Registration Dossier

Administrative data

Endpoint:
short-term repeated dose toxicity: dermal
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
1969
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: An old study conducted before GLP or standard guidelines were introduced. However, the study was undertaken at a recognised laboratory, and there are sufficient data reported to provide a supplementary assessment for a second route of exposure.
Cross-reference
Reason / purpose:
reference to same study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1969
Report Date:
1969

Materials and methods

Test guideline
Qualifier:
no guideline available
Deviations:
not specified
Principles of method if other than guideline:
A standard design for repeat dermal application toxicity study
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
A clear, oily liquid with a faint, unpleasant odour. Received on 10 January1969 and assumed to be 100% active.

Test animals

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

Administration / exposure

Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
24 hours per day, five days per week for six weeks
Frequency of treatment:
0nce a day, five days a week
Doses / concentrations
Remarks:
Doses / Concentrations:

Basis:
nominal per unit body weight
No. of animals per sex per dose:
Four male at 0.5 ml/Kg and four males at 2.5 ml/Kg
Control animals:
yes, sham-exposed

Results and discussion

Effect levels

open allclose all
Dose descriptor:
NOEL
Remarks:
(Systemic)
Effect level:
> 2.5 other: ml/kg/day
Sex:
male
Basis for effect level:
other: No systemic toxicity
Dose descriptor:
NOAEL
Remarks:
(Local)
Effect level:
0.5 other: ml/Kg/day
Sex:
male
Basis for effect level:
other: Mild dermal irritation

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

There was no evidence of systemic toxicity from repeated dermal exposures to MRD-69-4 as based on general appearance and behavior, clinical laboratory studies, and gross and microscopic visceral pathology.

 

Compound effect was confined to gross and microscopic alterations of the skin. Grossly, MRD-69-4 at the 0.5 ml/kg/day level produced generally mild dermal irritation which was slightly more severe than irritation produced by mineral oil at 2.5 ml/kg/day; at the 2.5 ml/kg/day level, slight or moderate (abraded skin only) erythema and slight desquamation were noted through the fifth week of application.

 

Histologically, skin sections showed slight acanthosis, slight hyperkeratosis, and slight dermatitis of comparable severity in control and compound-treated animals. Sections of kidney, liver, and skin from control and test animals were comparable histologically; lesions encountered were consistent with incidental disease.

Applicant's summary and conclusion

Conclusions:
There was no evidence of systemic toxicity from repeated daily dermal exposure to MRD-69-4 for six weeks. Mild irritation was observed at the application sites of animals treated with MRD-69-4, although there was no histopathological difference in the severity of the skin changes between test and control animals.
Executive summary:

In a six week dermal toxicity study, groups of four New Zealand White rabbits received 24-hour daily applications of MRD-69-4 at 0.5 or 2.5 ml/Kg, five times a week, to the closely clipped intact (two animals per group) or abraded (two animals per group) abdominal skin, wrapped with gauze adhesive tape and fitted with neck collars. Control animals (three males and one female) received mineral oil at 2.5 ml/Kg. Clinical signs were recorded daily, haematology and urinalysis undertaken initially and terminally, and histopathology was performed on the liver, kidneys and skin. There was no evidence of systemic toxicity. Mild irritation was observed at the application sites of animals treated with MRD-69-4, although there was no difference in the severity of histopathological skin changes apparent between test and control animals. The systemic NOEL was considered to be 2.5 ml/kg/day (estimated to be 2500 mg/kg/day) and the local NOAEL was considered to be 0.5 mg/kg/day (estimated to be 500 mg/kg/day).

The dermal toxicity study was considered to be a suitable supporting study for classification.