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Diss Factsheets

Administrative data

Endpoint:
short-term repeated dose toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1982
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The study was not conducted to GLP and did not follow a standardised guideline, however it is a well documented study and includes a well reported results section

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1982

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 410 (Repeated Dose Dermal Toxicity: 21/28-Day Study)
Deviations:
yes
Remarks:
less animals used than recommended by guideline,
GLP compliance:
not specified
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Hydroxylammonium nitrate
EC Number:
236-691-2
EC Name:
Hydroxylammonium nitrate
Cas Number:
13465-08-2
Molecular formula:
H3NO.HNO3
IUPAC Name:
hydroxylammonium nitrate
Details on test material:
The test material was recieved from Ballistics Research Laboraoty, Aberdeen Proving Ground, MD, with lot identification from the Naval Ordinance Station, Indian Head, MF of NOSIH Batch R149/151.

Test animals

Species:
rabbit
Strain:
New Zealand White
Sex:
male
Details on test animals or test system and environmental conditions:
Male New Zealand White Rabbits ranged in weight from 2.2 -2.7 kg and were housed individually in stainless steel cages with food and water available ad libitum

Administration / exposure

Type of coverage:
other: none-occlusive
Vehicle:
not specified
Details on exposure:
The test solution was aplied with a microsyringe onto the clipped mid-lumbar region of the rabbit. Control animals were treated with water. Following each application, the area was covered by a non-occlusive patch to prevent the animal from licking the area. On the weekly shaving day, the compound was applied 4 hours after shaving.
Details on analytical verification of doses or concentrations:
No data.
Duration of treatment / exposure:
The test solution was applied 5 days a week for 3 weeks.
Frequency of treatment:
The test solution was applied 5 days a week for 3 weeks.
Doses / concentrations
Remarks:
Doses / Concentrations:
0.7, 1.5, 2.9, 5.9, 11.7 mg/kg bw/day
Basis:
nominal per unit body weight
No. of animals per sex per dose:
5/male/dose
Control animals:
yes
Details on study design:
The doses applied were fractions of the acute dermal occluded LD50 (70 mg/kg).
The applied doses were: 0 (control), 0.7, 1.5, 2.9, 5.9 and 11.7 mg/kg.
Animals were weighed weekly and doses for that week were calculated from this weight.
Positive control:
No data

Examinations

Observations and examinations performed and frequency:
Animals were inspected daily prior to treatment. Animals were weighed weekly to to determine the following weeks dose.
Sacrifice and pathology:
All animals were sacrificed at the end of the study period and necropsied.
Other examinations:
No data.
Statistics:
Results from each test group were compared with the control group. Results were compared statistically with a Mann-Whitney U-test. Results were considered stastically significant at 0.05.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Dermal irritation:
effects observed, treatment-related
Description (incidence and severity):
Dermal irritation was oberved at doses of 0.7 mg/kg and greater
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
There was a decrease in bodyweight in animals dosed with 11.7 mg/kg
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
Changes in blood parameters were observed at doses of 2.9 mg/kg and higher
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
At concentrations greater than 2.9 mg/kg, spleen weights were higher than control animals
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Splenic haematopoiesis was observed at doses of 2.9 mg/kg and higher
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Extramedullary haematopoiesis observed at doses of 2.9 mg/kg and higher
Histopathological findings: neoplastic:
no effects observed
Details on results:
Histopathology:
At the end of the study period, animals in all treatment groups (not controls) displayed a high incidence of dermatitis. The incidence and severity of ulcerative dermatitis was dose-dependent. Ulcerative dermatitis was characterised by marked necrosis and a loss of epidermis with acute and chronic inflammatory infiltrates extending from the base of the epithelia necrosis into the dermis. In some instances superficial crusting composed of necrotic cellular debis and kerating was observed.

Chronic dermatitis did not show a definite dose-response among treatment groups. Chronic dermatitis was characterised by acanthosis, hyperkeratisis and dermal infiltrates of predominantly mono-nuclear cells. Infiltrates were varied (focal to diffuse) and extended from the epidermis to underlying musculature.

Clinical chemistry and haematology:
After the first dose of hydroxylammonium nitrate, blood samples taken 24 hours after application from animals receiving the highest dose contained Heinz bodies. One week after the initiation of dosing, blood samples from animals receiving the top three doses of the chemical were observed to contain Heinz bodies. Anemia was observed in all treatment groups except the lowest and control animals. RBC count, haemoglobin concentration, haemtocrit were lower in these animals and the MCV higher.

No changes in clinical chemistry parameters were detected.

Organ weights and gross pathology:
At necropsy, the relative spleen weight was higher in animals administered the three highest doses (2.9 - 11.7 mg/kg ) compared to controls, these animals also displayed splenic haematopoiesis. The colour of spleens ranged from dark red to black corresponging with increasing dose.
Extramedullary haematopoiesis was also observed in the liver of animals administered the two highest doses of the test chemical. Animals administered the highest dose also displayed higher relative heart weights.

Effect levels

open allclose all
Dose descriptor:
LOAEL
Effect level:
0.7 mg/kg bw/day (nominal)
Basis for effect level:
other: Local effects
Dose descriptor:
NOAEL
Effect level:
0.7 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: systemic effects

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Dermal aplication of hydroxylammonium nitrate to rabbits caused dose dependent dermatitis with increasing severity related to higher doses. At the three highest doses, animals displayed heamolytic anemia and the formation of Heinz bodies in red blood cells. A LOAEL of 0.7 mg/kg bw/day, based on dermatitis can be derived from this study.
Executive summary:

In an acute dermal toxicity study similar to OECD Guideline 410, New Zealand White rabbits, 0.7, 1.5, 2.9, 5.9 and 11.7 mg/hydroxylammonium nitrate/kg was applied dermally on the mid-lumbar region for 5 days/week for 3 weeks. Animals displayed dose dependent dermatitis with increasing severity related to higher doses. At the three highest doses, animals displayed haemolytic anemia and the formation of Heinz bodies in red blood cells. Animals from these dose groups also displayed extramedullary haematopoiesis. A LOAEL of 0.7 mg/kg based on dermatitis can be derived from this study for local effects and a NOAEL of 0.7 mg/kg bw/day for systemic effects. This study is considered to be reliable and therefore hydroxylammonium nitrate is considered to cause dermatitis, haemolytic anemia and extramedullary haematopoiesis after dermal application in rabbits.