Ethylene dinitrate

Repeated dose toxicity: dermal

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

Test material information

Constituent 1

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 / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
15 mg/kg
Basis:
nominal per unit body weight

Doses / concentrations 2

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

1

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

2

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

3

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