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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
fertility, other
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Non-GLP, available as unpublished report, minor restrictions in design and/or reporting but otherwise adequate for assessment
Cross-reference
Reason / purpose:
reference to same study

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
1970
Report Date:
1970
Reference Type:
secondary source
Title:
Unnamed
Year:
1978
Report Date:
1978

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Four groups of each 8 beagles were dosed daily for 3 months with capsules containing 0, 0.15, 0.5, and 1.5 mg/kg test substance.
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: particulate/powder
Details on test material:
- Carbon content: 52.2%
- ThOD: 2.310 mg O2/mg considering total nitrification; 1.027 mg O2/mg considering no nitrification
- Water solubility (SDS): 2 g/L very slightly soluble
- Vapour pressure (SDS): 0.00003 mm Hg at 25°C
- State of matter and appearance (CoA): Off-white to beige powder
- Storage conditions (CoA): At < 30°C in a tightly closed container at a dry and well-ventilated place.
- Waste disposal: Waste will be disposed of in accordance with federal, state and local environmental control regulations.

Test animals

Species:
other: dog
Strain:
other: beagle
Sex:
male/female
Details on test animals and environmental conditions:
Thirty-two beagles were randomly divided into groups of four males and four females and maintained throughout the test on the usual stock diet.

Administration / exposure

Route of administration:
oral: capsule
Vehicle:
other: lactose, maize starch, magnesium stearate
Details on exposure:
Tablets test substance were placed in hard gelatin capsules. Tablet composition:
- 0.6 mg test substance, 91 mg lactose, 7.4 mg maize starch, and magnesium stearate 1.0 mg (total tablet weight of 100 mg)
- 5 mg test substance, 180 mg lactose, 13 mg maize starch, and magnesium stearate 2.0 mg (total tablet weight of 200 mg)
- 6 mg test substance, 180 mg lactose, 12 mg maize starch, and magnesium stearate 2.0 mg (total tablet weight of 200 mg)
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
3 months
Frequency of treatment:
daily
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 0.15, 0.5, and 1.5 mg/kg bw
Basis:
actual ingested
No. of animals per sex per dose:
4
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: based on a preliminary test with a male and female beagle dosed daily with increasing doses for the duration of 39 days.
- Post-exposure recovery period: at the end of the three month period one male and one female dosed with 5 mg/kg bw remained undosed for six weeks to assess the reversibility of any lesions.

Examinations

Parental animals: Observations and examinations:
GENERAL CONDITION

HEAMATOLOGICAL EXAMINATIONS
Blood from each dog was examined before the test began and after one, two and three months of dosing. The examination consisted of haemoglobin estimation, packed cell volume, total white blood cell count, differential white cell count platelets and mean cell haemoglobin.

BONE MARROW FINDINGS
Bone marrow smears from the femoral marrow and samples from the sternal marrow were taken from all dogs at autopsy

URINE ANALYSIS
Urine was collected from each animal before the test began and on days 42 and 91 of treatment.

CLINICAL CHEMISTRY
All dogs were bled for clinical chemical estimations before the test began and on days 40 and 89 of dosing. The investigations made were: blood sugar, serum urea, total protein, electrolytes (Na+, K+, and Ca++), serum alkaline phosphatase activity, serum aspartate amino transferase activity (AST) and serum isocitrate dehydrogenase activity (ICD). In addition to this, the serum enzymes (alkaline phosphatase, AST and ICD were measured in two males and two females of control and top dose group on days 5 , 12 , 16 and 21.

CLINICAL PHARMACOLOGY
Observations were made on arterial blood pressure, heart rate, respiration rate and E.C.G.of all dogs twice before treatment commenced, and after one week and one and three months of dosing.

SERUM LEVEL ASSAYS
Serum concentrations were measured in dogs treated for 41, 55 and 90 days.
Postmortem examinations (parental animals):
AUTOPSIES
An autopsy was performed on every dog. The organs were weighed and samples of tissues put into fixative for histological examination.

HISTOLOGICAL EXAMINATION
The following tissues of each animal were examined: kidneys, adrenals, heart, liver, lung, spleen, pancreas, thymus, lymph nodes (abdominal, thoracic and neck), gonads and accessory sex organs, mammary glands, thyroid, stomach, small intestine, large intestine, bladder, quadriceps muscle, eyes, pituitary, and brain.

