Orthosulfamuron

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2000

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2001

Report date:

2001

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)

Deviations:

yes

Remarks:

Deviations: on the first day of treatment males of the low and mid dose levels received a higher dose than that foreseen (i.e. 250 mg/kg bw and 500 mg/kg bw instead of 150 mg/kg bw and 450 mg/kg bw, respectively)

GLP compliance:

yes (incl. QA statement)

Test material

Test material information

Constituent 1

Test material form:

solid: particulate/powder

Specific details on test material used for the study:

Test material:
IR5878
Batch number: FCF/T/168-00 (ex 20525/03/9)
Purity: 98.54 ± 0.51 %

Test animals

Species:

dog

Strain:

Beagle

Sex:

male/female

Details on test animals or test system and environmental conditions:

Test animals:
Species and Strain: Male and Female Beagle dogs
Age: 7 months
Body weight: 5.53 ÷ 8.38 kg
Housing: limited-access dog facility. Individual pens.
Feed: diet “Altromin H”, produced by A. Rieper, Vandoies (BZ), Italy. The diet was supplemented by the Producer with vitamins and trace elements. The diet was distributed once a day. Water was distributed ad libitum.

Environmental conditions:
Temperature and humidity measured during the study were 19 ± 2°C and 55 ± 10%, respectively.
Light: artificial lighting with a 12-hour circadian cycle (07:00 – 19:00).

Administration / exposure

Route of administration:

oral: capsule

Details on route of administration:

Groups of three Beagle dogs/sex were given by gelatine capsules doses of 0 (empty capsules), 150, 450 or 1000 mg/kg/day.

Vehicle:

other: Gelatine

Details on oral exposure:

The purpose of the study was to evaluate the effects of repeated administrations of IR5878 to male and female Beagle dogs. IR5878 was administrated by oral route once a day per 7 days a week, for 4 consecutive weeks to 12 males and to 12 females of Beagle dog. Groups of three Beagle dogs/sex were given by gelatine capsules doses of 0 (empty capsules), 150, 450 or 1000 mg/kg/day. These dosages were determined in a preliminary tolerability study, which had the purpose of assessing the toxic effects resulting from the oral administration of IR5878 to Beagle dogs and to determine the maximum tolerated dose to be used in this study (see point 05.03.01/03).

Duration of treatment / exposure:

. IR5878 was administrated by oral route once a day per 7 days a week, for 4 consecutive weeks to 12 males and to 12 females of Beagle dog.

Frequency of treatment:

. IR5878 was administrated by oral route once a day per 7 days a week, for 4 consecutive weeks to 12 males and to 12 females of Beagle dog.

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

0 mg/kg bw/day (actual dose received)

Doses / concentrations 2

Dose / conc.:

150 mg/kg bw/day (actual dose received)

Doses / concentrations 3

Dose / conc.:

450 mg/kg bw/day (actual dose received)

Doses / concentrations 4

Dose / conc.:

1 000 mg/kg bw/day (actual dose received)

No. of animals per sex per dose:

IR5878 was administrated by oral route once a day per 7 days a week, for 4 consecutive weeks to 12 males and to 12 females of Beagle dog. Groups of three Beagle dogs/sex were given by gelatine capsules doses of 0 (empty capsules), 150, 450 or 1000 mg/kg/day.

Examinations

Observations and examinations performed and frequency:

Clinical observations were carried out daily, body weight and food consumption measurements were recorded weekly during treatment, ophthalmoscopy and laboratory investigations (haematology, blood chemistry and urinalysis) were carried out before the treatment and at study termination.

Sacrifice and pathology:

All the animals were sacrificed at the end of the dosing period for pathology examinations (organ weights and histopathology).

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Ophthalmological findings:

no effects observed

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

no effects observed

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

Organ weight: IR5878 induced a slight increase in mean liver weights (absolute and relative) in highest dose females, when compared to controls. This change did not reach statistical significance, and was due to an outlier individual liver weight (female No. 3168). No other treatment-related changes were observed.

