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Repeated dose toxicity: other routes

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Administrative data

Endpoint:
repeated dose toxicity: other route
Remarks:
other: non-standard test
Type of information:
experimental study
Adequacy of study:
disregarded due to major methodological deficiencies
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
No standard study design. Incomplete report of results, small animal number, no single values reported. Omura 1996b, Hamster (section 7.8.1) Omura et al. Testicular toxicity evaluation of arsenic-containing binary compound semiconductors, gallium arsenide and indium arsenide, in hamsters. Toxicol Lett 16, 1996b, 123-129. Hirata 1997, Hamster (section 7.1.1) Biomedical research on trace elements1997;8 191-192 In a first series of publications only data on reproduction toxicity of the male animals were published (Omura 1996, Hirata 1997). Tanaka et al. (2000): The missing data on systemic toxicity were published, showing slight to severe inflamatory responses in the lung and slight to mild lesions in the convoluted tubules of the kidney. These data on the lung weights indicate that the testicular changes are a consequence of a systemic impairment of the animals by the inflamatory reactions to GaAs in the lung.
Cross-reference
Reason / purpose:
reference to same study

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
2000
Report Date:
1999

Materials and methods

Principles of method if other than guideline:
The systemic and testicular toxicity of gallium arsenide (GaAs) was examined in Syrian golden hamsters rats by repetitive intratracheal instillation of this substance in suspension, twice a week for a total of 8 weeks (16 times).
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): gallium arsenide
- Physical state: solid, GaAs was pulverized finely and passed through a 400-mesh microsieve.
- Analytical purity: 99.9999%
- Impurities (identity and concentrations): GaAs powder contained 0.02% (wt%) of zirconium and a trace amount of yttrium. (contradictory data to the analytical purity)
- mean diameter: 1.32 µm
No further details are given.

Test animals

Species:
hamster, Syrian
Strain:
not specified
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Japan SLC Inc., Hamamatsu, Japan
- Age at study initiation: approx. 12 weeks
- Weight at study initiation: mean +- SE: 124.9 +- 10.36 g (range 104.2-148.5) (Comment: this is the average weight of 30 hamsters of which 8 were used for GaAs instillation, the others were controls, instilled with InAs or As2O3)
- Diet. ad libitum, CE-2, Clea Japan Inc., Tokyo, Japan
- Water: ad libitum
- Fasting period before study: no
- Housing: 4 in a stainless steel cage
- Acclimation period: 6 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23 - 25 °C
- Humidity (%): 50 - 60 %
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
other: intratracheal
Vehicle:
other: 1 ml/kg bw. phosphate buffer solution (0.025 M, pH 6.9)
Details on exposure:
After pretreatment with subcutaneous injection of 0.1 ml atropine sulfate /animal the powder of the test material was suspended in a phosphate buffer solution (PBS) and instilled into the trachea of rats anesthetised using ether.
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
8 weeks
Frequency of treatment:
2 times a week, exact days not given, 16 instillations
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 7.7 mg gallium arsenide/ kg bw.,
- Dose selection rationale:
- The total instillation dose of GaAs was 123.2 mg GaAs/ kg bw. and approximately the single dose used by Webb et al. (1986).
No. of animals per sex per dose:
8 males only
Control animals:
yes, concurrent vehicle
Details on study design:
no data

Examinations

Observations and examinations performed and frequency:
body weights on the days of treatment
Sacrifice and pathology:
SACRIFICE
- The rats were sacrificed using an overdose of ether within 24 hours after the final instillation.
ORGAN WEIGHTS: Lung, spleen, kidney, liver

GROSS NECROPSY: no data
HISTOPATHOLOGY:
lung, spleen, liver, kidney,
The visceral organs were fixed in 10% neutral buffered formalin solution.
Fixed tissures were embedded in paraffin, cut into 6 µm sections, and stained with hematoxylin and eosin. Selected sections were stained with periodic acid Schiff (PAS), Elastica-van Gieson and Masson's trichrome.
- The right testis was fixed in Bouin's solution, embedded in paraffin, thinly sectioned, and stained with periodic acid Schiff reagent (PAS) and Mayer's hematoxylin.
- Degenerating germ cells at each stage of the cycle of the seminiferous epithelium were examined with the light microscope. Degenerating late elongated spermatids at stages IX, X, and XI were counted in all round or ovoid cross-sections of seminiferous tubules in one transverse section of the testis (18-50 cross-sections of the tubule).
- Nuclei of Sertoli cells were also counted.
- The count of degenerating elongated spermatids was expressed per tubule and per 100 Sertoli nuclei. In the statistical analysis of the count of degenerating spermatids, a mean value in one transverse section of the testis of the rat was treated as the representative value of that animal.
Statistics:
- For body weight, testis weight, epididymal weight and sperm count, results were analyzed for mean and standard deviation and F-test was performed for evaluation equality of variance. If a significant difference was found in variance, t test with Welch's correction was used for statistical analysis, and t test without correction was used in other cases. In the case of the rate of abnormal sperm, Mann-Whitney test was used for statistical analysis. The results were interpreted as significant below a level of 0.05.
Fisher's least siginificant difference procedure was used in the case of body weight gain and organ weight after a one-way analysis of variance. In all statistical comparisons, a p value of less than 0.05 was used to indicate significant differences.

Results and discussion

Results of examinations

Clinical signs:
not specified
Mortality:
not specified
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:
not examined
Clinical biochemistry findings:
not examined
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):
increased lung weights, decreased kidney weights, reduction in epididymal sperm count, marked increase in abnormal sperm
Gross pathological findings:
not specified
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
severe inflammatory changes in the lung, slight to mild progressive lesions in the convoluted tubules of the kidney

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Omura 1996b, Hamster (section 7.8.1) Omura et al. Testicular toxicity evaluation of arsenic-containing binary compound semiconductors, gallium arsenide and indium arsenide, in hamsters. Toxicol Lett 16, 1996b, 123-129.
Hirata 1997, Hamster (section 7.1.1) Biomedical research on trace elements1997;8, 191-192
In a first series of publications only data on reproduction toxicity of the male animals were published (Omura 1996, Hirata 1997). Tanaka et al. (2000): The missing data on systemic toxicity were published, showing slight to severe inflamatory responses in the lung and slight to mild lesions in the convoluted tubules of the kidney. These results might indicate that the testicular changes are a consequence of a systemic impairment of the animals by the inflammatory reactions to GaAs in the lung.
Nowadays the incomplete report of study results would be a severe deviation from GLP-regulations
Executive summary:

Groups of 8 male Syrian golden hamsters were treated 2 times a week for 16 weeks with intratracheal instillations of 0 or 7.7 mg gallium arsenide/kg bw.. After pretreatment with a subcutanous injection of 0.1 ml atropine sulfate and anethesia with ether the intratracheal administration of 1 ml / kg bw. phosphate buffer solution containing suspended GaAs was done.

One day after the last instillation the animals were killed and autopsied.

Body weight: no differences to the control group,

Organ weights: significant increase in lung weight, significant decrease in the liver weight.

Histopathology: severe inflammatory changes in the lung, slight to mild progressive lesions in the convoluted tubules of the kidney.

These results might indicate that the testicular changes are a consequence of a systemic impairment of the animals by the inflamatory reactions to GaAs in the lung.