilirubin, sodium potassium, chloride, calcium, inorganic phosphorus.

- Time schedule for collection of urine: pretest, months 3 and 6 and study termination
- Animals fasted: No
- Parameters checked: appearance, specific gravity, pH, protein, glucose, ketones, bilirubin, occult blood, urobilinogen, microscopic analysis

Sacrifice and pathology:
- Parameters checked: organ weights - adrenals, heart, kidneys, liver, ovaries, testes, thyroid/parathyroid

- Parameters checked: adrenals, aorta (abdominal), bone (sternum), bone marrow (sternum), brain, epididymides, oesophagus, eyes with optic nerve, gall bladder, heart, intestine, kidneys, liver, lungs, lymph nodes (mesenteric, mediastinal), mammary gland, nerve (right sciatic), ovaries, pancreas, pituitary, prostate, salivary gland, skeletal muscle, skin, spinal cord, spleen, stomach, testes, thymus, thyroid/parathyroid, tongue, trachea, urinary bladder. uterus, gross lesions
Statistical evaluation applied to body weight, food consumption, haematology, clinical chemistry, terminal organ weight, and organ:body weight ratio data. Difference among means of data was determined by one-way analysis of variance if groups had equal variance (assessed by Bartlett's test), otherwise differences among means determined by Kruskal-Wallis test. Significance of difference from controls assessed by Dunnett's test where variance among means was equal and by Dunn's Rank Sum where variances where not equal. Trend in the dose levels were identified by either regression techniques (equal variance) or by Jonckheeres test (non-equal variance).

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
From week 8 until test termination, the high dose animals were observed to be thin. During the last 3 months, the high dose animals were observed to be dehydrated. In addition, the high dose animals developed scabs/sores and alopecia from week 29 at a higher incidence than in the control animals.
mortality observed, treatment-related
Description (incidence):
A high dose male and a high dose female were sacrificed on days 81 and 349, respectively due to a moribund and emaciated condition. The marked loss of body weight in these animals was considered to be treatment related.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Mean body weight and body weight gain was significantly reduced in the 1250 and 1875/2500 mg/kg groups compared to the controls. During the first 8 weeks of the study, mean weight loss in the 1250 and 2500 mg/kg animals was severe (0.4-0.5 and 1.9-2.6 kg, respectively). As a result of this marked weight loss, the high dose level was reduced to 1875 mg/kg to avoid early mortality due to rapid weight loss. Once the dose was reduced to 1875 mg/kg, weight loss was less rapid over the remainder of the study, with losses of 0.1 and 0.6 kg recorded in high dose males and females, respectively. There was a slight weight gain in the 1250 mg/kg animals over this period, although the gain was markedly lower than in the control groups. Overall, body weight at week 52 was reduced by 42.5 and 49.5 % in males and females administered 1850 mg/kg test material in the diet when compared to the controls (statistically significant at P<0.01 level), while corresponding male and female weight loss in the 1250 mg/kg group at week 52 was 17.7 and 19.8 % (statistically significant at P<0.05 level) (see Table 1).
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Decreased food consumption in the high dose animals was noted from week 1 and was observed to continue throughout the study. On decreasing the high dose at week 8, food consumption increased, but was still lower than in the controls.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
Description (incidence and severity):
Ophthalmoscopic examination indicated no treatment related ocular effects at any dose level.
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
There was a statistically significant decrease in erythrocyte count and associated haematocrit and haemoglobin levels in the 1875 mg/kg males and females at months 3, 6 and 12 and in the 1250 mg/kg males at months 6 and 12. Platelet count was greater than control values in the 1250 and 1875 mg/kg females at all intervals and at months 6 and 12 in the high dose males.
Clinical biochemistry findings:
effects observed, non-treatment-related
Description (incidence and severity):
Slight, but statistically significant, differences were recorded for blood urea nitrogen, total protein, albumen, alkaline phosphatase and serum electrolytes, most notable in the high dose group, but also sporadically across all dietary dose levels. However, the absolute values are all considered to be within normal limits for these parameters and so the differences from the control were not considered to be toxicologically significant.
Urinalysis findings:
no effects observed
Description (incidence and severity):
There were no treatment related trends or differences from the control animals in the urinalysis data.
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Organ to body weight ratios were increased from the controls, predominantly in the high dose group, but incidences were also noted in some of the 1250 mg/kg animals. The increased organ to body weight ratios were attributed to the reduced overall body weights in these groups. A decrease in the absolute organ weight of heart, kidneys and ovaries was measured in the high dose animals, but these effects were again attributed to the low overall body weight.
Gross pathological findings:
not specified
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
With the exception of erythroid/myeloid depletion of the bone marrow in one of the two high dose animals sacrificed prior to study termination, there were no other remarkable findings in these animals. Necropsy of all the other animals at test termination revealed an increased incidence of red/tan/white foci in the lungs of high dose group. Microscopically, these changes were associated with congestion or serosal inflammation and were considered to be treatment related. Other treatment related changes included an increased incidence of erythroid/myeloid depletion/atrophy of the bone marrow in the high dose animals and a slightly increased incidence/severity of involution of the thymus in the 1250 mg/kg females and the high dose males and females. All other pathological observations were not considered to be treatment related.
Histopathological findings: neoplastic:
no effects observed