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Histology: treatment induced in the liver of the outlier female No. 3168 slightly hypertrophy of the centrilobular hepatocytes. As no degenerative or inflammatory effects were observed, hypertrophy could be considered as a metabolic adaptive change of the liver, rather than a toxic effect. No other treatment-related histological modifications were seen.

Effect levels

1

Key result

Dose descriptor:

NOAEL

Effect level:

>= 1 000 mg/kg bw/day (actual dose received)

Based on:

act. ingr.

Sex:

male/female

Basis for effect level:

body weight and weight gain

food consumption and compound intake

gross pathology

haematology

mortality

ophthalmological examination

urinalysis

2

Key result

Dose descriptor:

NOEL

Effect level:

>= 450 mg/kg bw/day (actual dose received)

Based on:

act. ingr.

Sex:

male/female

Basis for effect level:

organ weights and organ / body weight ratios

Target system / organ toxicity

Critical effects observed:

yes

Lowest effective dose / conc.:

1 000 mg/kg bw/day (actual dose received)

System:

hepatobiliary

Organ:

liver

Treatment related:

yes

Any other information on results incl. tables

Findings

Clinical observation

Mortality: no animals died during the study.

Clinical signs: no clinical signs were observed during the study.

Body weight and food consumption: no effects on body weight or on food consumption were noted at any dose.

Ophthalmic examination: no eye changes were seen in any dog.

 

Laboratory investigations

Haematology: no changes attributable to oral treatment with IR5878 were noted at any dose tested.

Blood chemistry: no treatment-related changes were seen in any animal at any dose tested.

Urinalysis: urine examination did not reveal treatment-related modifications at any dose.

 

Post mortemexaminations

Organ weight: IR5878 induced a slight increase in mean liver weights (absolute and relative) in highest dose females, when compared to controls. This change did not reach statistical significance, and was due to an outlier individual liver weight (female No. 3168). No other treatment-related changes were observed.

 

Table 5.3-10   4-week dietary study in dogs: absolute and relative liver weights(individual female No. 3168 values)

	Males				Females
	0           mg/kg bw/d	150        mg/kg bw/d	450        mg/kg bw/d	1000       mg/kg bw/d	0           mg/kg bw/d	150        mg/kg bw/d	450        mg/kg bw/d	1000       mg/kg bw/d
Absolute (g)	325.16	318.02	363.56	349.80	292.92	252.28	279.80	350.86(395.50)
Relative (%)	3.39	3.64	3.99	3.71	3.73	3.29	3.53	4.05      (5.04)

 

Gross pathology: no treatment-related changes were seen.

Histology: treatment induced in the liver of the outlier female No. 3168 slightly hypertrophy of the centrilobular hepatocytes. As no degenerative or inflammatory effects were observed, hypertrophy could be considered as a metabolic adaptive change of the liver, rather than a toxic effect. No other treatment-related histological modifications were seen.

Applicant's summary and conclusion

Conclusions:

IR5878 administrated by oral route (by capsule) to dogs for 4 consecutive weeks at the dose of 150, 450 and 1000 mg/kg/day induced a few adaptive changes in liver only at the highest dose, in one female.
In consideration of the above changes, NOAEL of the study is of 1000 mg/kg/day and NOEL is of 450 mg/kg/day.

Executive summary:

In order to evaluate the effects of repeated administrations of IR5878 to male and female Beagle dogs, IR5878 was administrated by oral route once a day per 7 days a week, for 4 consecutive weeks to 12 males and to 12 females of Beagle dog. Groups of three Beagle dogs/sex were given by gelatine capsules doses of 0 (empty capsules), 150, 450 or 1000 mg/kg/day.

IR5878 induced a few adaptive changes in liver only at the highest dose, in one female. In consideration of the above changes, NOAEL of the study is of 1000 mg/kg/day and NOEL is of 450 mg/kg/day.