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Diss Factsheets

Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2004
Report date:
2004

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
Deviations:
no
Principles of method if other than guideline:
Annex V to Council Directive 67/548/EEC on the approximation of lws, regulations and administrative provisions relating to the classification, packaging and labelling of dangerous substances, published in the twenty-second Adaption, Commission Directive 96/54/EC, 30 July, 1996, B.7, OJEC L248, 213-217 (Repeated dose (28 days) Toxicity (oral))
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
4,6-dichloro-5-nitro-2-(propylsulfanyl)pyrimidine
EC Number:
700-475-0
Cas Number:
145783-14-8
Molecular formula:
C7H7Cl2N3O2S
IUPAC Name:
4,6-dichloro-5-nitro-2-(propylsulfanyl)pyrimidine

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
Diet (CT1) and mains water supplied by an automatic system were available ab libitum. Each batch of diet is routinely analysed for composition and for the presence of contaminants. Water is also periodically analysed for the presence of contaminants. No contaminants were found to be present in the diet or water at levels considered to be capable of interfering with the purpose or outcome of the study.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Representative samples of dosing preparations were analysed prior to dosing on day 1 of the study and at intervals during the study to verify the achieved concentration of UL111 in corn oil. Samples and standards were analysed by HPLC. The mean concentration for all batches of dosing preparations analysed and subsequently dosed on the study were within 10% of the nominal concentration.
Duration of treatment / exposure:
28 days
Frequency of treatment:
Daily, 7 days each week
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 15, 150 and 225 mg/kg bw/day (m/f)
Basis:
nominal in diet
No. of animals per sex per dose:
5 males per dose
5 females per dose
Control animals:
yes
Details on study design:
The dose levels selected were based on the results of a preliminary 20-day dose-range finding study consisting of 5 groups of 2 male and 2 female rats per group (study number CTL/KR1537). The dose levels in the study were 0, 50, 150, 300 and 450 mg/kg day UL111. Groups 2 - 4 were terminated after 14 days of dosing. Group 5 was added to the study on day 11 and terminated after 7 days of dosing ie. day 18. At a dose level of 15 mg/kg/day for 14 days mean bodyweights in males and females were similar to controls. Dose levels 300 and 450 mg/kg/day were considered unsustainable for a 28 day study due to the severity of the clinical changes. Both males and females given 150 mg/kg/day showed similar mean bodyweights to control values, and few clinical signs were observed. A dose level of 225 mg/kg/day was considered to be appropriate for the 28 day study.

Examinations

Observations and examinations performed and frequency:
Detailed clinical observations, including the finding of no abnormalities detected, were recorded daily.
Locomotor activity was monitored by an automated activity recording apparatus. All animals were tested on day 28.
At scheduled termination (day 29) all surviving rats were bled by cardiac puncture and samples were analysed by Clinical Pathology, CTL (haematology, blood clinical chemistry and urine clinical chemistry paramters.

Sacrifice and pathology:
All animals were subjected to a full macroscopic examination post mortem. This involved an external observation and a detailed internal examination of all organs and structures. All tissues processed from the control and top dose and all abnormalities from all groups were examined by light microscopy.
Other examinations:
Functional observational battery: detailed clinical assessments and quantitative assessments of landing foot splay, muscle weakness and sensory perception were made on day 28 for all animals.
Statistics:
All data were evaluated using analysis of variance and/or analysis of covariance for each specified parameter using the MIXED procedure in SAS (1999)

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Salivation, diarrhoea at 225 and 150 mg/kg/day
Mortality:
mortality observed, treatment-related
Description (incidence):
Salivation, diarrhoea at 225 and 150 mg/kg/day
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Lower bodyweight in males, 225 or 150 mg/kg/day
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Description (incidence and severity):
Effects were observed, but considered negligible.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
Effects were observed, but considered negligible.
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Brweight lower than control (225 and 150 mg/kg)
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
At a dose level of 225 mg/kg/day all animals of both sexes had salivation and signs of diarrhoea. Salivation (all animals) and signs of diarrhoea (2/5 males) were also seen at 150 mg/kg/day.
Bodyweights in males given 225 or 150 mg/kg/day were statistically significatnly lower than controls.
Brain weight, heart weight statistically significantly lower than controls in males given 225 mg/kg/day (brain) and 150 and 225 mg/kg/day (heart)

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
15 mg/kg bw/day (nominal)
Based on:
act. ingr.
Sex:
male
Basis for effect level:
other: Toxicity
Dose descriptor:
NOAEL
Effect level:
225 mg/kg bw/day (nominal)
Based on:
act. ingr.
Sex:
female
Basis for effect level:
other: Toxicity

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion