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Repeated dose toxicity: dermal

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Administrative data

Endpoint:
chronic toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: This study should be used with caution because the bulk of the text is in Japanese, so any qualifications or limitations that may have been identfied by the authors wre not known at the time of this review.

Data source

Reference
Reference Type:
publication
Title:
Percutaneous chronic toxicity of 10% nitroglycerin (NT-1 ointment) in rabbits
Author:
Imoto, S., Kuramoto, M., Iwabuchi, K., Nagai, H. and Shimpo, K.
Year:
1986
Bibliographic source:
The Journal of Toxicological Sciences (Japanese): 11 (Suppl. II): 31-57.

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Groups of male New Zealand white rabbits were administered NT-1 ointment to the back skin for 26 weeks at daily doses of 15, 60 and 240 mg/kg. Both dermal and systemic responses were reported.
GLP compliance:
not specified
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Glycerol trinitrate
EC Number:
200-240-8
EC Name:
Glycerol trinitrate
Cas Number:
55-63-0
Molecular formula:
C3H5N3O9
IUPAC Name:
propane-1,2,3-triyl trinitrate

Test animals

Species:
rabbit
Strain:
New Zealand White
Sex:
male

Administration / exposure

Type of coverage:
occlusive
Vehicle:
not specified
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
26 weeks
Frequency of treatment:
24 hours over 26 weeks (continuous)
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
15 mg/kg
Basis:
nominal per unit body weight
Remarks:
Doses / Concentrations:
60 mg/kg
Basis:
nominal per unit body weight
No. of animals per sex per dose:
vehicle control (n=14), non-treated control (n=15), 15 mg/kg (n=14), 60 mg/kg (n=15), 240 mg/kg (n=14)
Control animals:
yes
Details on study design:
Three dose groups, one vehicle control group, and one non-treated control group.
Positive control:
yes, vehicle control

Examinations

Observations and examinations performed and frequency:
DERMAL IRRITATION (if dermal study): Yes

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Time schedule: daily

WATER CONSUMPTION: No data

HAEMATOLOGY: Yes
- Time schedule for collection of blood: end of administration (6 months) and end of 1- month recovery period
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: all animals at end of administration period, 5 animals/group at end of recovery period
- Parameters examined: hemoglobin, hemotocrit, reticulocyte, white blood cell count, hemogram (%), lymphocyte count, eosinophil, basophil, monocyte, lymphocyte, platelet, prothrombin time, activated partial thromboplastin time.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: end of administration (6 months) and end of 1- month recovery period
- Animals fasted: No data
- How many animals: all animals at end of administration period, 5 animals/group at end of recovery period
- Parameters examined: GOT, GPT, ALP, LDH, CPK, total protein, albumin/globulin, protein fraction (%), blood urinary nitrogen, total bilirubin, creatinine, glucose, triglyceride, total cholesterol, free cholesterol, phospholipid, Na, K, Ca, Cl, Fe.

Hair examinations
- Time schedule: end of administration (6 months) and end of 1- month recovery period
- How many animals: all animals at end of administration period, 5 animals/group at end of recovery period
- Fur was judged as either "sleek" or "not sleek"
Sacrifice and pathology:
GROSS PATHOLOGY: Yes (absolute and relative organ weights - brain, hypophysis, submandibular gland, thyroid, thymus, heart, lung, liver, spleen, kidney, adrenal, testis, prostate)
HISTOPATHOLOGY: Yes (rabbit skin treated site - thickening of epidermis, cell infiltration, elongated of rete ridges, Touton giant cells, hyperkeratosis; rabbit skin boundary site - thickening of epidermis, cell infiltration)
Statistics:
Statistical methods were used to determine whether there were significant differences between treatment groups and controls, but the methods used could not be determined given that the study was largely in Japanese.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Dermal irritation:
effects observed, treatment-related
Description (incidence and severity):
erythema, edema, papules, scales, and thickening of the skin
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
increased white blood cells (neutrophils)
Urinalysis findings:
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
increased kidney and heart weights
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed

Effect levels

open allclose all
Dose descriptor:
LOAEL
Remarks:
dermal effects
Effect level:
15 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: dermal effects
Remarks on result:
other: no NOAEL was determined for dermal effects
Dose descriptor:
NOAEL
Remarks:
systemic effects
Effect level:
60 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: systemic effects
Dose descriptor:
LOAEL
Remarks:
systemic effects
Effect level:
240 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: systemic effects

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

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