Effect levels

Key result
Dose descriptor:
Effect level:
160 ppm
Based on:
test mat.
Basis for effect level:
body weight and weight gain
food consumption and compound intake
histopathology: non-neoplastic
Remarks on result:
other: Equivalent to 4 mg/kg bw/day

Target system / organ toxicity

Key result
Critical effects observed:

Any other information on results incl. tables

Table 1: Mean terminal body weights

 Dose (mg/kg diet)  Body weight (kg) - males  Body weight (kg) - females
 0  11.3  10.1
 160  11.6  9.5
 1250  9.3  8.1
 2500/1875  6.5  5.1

Applicant's summary and conclusion

Under the conditions of the test, based on the reduced body weight, haematological effects and pathological findings, recorded in this study, the No Observed Adverse Effect Level was 160 mg/kg in the diet. This is equivalent to 5 mg/kg body weight/day.
Executive summary:

The test material was administered orally at dose levels of 160, 1250 and 2500 ppm for a period of 12 months to six dogs per sex per group. The high-dose level was reduced to 1875 ppm at week 9 as a result of excessive body weight loss. Physical observations, ophthalmoscopic examinations, body weight, food consumption measurements, hematology, clinical chemistry and urinanalysis were performed on all animals pretest and at selected intervals throughout the study. At the end of the study, all survivors were sacrificed, selected organs were weighed and organ/body weight ratios calculated. Complete gross post-mortem examinations and histopathological examinations of selected tissues were conducted on all animals.

Treatment with the test material at doses up to 1875 ppm for one year did not produce any ocular abnormalities or differences in clinical chemistry or urinanalysis parameters.

Two high-dose animals died during the study; the deaths were attributed to marked body weight loss and this was considered to be treatment-related. Physically the high-dose animals were thin over the majority of the study period and were frequently noted as dehydrated over the last three months of the study.

Marked decreases in group mean body weight and body weight gain were noted in the mid- and high-dose groups compared to the controls. Controls gained approximately 2 kg over the study period, the mid-dose group gained very little weight (<0.3 kg) while high-dose males and females lost 2.9 and 2.6 kg respectively. The decreased weight gain is most likely due to decreased food consumption.

Erythrocyte count and associate hematocrit and haemoglobin levels were significantly decreased compared to controls in high-dose males and females at months 3, 6 and 12 and in mid-dose males at months 6 and 12. Platelet counts were elevated from controls in the 1250 and 1875 ppm females at all intervals and in high-dose males at 6 and 12 months.

Organ to body weight ratios were increased from controls predominantly in the high-dose animals and occasionally in the mid-dose animals. The differences were attributed to low body weights.

Microscopic examination of tissues revealed treatment-related findings in the lungs, thymus and bone marrow. Red/tan/white foci were noted in the lung of high-dose males. Microscopic examination revealed these foci to be areas of congestion or aerosol subacute/chronic inflammation. Involution of the thymus occurred with slightly greater severity and incidence than controls in mid-dose females and high-dose males and females. Erythroid/myleoid depletion/atrophy of the bone marrow also occurred with a greater incidence and severity in high-dose animals compared to controls.

The NOAEL was determined to be 160 ppm (equivalent to 5 mg/kg/day). In females, treatment at this dietary concentration only induced 26 % lower weight gain which had limited impact on the mean body weight that was only 5.9 % lower than the control at week 52 and therefore not statistically or toxicologically significant.