Registration Dossier

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
20 July to 5 November 1999
Reliability:
1 (reliable without restriction)

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1999
Report Date:
1999

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
not specified
Qualifier:
according to
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Deviations:
not specified
GLP compliance:
yes
Test type:
acute toxic class method
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
other: Solid
Details on test material:
- Name of test material (as cited in study report): Pymordiol
- Physical state: Cream white solid
- Purity of test material: 96 wt%
- Lot/batch No.:DGM096K1A
- Expiration date of the lot/batch: 1 January 2001
- Stability under test conditions: Stable through test period
- Storage condition of test material: At room temperature in the dark

Test animals

Species:
rat
Strain:
other: Wistar Crl:(WI) BR
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: Approximately 7 weeks old
- Weight at study initiation: Within 20% of sex mean
- Fasting period before study: Overnight prior to dosing until approximately 3-4 hours after administration of the test substance.
- Housing: Group housing of 3 animals per sex per cage in polycarbonate cages containing purified sawdust as bedding material.
- Diet (e.g. ad libitum): Free access to standard pelleted laboratory animal diet (Carfil Quality BVBA, OUd-Turnhour, Belgium).
- Water (e.g. ad libitum): Free access to tap water
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21˚C
- Humidity (%): 50%
- Air changes (per hr): 15 Air changes per hour
- Photoperiod (hrs dark / hrs light): 12 hours of artificial fluorescent light/12 hours dark.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
polyethylene glycol
Details on oral exposure:
VEHICLE
- Amount of vehicle (if gavage): 10mL/kg
- Justification for choice of vehicle: The vehicle was selected based on a pretest performed at NOTOX.

DOSAGE PREPARATION (if unusual): Formulations (w/w) were prepared within 4 hours prior to dosing. Homogeneity was accomplished to a visually acceptable level.

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: Toxicity of the test substance was assessed by stepwise treatment of groups of 3 animals.
Doses:
200 mg/kg
2000 mg/kg
No. of animals per sex per dose:
3 Animals
Control animals:
not specified
Details on study design:
- Duration of observation period following administration: 15 days
- Frequency of observations and weighing: Twice daily
- Necropsy of survivors performed: Yes, by asphyxiation using oxygen/carbon dioxide procedure.
- Other examinations performed: clinical signs, body weight, organ weights, histopathology, other: Twice daily viability/mortality; body weights Days 1 (pre-admin), 8 and 15 and at death; clinical signs were taken on day 1 and once daily thereafter, until day 15.

Results and discussion

Effect levels
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 200 - < 2 000 mg/kg bw
Based on:
test mat.
Mortality:
The incidence of mortality is reported in Table No. 1 below.

Two females and two males were found dead on days 2 and 4 and on days 4 and 5, respectively. The two other animals (one female and one male) were sacrificed moribund on day 7 and day 5, respectively, as indicated by the combination of clinical signs and considerable body weight loss observed in these animals.
Clinical signs:
Within the 200 mg/kg dose group, signs of alopecia and/or scabs (in the neck) became apparent in two females during week 2. Based on the time of occurrence, these findings were considered not related to treatment and of no toxicological significance.

Within the 2000 mg/kg dose group lethargy was observed in all males on day 1. From day 2 (males) or day 3 (females) clinical signs became apparent among the animals, including hunched posture, uncoordinated movements, piloerection, ventro-lateral recumbency, lethargy, tremors, slow breathing, red staining of the snout, dehydration and emaciation. No clinical signs of toxicity were apparent in one female prior to its death on day 2.
Body weight:
All animals treated at 2000 mg/kg surviving for several days showed considerable body weight loss. The fact that over 20% body weight loss was observed, the animals were sacrificed; they being moribund was one of the criteria for this decision.
Gross pathology:
Reduced spleen and thymus size was found among the 2000 mg/kg treated animals, at macroscopic post mortem examination.

Any other information on results incl. tables

Table 1:

Dose Level (mg/kg) Mortality Sex Date of Treatment
200 0/3 females 20-Jul-99
200 0/3 males 22-Jul-99
2000 3/3 females 27-Jul-99
2000 3/3 males 29-Jul-99

Applicant's summary and conclusion

Interpretation of results:
harmful
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Under the current test conditions the oral LD50 value for the test substance is within the following range 200-2000 mg/kg body weight.