Aluminum zirconium chloride hydroxide

Repeated dose toxicity: dermal

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

Test material information

Constituent 1

Reference substance name:

Zirconium aluminum chlorhydrate/glycine complex Active Premix.

IUPAC Name:

Zirconium aluminum chlorhydrate/glycine complex Active Premix.

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 or test system 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 / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
2 mL/kg bw/day
Basis:
nominal per unit body weight

Doses / concentrations 2

Remarks:

Doses / Concentrations:
ca. 170 mg Al/kg bw/day
Basis:
other: based on element Al

Doses / concentrations 3

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

1

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.

2

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'

3

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.