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Toxicological information

Repeated dose toxicity: dermal

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Administrative data

Endpoint:
short-term repeated dose toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1981

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 410 (Repeated Dose Dermal Toxicity: 21/28-Day Study)
Deviations:
yes
Remarks:
one-half tested with intact skin and one-half with abraded skin
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
MBS Santocure MOR Lot 9B-0073, purity: 95.6 %

Test animals

Species:
rabbit
Strain:
New Zealand White
Sex:
male/female

Administration / exposure

Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
21 days
Frequency of treatment:
6 hours/ 5 days per week
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 125, 500, 2000 mg/kg bw/d
Basis:

No. of animals per sex per dose:
5 per dose and sex (intact skin) and 5 per dose and sex (abraded skin)
Control animals:
yes

Results and discussion

Effect levels

Dose descriptor:
NOAEL
Effect level:
> 2 000 mg/kg bw/day
Sex:
male/female
Basis for effect level:
other: no major signs of local or systemic toxicity were noted

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

General observations:

Clinical signs:

No compound related signs were noted for any animal in the test group during the study.

A number of incidental and spontaneous signs were noted for a few rabbits in the control and test groups. These observations included: clear and purulent nasal discharge, clear and purulent ocular doscharge, no stool in pan, soft stool, diarrhea, mucoid diarrhea, yellow mucoid diarrhea, possible anorexia and emaciation. One male of the 125 mg/kg bw/d group exhibited possible anorexia, hyperactivity and soft stool prior to being found dead. One female of the 500 mg/kg bw/d group appeard normal prior to death. One male of the 2000 mg/kg bw/d group was noted as having possible anorexia, no stool in pan, and was emaciated prior to death. One female of the control group, exhibited possible anorexia, emaciation, mucoid diarrhea, purulent ocular discharge, prostration, hypothermia, bradypnea, ataxia and hypoactivity prior to being sacrificed. There were no remarkable differences in the incidence of animals exhibiting anorexia among the control and test groups.

Mortality:

No treatment related death was noted, 1/5 male 125 mg/kg bw/d (abraded skin) was found dead on study day 10; 1/5 female of the 500 mg/kg bw/d group 8intact skin) was found dead on day 14 and 1/5 male of the 2000 mg/kg bw/d group (intact skin) was found dead on study day 8.

Dermal irritation:

The majority of the rabbits in both the control and test groups (abraded and intact skin) exhibited no dermal irritation during the study period except for a frw rabbits in the control group which exhibited very slight desquamation. Some rabbits also exhibited red raised areas on the shaved back. In the three test articel groups 125, 500 and 2000 mg/kg bw/d, a few rabbits exhibited very slight to slight erythema, edema and desquamation during the study period. No eschar or exfoliation was observed in any group.

Body weights:

No statistically significant differences were seen in group mean body weights.

Clinical laboratory tests

Hematology:

Sight decreases in hematocrit, hemoglobin and total erythrocytes were seen for females at 2000 mg/kg bw/d.Although the means of these values for the females receiving 2000 mg/kg bw/d were statistically significant lower (p<0.05) than the mean of the control females the actual differences were slight. In the absence of any changes for males reveiving 2000 mg/kg bw/d it was considered that this decrease in hematologic parameters for females receiving 2000 mg/kg bw/d was not related to the test substance.

Biochemistry:

Lactic dehydrogenase (LDH) activity was lower and cholesterol values werehigher for males at 2000 mg/kg bw/d when compared to control. Cholesterol values also were higher for males at 500 mg/kg bw/d. These differences were not statistically significant, and because of the wide range of these values, the authors considered these differences (LDH and cholesterol) as not related to the test substance.

Incidental findings included a decreased potassium level for one male at 500 mg/kg bw/d and moderate to market increases in creatinine and blood urea nitrogen levels and decrease in serum calcium for one female at 2000 mg/kg bw/d.

Pathology:

Gorss obervations:

The skin from the application site was mostly unremarkable, three animals of the 500 mg/kg bw/d group and two of the 2000 mg/kg bw/d group presented prominent vessels or pinpoint hemoohagic areas subcutaneously.

The systemic observations were mainly in the lung, they were interpreted as congestion or pneumonic areas mainly. The contents of the gastrointestinal tract were decribed as watery in control and treated animals.

Body and organ weights:

The body weight means of males and females of the control and treated groups were simular. most of the absolute and relative organ weights were within the usual range. Only relative weight mean of testes from the 125 mg/kg bw/d group were increased. The author stated that the biological significance of this increase is unknown.

Histopathology:

The skin from the site of application of the males presented mainly hyperkeratosis, acanthosis, and infiltration of inflammatory cells in the dermis. The incudence and severity of the lesions appears to be greater in the control and low dose groups than in the higher dose groups. Simular findings were noted for the site of application of the females. The skin from the untreated site presented simular lesions.

The other organs presented cases of pneumonia, nephritis and some other lesions which were considered unrelated to the application of the test substance.

Applicant's summary and conclusion