Registration Dossier

Administrative data

Endpoint:
short-term repeated dose toxicity: dermal
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
1975
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
other: Reliability of 3 assigned because the study does not meet important criteria of today's standard methods (intermittent exposure over a short time period).

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1975
Report Date:
1975

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: not known
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rabbit
Strain:
other: albino
Sex:
male

Administration / exposure

Duration of treatment / exposure:
17-19 days
Frequency of treatment:
2 or 3 times/week
Doses / concentrations
Remarks:
Doses / Concentrations:
0.2, 0.4, and 0.8 ml/kg
Basis:
other: nominal
No. of animals per sex per dose:
four males/dose
Control animals:
other: dosed with 2.0 ml/kg of distilled water
Details on study design:
Groups of four male albino rabbits, between 2.0 and 2.3 kg, received 8 inunctions; three the first week (M, W, F), three the second week (M, W, F) and two the third week (M, W) at 0.8 ml/kg and 0.2 ml/kg of A-172.  The 0.4 ml/kg dosage group received 7 inunctions; two the first week (W, F), three the second week (M, W, F) and two the third week (M, W).  A control group for each level was inuncted with 2.0 ml/kg of distilled water.  As the skin penetration LD50 of A-172 was 1.50 ml/kg (CHF Report 17-27, dated 2/5/54), approximately one quarter of t he LD50, or 0.4 ml/kg, was the first dosage level selected for study. The dose was gently massaged, using a glass test tube as the applicator, onto the clipped skin on the belly and on the flanks as the size of the dose necessitated.  The 0.8 and 0.4 ml/kg levels were inuncted by applying one-half of the dose and rubbing for one minute during two successive 15-minute periods.  The 0.2 ml/kg level was applied in a single dose rubbed for one minute.  One hour after the last application, the skin was gently blotted with cleansing tissue to remove any unabsorbed liquid to prevent ingestion by licking the skin.  The rabbits were then returned to their home cages.

Examinations

Observations and examinations performed and frequency:
The rabbits were weighed before each dose and that day's dose calculated.  All abnormal responses and signs, as well as skin responses, were recorded.  The rabbits were killed on Friday of the third week after weighing and recording skin responses. 
Sacrifice and pathology:
 Liver and kidneys of each rabbit were weighed at sacrifice and appropriate tissues taken for possible future microscopic examination.
Statistics:
Statistical comparisons were performed by the homogeneity and analysis of variance procedures.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Dermal irritation:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Gross pathological findings:
effects observed, treatment-related
Details on results:
Two deaths occurred during the study, one at the 0.8 ml/kg dosage level and one at the 0.4 ml/kg level.  Both deaths were on calendar day 16 after receiving 7 doses.  The autopsy indicated that the liver was mottled and kidneys pale and congested for the dead rabbit at 0.8 ml/kg.  Nothing remarkable was found for the other rabbit at 0.4 ml/kg although both had a large reduction in body fat.  One death occurred in the distilled water control group for the 0.2 ml/kg dosage level.  The rabbit received 3 doses and died on study day 7.  It had severe diarrhea, which was diagnosed as the probably cause of death.
The rabbits at 0.8 ml/kg and 0.4 ml/kg were statistically different in mean body weight change from the control rabbits.  Mean body weight changes were statistically equivalent to the control group in the 0.2 ml/kg dosage level.  All three dosage levels were statistically equivalent to the control groups when liver and kidney weights per se and as percentages of body weight were examined.  Desquamation was the only abnormal skin response noted at the 0.8 ml/kg level, with the 0.4 ml/kg and 0.2 ml/kg levels showing practically no skin responses.

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
0.2 other: ml/kg bw
Sex:
male
Dose descriptor:
LOAEL
Effect level:
0.4 other: ml/kg bw
Sex:
male

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
The maximum no ill-effect level was 0.2 ml/kg with the minimum effect level being 0.4 ml/kg for 7 or 8 inunctions.