Results and discussion

Results: P0 (first parental generation)

Details on results (P0)

PRELIMINARY STUDY
The female vomited approximately 2.5 hours after dosing 0.5 mg/kg test substance on the fifth day and was slightly ataxic after a dose of 0.6 mg/kg four days later. The male vomited on several occasions; after the twenty-first dose (1.3 mg/kg), the twenty-eight dose (1.5 mg/kg) and after feeding on the twenty-ninth day. No histological changes were observed in either of the animals.

GENERAL CONDITION
One control female developed eczema on its back and was dosed for five days with 2 mL Streptopen and 1 mL Betsolan. After the fifth week of treatment many of the dogs receiving the highest dose salivated profusely before dosing on several occasions. Also one male in the same group refused to eat on days 9 and 10 of treatment. Vomiting occurred sporadically in six of the animals in the highest dose groups and three in the middle dose group from the ninth day onwards. It usually occurred after dosing but occasionally the dogs vomited before dosing. One female in Group 4 was sick on several occasions and passed blood in the faeces on day 95: she was killed on that day and found to have an ileo-caecal intussusception. Weight gains were similar in the males in all groups, but the females receiving the highest dose lost weight from time to time.

HEAMATOLOGICAL EXAMINATIONS
There were no changes in the haematological values attributable to the administration of the test substance.

BONE MARROW FINDINGS
The female in the highest dose group that was killed and found to have an intussusception showed megaloblatic hyperplasia. This was possibly related to poor intestinal absorption due to the ileo-caecal ulceration.

URINE ANALYSIS
There were no changes attributable to the administration of the test substance.

CLINICAL CHEMISTRY
There were no changes attributable to the administration of the test substance.

CLINICAL PHARMACOLOGY
Respiration rates and E.C.G.s of all animals remained within normal limits. There were no changes attributable to the administration of the test substance.

SERUM LEVEL ASSAYS
The compound is well absorbed after oral administration.

ORGAN WEIGHTS
There were no significant differences between the weights of the various organs in treated and control groups.

HISTOLOGICAL EXAMINATION
There were no changes attributable to the administration of the test substance.
At autopsy many of the animals, both treated and control, were observed to have large reddish areas in the lungs. These were patches of pneumonia or nodules of inflammatory cells. Cross sections of nematodes were also present in many sections of the lung. Due to an oversight in animal husbandry the dogs used in this experiment did not have the usual treatment with anthelmintics prior to the start of dosing. All the lesions in the lungs are therefore thought to be attributable to the larval worms.
One female receiving the highest dose (1.5 mg/kg) had a small cystadenoma in the thyroid, and the female in this group which was killed on day 95 showed ulceration of the colon in the area of intussusception. Intussusception is not uncommon in these dogs.

All other changes seen were those normally found in these dogs.
At the end of the three month period of dosing one male and one female dog from Croup 4 (1.5 mg/kg) were left undosed for six weeks to assess the reversibility of any lesions. At the end of the six weeks both dogs were autopsied in a similar manner to the others. No pathological changes attributable to the administration of the test substance were found. Both dogs showed areas of bronchopneumonia and inflammation in the lungs but this was thought to be related to the infestation of the lungs by larval nematodes.

Effect levels (P0)

Dose descriptor:
NOAEL
Effect level:
>= 1.5 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No histological abnormalities were observed in the sex organs.

Target system / organ toxicity (P0)

Critical effects observed:
no

Results: F1 generation

Effect levels (F1)

Remarks on result:
not measured/tested

Target system / organ toxicity (F1)

Critical effects observed:
not specified

Overall reproductive toxicity

Reproductive effects observed:
no

Applicant's summary and conclusion

Conclusions:
No pathological changes were found in the sex organs which could be related to the treatment with the test substance. Under the conditions of this test the NOAEL for fertility is 1.5 mg/kg bw.
Executive summary:

Four groups of each 8 beagles were dosed daily for 3 months with 0, 0.15, 0.5, and 1.5 mg/kg bw test substance via capsules. There were no test substance attributable changes observed with haematological examination, bone marrow examination, urine analysis, clinical chemistry and clinical pharmacology. Vomiting occurred in six of the eight animals dosed with 1.5 mg/kg bw test substance and in three of the eight receiving 0.5 mg/kg bw test substance. No other test substance related changes were observed. As no pathological changes were found in the sex organs which could be related to the treatment with the test substance, the NOAEL for fertility is 1.5 mg/kg bw.