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Toxicological information

Acute Toxicity: other routes

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Administrative data

Endpoint:
acute toxicity: other routes
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Although the study was conducted according to GLP and well documented methods, " Practical guide 10: How to avoid unnecessary testing on animals", Section 3.3.2 states it is important that the reliability indicator (Klimisch score) reflects the assumptions of similarity. Thus, a score of 1 (reliable without restrictions) should normally not be used for results derived from read-across.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1988
Report Date:
1989

Materials and methods

Principles of method if other than guideline:
DuP 753 was administered in single intraperitoneal doses of 25, 50, 100 or 200 mg/kg to groups of 5 male and female albino rats. Control rats received an equivalent volume of the vehicle. Over a two week period, observations for mortality, clinical signs and body weight were made.
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: particulate/powder
Remarks:
migrated information: powder
Details on test material:
- Name of test material (as cited in study report): DuP 753
- Substance type: bulk powder
- Physical state: solid
- Analytical purity: 99.2%
- Lot/batch No.: INE-3340-15

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Kingston, NY
- Age at study initiation: 8 weeks

- Housing: Individually housed in stainless steel wire mesh cages
- Diet (e.g. ad libitum): Certified Agway Prolab RMH 3000 pelleted food ad libitum (except for fasting prior to necropsy)
- Water (e.g. ad libitum): Ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 72 +/- 2°C
- Humidity (%): 40-70%
- Photoperiod (hrs dark / hrs light): 12 hrs light/12 hrs dark

IN-LIFE DATES: From: 4 October 1988 To: 19 October 1988

Administration / exposure

Route of administration:
intraperitoneal
Vehicle:
water
Details on exposure:
DuP 753 was prepared once on the designated day of dosing as a solution in Sterile Water for Injection. Doses were administered to the rats by intraperitoneal injection at a volume/body weight of 2 mL/kg. Control animals received an equivalent volume/body weight of the vehicle. Individual doses of DuP 753 were based on a pre-dose body weight measured prior to dosing.
Doses:
0, 25, 50, 100 and 200 mg/kg
No. of animals per sex per dose:
5 male/5 female
Control animals:
yes
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Page of the study report that describes this is missing
- Necropsy of survivors performed: yes
- Other examinations performed: mortality, clinical signs, body weight,gross pathology

Results and discussion

Effect levelsopen allclose all
Sex:
male/female
Dose descriptor:
other: NOAEL
Effect level:
ca. 100 mg/kg bw
Based on:
test mat.
Sex:
male/female
Dose descriptor:
other: Maximum Tolerated Dose
Effect level:
ca. 100 - < 200 mg/kg bw
Based on:
test mat.
Mortality:
There was no mortality associated with the administration of the vehicle or with doses of 25, 50 or 100 mg DuP 753/kg bw. Drug related mortality was observed in rats treated with 200 mg DuP 753/kg bw. Three males and one female died approximately 3 to 5 days post-dose.
Clinical signs:
There were no clinical signs noted in the low dose group (25 mg/kg) that were considered to represent a toxicologically adverse effect of treatment. Mild clinical signs related to DuP 753 were noted in the 50 and 100 mg/kg groups and included soft stools, ataxia and perianal staining. Clinical signs observed in rats treated with 200 mg DuP 753/kg consisted of ataxia, decreased motor activity, perianal staining, urogenital staining, dehydration, soft/mucoidal stools, pale ears, rough coat, material around eyes, mouth, paws and/or nose and labored breathing.
Body weight:
A treatment related body weight loss was exhibited in the high dose group (100 mg/kg) male and female groups from Study Day 1 to Study Day 2. Thereafter, the surviving high dose rats gained weight at a rate comparable with that of the control group.
Gross pathology:
Gross post-mortem findings considered to be related to DuP 753 were noted in the gastrointestinal tract of the 200 mg/kg group and included: abnormal size (distension) of the jejunum and duodenum, thickened wall of the jejunum and cecum and firm consistency of the contents found in the jejunum and ileum.

Applicant's summary and conclusion

Conclusions:
Based on the absence of significant dos-related effects and mortality, the single intraperitoneal no-observable-adverse-effect-level (NOAEL) was considered to be 100 mg DuP 753/kg and the single intraperitoneal maximum tolerated dose (MTD) of DuP 753 was considered to be >100 but <200 mg/kg.