Registration Dossier

Administrative data

Endpoint:
sub-chronic toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Study conducted before internationally agreed test guidelines were applicable. Methods, experimental details and results are reported in detail, and the study design is comparable to modern guidelines. Thus, the study is considered as relible with (minor) restrictions and suitable to derive conclusions for the hazard assessment.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1977
Report Date:
1977

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
A 91-day percutaneous toxicity study in rabbits was performed to evaluate the dermal and systemic toxicity of the test material. The test material was applied undiluted, to the shaven backs of 3 male and 3 female New Zealand White rabbits. Daily applications of 2 mL/kg bw/day of the test material (ca. 950 mg /kg/day based on the active ingredient "ZAG") were made 5 days per week for 13 weeks. A control group had an equivalent volume (2 mL/kg) of distilled water applied under the ssame regimen as the test group. Pharmacotoxic signs, mortality, skin reactions, body weight haematological values, organ weights, gross pathology and histopathology were examined.
GLP compliance:
no
Remarks:
at the time of conduct, GLP was not compulsory.
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
other: liquid
Details on test material:
- Name of test material (as cited in study report): UDL-1641 (Zirconium aluiminium chlorhydrate/glycine complex Active Premix)
- Physical state: clear liquid
- Analytical purity: 100% ZAG Active Premix
- Composition of test material, percentage of components: 47.48% ZAG and 52.52% distilled water.

Test animals

Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 2265 - 2697 grams
- Housing: the rabbits were individually housed in wire metabolism cages in an environmentally controlled room.
- Acclimation period: two weeks prior to initiation

ENVIRONMENTAL CONDITIONS
- Temperature: ca. 24°C
- Humidity: 50%
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Type of coverage:
open
Vehicle:
unchanged (no vehicle)
Details on exposure:
TEST SITE
- Area of exposure: the backs of the rabbits were carefully shaved (as needed) prior to applying the test material and distilled water. Approximately 30% of the back was shaven. The skin was abraded twice weekly for two weeks, but abrading was then discontinued for the duration. Abrading of the skin was accomplished using the head of an electric hair-clipper.
The test material was applied with a syringe to the back and spread over the shaved area with a glass rod.

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2.0 mL/kg bw/ day
- Constant volume or concentration used: yes, constant volume

Analytical verification of doses or concentrations:
no
Details on analytical verification of doses or concentrations:
none
Duration of treatment / exposure:
91 days
Frequency of treatment:
daily for five days per week
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
2 mL/kg bw/day
Basis:
nominal per unit body weight
Remarks:
Doses / Concentrations:
ca. 170 mg Al/kg bw/day
Basis:
other: based on element Al
Remarks:
Doses / Concentrations:
ca. 100 mg Zr/kg bw/day
Basis:
other: based on element Zr
No. of animals per sex per dose:
3 males / 3 females
Control animals:
yes
Details on study design:
not applicable
Positive control:
none

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
- Cage side observations checked: animals were observed for mortality, pharmacotoxic signs, and skin reactions.

DETAILED CLINICAL OBSERVATIONS: No

DERMAL IRRITATION: Yes (scored according to the scale given in the field "Any other information on materials and methods incl. tables" below)
- Time schedule for examinations: daily

BODY WEIGHT: Yes
- Time schedule for examinations: once weekly

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No

WATER CONSUMPTION: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: prior to initiation and again at termination, blood was taken from ear vein and subjected to haematological determination
- How many animals: all
- Parameters examined: haemoglobin, haematocrit, erythrocyte count, total leucocyte count, differential leucocyte count, mean corpuscular volume, mean corpuscular haemoglobin, and mean corpuscular haemoglobin concentration.

CLINICAL CHEMISTRY: No

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
At the completion of the compound application period, all rabbits were sacrificed with an overdose of sodium pentobarbital administered intravenously in a marginal ear vein. All rabbits were necropsied. At necropsy, contents of the thorax and abdomen were examined in situ and specimens of the following tissues and organs were removed and fixed in buffered neutral 10% formalin: Skin (treated and untreated), brain, pituitary, salivary gland, tongue, trachea, oesophagus, thyroid, parathyroid aorta, bronchial nodes, thymus, heart, lungs, sciatic nerve, spinal cord, ureters, urethra near bladder, bone marrow, liver, spleen, pancreas, stomach, duodenum, jejunum, colon, adrenals, kidney, mesenteric lymph nodes, bladder, prostate, uterus, vaginal wall, ovary/testis, psoas muscle, seminal vesicles, and other tissues with gross lesions.
Hematoxylin and eosin stained paraffin sections of the above tissues from each rabbit were prepared and examined microscopically.
Other examinations:
Organ weights:
The following organs were weighed: brain, liver, spleen, adrenals, kidney, and ovary/testis.
At necropsy, weigh the liver and kidneys from all animals for determination of organ/body weight ratios.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Dermal irritation:
effects observed, treatment-related
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITY
No changes in appearance or behaviour were observed nor were there other signs of pharmatoxic effect. Only occasional indications of nasal discharge and/or lacrimation were observed in all groups.

BODY WEIGHT AND WEIGHT GAIN
No adverse effect on body weight gain attribute to compound administration was noted.

DERMAL IRRITATION
The results obtained in evaluating the skin reactions indicated average scores of 0.5 or less for rabbits for erythema only.

HAEMATOLOGY
While minor variations occurred, there were no consistent differences between the control group and the test group.

ORGAN WEIGHTS
No compound related variations in organ weights were observed in any of the rabbits in the treated group.

GROSS PATHOLOGY
Other than the skin changes, no compound related gross lesions were observed in any of the rabbits in the treated group. Gross lesions observed were those which commonly occur spontaneously in untreated rabbits in this laboratory.

HISTOPATHOLOGY: NON-NEOPLASTIC
Compound related microscopic lesions were seen in the skin at the application site in all rabbits in the treated group. In the test group, very slight to slight inflammatory cell infiltrate in dermis was common in all rabbits and very slight hyperkeratosis and acanthosis occurred in 2 rabbits. Microscopic lesions in treated rabbits other than those described above were generally those which commonly occur in untreated rabbits in the laboratory that carrying out the study and were not considered significant.

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
2 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: The test material is called "ZAG Premix", which is a 47.5% solution of aluminium zirconium chloride hydroxide glycine in water. The dose was 2 mL of the undiluted test item per kg bodyweight per day.
Dose descriptor:
NOAEL
Effect level:
170 mg/kg bw/day
Based on:
element
Remarks:
Al
Sex:
male/female
Basis for effect level:
other: see 'Remark'
Dose descriptor:
NOAEL
Effect level:
100 mg/kg bw/day
Based on:
element
Remarks:
Zr
Sex:
male/female
Basis for effect level:
other: see 'Remark'

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Very slight to slight erythema was observed in rabbits treated with the test material. The distilled water control gave no evidence of skin irritation. No body weight changes, nor gross pharmacotoxic signs, attributable to application of the test material, were observed.
Except for the skin changes noted above, no gross lesions or variations in organ weights were observed in any of the rabbits in the treated group. Compound related microscopic lesions in the skin at the application site, consisting of dermal inflammatory cell infiltrate and hyperkeratosis and acanthosis, were observed in rabbits in the treated group.
For systemic effects following dermal application, no adverse effects were observed at the only tested dose (limit test), thus: NOAEL of 2000 mg/kg bw/day, based on test item (47.5% solution of "impalpable ZAG". This corresponds to NOAEL of ca. 170 and ca. 100 mg/kg/day based on Al and Zr respectively.