Registration Dossier

Administrative data

Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: basic information given, scientifically acceptable

Data source

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

Materials and methods

Principles of method if other than guideline:
This study was intended to provide information on the health hazards likely to arise from a short-term accidental exposure to the test material by the dermal route.
GLP compliance:
yes
Remarks:
testing lab.
Test type:
standard acute method
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals and environmental conditions:
Young adult albino rabbits (at least 8 weeks old at study initiation) were used; females were nulliparous and non-pregnant. The body weights of males was 2.4 - 3.2 kg, females weighing 2.7 - 3.3 kg. All animals were checked for viability twice daily. Prior to assignment animals were examined to ascertain suitability for the study. The animals were individually housed in stainless steel cages. The animals were identified using a monel ear tag. Animals were randomly placed in cages up receipt and were placed on study as available at the time of study initiation. Animals considered unsuitable for study because of poor health or outlying body weights were excluded.
Room temperature was 60-70°F and the humidity was 30-70%. Food and water was available ad libitum.

Administration / exposure

Type of coverage:
not specified
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
Administration to the clipped skin of the trunk. The test material was administered as received; no preparation was necessary.
On the day before dosing (approx. 18 h prior to dosing), the hair of each rabbit was closely clipped from the trunk (dorsal and ventral surface and sides from scapular to pelvic area) in the 250 mg/kg dose group and on the sides and dorsal surface for the 50, 125 and 190 mg/kg dose groups using an electric clipper, so as to expose at least 10% of the body surface area. The skin remained intact, i.e. no abrasions were made.
Duration of exposure:
single doses, 14-day observation
Doses:
50, 125, 190, 250 mg/kg
No. of animals per sex per dose:
5
Control animals:
not specified
Details on study design:
Duration of observation period following administration: 14 days
A viability check was made twice daily; observations of pharmacologic and toxicologic signs were made approx. 1, 2 and 4 h after dosing and daily thereafter for 14 days.
Neurological evaluations were performed at 1, 2, 4 and 24 hours after dosing and on days 7 and 14.
Any animal which did not survive for 14 days were weighed at the time of death or at the time they were found dead.
Carboxyhemoglobin levels were measured 1 and 4 hours post-dose. Blood was obtained via venipuncture of the auricular artery from all surviving animals.
Gross post-mortem examinations were performed on all animals which died were found dead during the study. At termination of the observation period (day 14), all surviving animals were killed by an intravenous overdose of sodium pentobarbital and examined grossly.

Results and discussion

Effect levels
Sex:
male/female
Dose descriptor:
LD50
Effect level:
56 - 170 mg/kg bw
Mortality:
50 mg/kg: 2/5 females on day 4 and 5 (males were not used at this dose level); 125 mg/kg: 3/5 males and 5/5 females on day 2 and 3; 190 mg/kg: 3/5 males on day 3 (no females were used at this dose level); 250 mg/kg: 4/5 males and 5/5 females on day 2 and 3.
Clinical signs:
The majority of abnormal signs occurred between 1 and 4 days after dosing and frequently occurred as ante-mortem abnormalities in animals that died. These signs included respiratory abnormalities (hyperpnea, dyspnea, hypoactivity, cyanosis, a blue tint to the iris and poor food consumption. With the exception of one male in the 190 mg/kg group, which continued to exhibit hyperpnea, cyanosis, emaciation and poor food consumption for most of the post-dose period, all surviviors were free of significant abnormalities within 5 days after dosing. No remarkable dermal abnormalities were seen.
Body weight:
Animals that died exhibited ante-mortem weight losses of 0.1 - 0.5 kg. One surviving male of the 190 mg/kg group exhibited a large weight loss with a subsequent gain (0.3 kg) between days 7 and 14. Other survivors exhibited minimal weight changes at days 7 and/or 14.
Gross pathology:
The majority of animals killed after 14 days were noted to have discoloration of the lungs. Although this is not a uncommon finding in laboratory rabbits, the high incidence suggests a possible relationship to test material administration. Other observations were unremarkable.

Applicant's summary and conclusion