Registration Dossier

Administrative data

Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1987

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
GLP compliance:
not specified
Test type:
standard acute method
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
SY-83; Lot number: AP6853

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals and environmental conditions:
Male and female Fischer 344 rats were obtained from Charles River Breeding Laboratories, Raleigh, North Carolina. Upon arrival,animals were quarantined for approximately 21days. Stringent disease control procedures were followed during quarantine to assure the use of healthy animals. Rats were observed fo rsigns of illness. The animals were judged to be healthy prior to utilization in this study and were 9-10 weeks old at initiation of exposure.
Animals were housed in an AAAIAC-accredited facility with a controlled environment. Th etemperature range was 71±5°F, while the humidity range was 50 ± 22 % with a brief excursion down to 18% during one day. The light cycle was maintained on a 12 hour light/dark cycle. Rats were individually housed in polycarbonate cages with filter tops and automatic watering devices. Corn-cob bedding was used and animals had free access to certified laboratory rodent chow which had been analyzed for environmental contaminants. Water and food were provided ad libitum, except during exposure.

Administration / exposure

Route of administration:
inhalation: aerosol
Type of inhalation exposure:
nose only
Vehicle:
other: unchanged (no vehicle)
Details on inhalation exposure:
tmosphere Generation:
A Collison nebulizer (BGI Industries) was used to generate the aerosol Compressed air was attached to the generator and the output from the aerosol was directed into a 4 liter dilution jar. Room air was allowed to dilute the aerosol before it was drawn into the exposure module under vacuüm. A continuous, dynamic exposure to aerosolized test material was achieved with the nose-only exposure units. The air flow in the exposure module was adjusted to approximately 5 L/min using a calibrated rotameter and was periodically monitored during exposure. The exposure module consisted of a 360 ml cylindrical chamber mounted horizontally with an inlet, outlet and sampling port. Sampling of the test atmosphere was done from a sampling port situated on the side of the exposure module. Samples from the exposure module were taken for gravimetric and particle size determinations. Determinations of oxygen content could not be performed due to a malfunction of the oxygen sensor.
Conditions for Animal Exposures:
Rats were held in cylindrical tubes which aligned the heads of the animals with the conical shaped openings on the exposure chamber. The nose of each animal protruded into the chamber for nose-only _
inhalation. The animals were held in place by a soft sponge which served as a plunger in the cylinder and prevented the animal from turning or backing out. Five rats were restrained on each side of the exposure module (males on one side, females on the other) as diagramed in Figure l of Appendix B. All rats of each concentration level were
exposed at the same time.
Determination of Aerosol Concentration and Particle Size Distribution:
Gravimetric determinations were made by pre-weighing a 24 mm diameter Whatman glass-fiber filter (GF/A), placing the filter in a filter holder, and connecting the filter to the sampling port of the exposure module. Air samples were drawn through the filter using a vacuüm
supply regulated by a flow meter. Flow rates were set 0.5 L/min and a sampling time of 4-8 min was used. The concentration of aerosol present in the chamber was calculated by the difference in weight of the filter divided by the volume of air sampled. Seven separate determinations were made and a time-weighted average was calculated for the total aerosol concentration.
Analytical verification of test atmosphere concentrations:
yes
Remarks:
Gravimetric, using a filter interception
Duration of exposure:
4 h
Concentrations:
7.94 mg/L
No. of animals per sex per dose:
5
Control animals:
yes
Details on study design:
Five male and five female rats were exposed to a nominal concentration of 7.94 mg/L of aerosolized test material for 4 hours. Analysis of at least three filter samples was performed to determine the purity of test material in the exposure module. The exposure atmosphere was also sampled to determine particle size distribution. A shamcontrolgroup of 5 male and 5 female rats was used and was exposed to air alone for 4 hours. Animals were weighed prior to treatment and at weekly intervals thereafter. Theanimals were observed for mortality and pharmacotoxic signs during exposure, at l and 3 hours following exposure and once daily thereafter for 14 days. Survival was recorded for each group. Complete necropsies were performed on all animals on day 15 of the study. At necropsy,all organs showing gross lesions, if any, were fixed in 10% buffered formalin. Histopathology was not performed.

Results and discussion

Effect levels
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 7.94 mg/L air
Exp. duration:
4 h
Mortality:
1 female died.
Clinical signs:
Animals were observed during exposure for signs of toxicity. Rapid breathing and eye tearing was observed in the treated group, while in the sham control group, respiration was calm and steady during exposure. One and three hours after exposure, the treated and control groups had a hunched posture, red stained fur surrounding the eyes (tearing), ruffled fur, and appeared ungroomed with soiled fur (stained brown). Female rats exposed to SY-83 appeared lethargic at one (2/5) and three hours (5/5). The two female rats that were lethargic at one hour also had rapid, shallow breathing and appeared to be gasping at both one and three hours. By 24 hours, most animals appeared normal and no unusual behavior or appearance was observed for the remainder of the test period. However,of the treated female rats, 4/5 had ruffled, ungroomed fur at 24 hours, and 3/5 had ruffled, ungroomed fur 2, 3 and 4 days after treatment. One female from the treated group had hunched posture, rapid and shallow breathing, and slight tremors, but these signs were observed only on day 5 post-treatment. One female rat from the treated group diedon Day 8 post-treatment. This animal was hunched with labored breathing and gasping on Day 7. All other animals survived to the end of the study.
Body weight:
Individual body weights for animals on test are given in Tables 4 and 5. At the beginning of the study, mean body weicihts for individual groups were within 20% of the overall mean for each sex. All groups of male rats gained weight within the first week after exposure in comparison to pre-exposure weights (3% for sham-exposed, 2< for SY-83,
respectively). Female rats in the sham group gained weight during the first week after exposure (less than 1%). Female rats in the treated group lost weight during the first week after exposure (7%). After 14 days, all surviving animals had gained weight in comparison to pre-exposure weights (14% for males, 7% for females). No significant differences were observed in body weight between treated and control groups.
Gross pathology:
All surviving animals were necropsied at the termination of the study. The aninal that died during the study was necropsied immediately. Necropsy results are shown in Table 6. No gross lesions were observed at necropsy.

Applicant's summary and conclusion

Interpretation of results:
practically nontoxic
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
In line with findings in oral study
Executive summary:

SY-83 was tested for lts acute inhalation toxicity. Male and female F344 rats were exposed to a concentration of approxinately 7.94 mg/L for 4 hours. Rapid breathing and eye tearing were observed during exposure. At one and three hours after exposure, all animnals (including the sham controls) had a hunched posture, ruffled and ungroomed fur, brown stained fur and red-stained fur surrounding the eyes (tearing). By 24 hours,female treated rats had ruffled and stained coats. All other animals appeared normal at 24 hours and for the remainder of the 14 day observation period. Several treated female rats continued to have ruffled fur up to 4 days after exposure. One female rat from the treated group died on Day 9. All other animals survived until the end ofthe study. Based on these results,the LC50 of SY-83 is greater than 7.94 mg/L.