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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From March 1989 to June 1989
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP toxicity study conducted under the US National Toxicology Program (NTP)
Cross-reference
Reason / purpose:
reference to same study

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
2000

Materials and methods

Objective of study:
other: lung and tissue burden
Test guideline
Guideline:
other: The 14-week study was conducted in compliance with FDA Good Laboratory Practice Regulations (21 CFR, Part 58). In addition, as records from the 14-week study were submitted to the NTP Archives, this study was auditied retrospectively.
Principles of method if other than guideline:
Lung and tissue burden study.The 14-week study was conducted in compliance with FDA Good Laboratory Practice Regulations (21 CFR, Part 58). In addition, as records from the 14-week study were submitted to the NTP Archives, this study was auditied retrospectively by an independent quality assurance contractor. Seperate audits covered completeness and accuracy of the pathology data, pathology speciems, final pathology tables, and a draft of this NTP Technical Report. Audit procedures and findings are presented in the reports and are on file at NIEHS. The audit findings were reviewed and assessed by NTP staff, and all comments were resolved or otherwise addressed during the preparation of this Technical Report.
GLP compliance:
yes

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, dark gray to black, fine powder
- Analytical purity: >98%, with total impurities <170ppm
- Lot/batch No.: M051988
- Stability under test conditions: gallium arsenide was found to be stable for 2 weeks at temperatures up to 60°C when stored protected from light. Stability was monitored by the study laboratory throughout the studies with chelometric titration. No degradation of the bulk chemical was detected.
- Storage condition of test material: The bulk chemical was stored in amber glass bottles with Teflon®-lined caps under a nitrogen headspace at room temperature.
- MMAD: 0.81 - 1.60 µm in the 14-week studies
- Origin: the analytical chemistry laboratory, Midwest Research Institute (Kansas City, MO) obtained gallium arsenide from Johnson Matthey, Inc. (Ward Hill, MA) and prepared the single lot.
No further details are given.
Radiolabelling:
no

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Simonsen Laboratories (Gilroy, CA)
- Age at study initiation: approx. 7 weeks old (4 weeks old on receipt)
- Weight at study initiation: range of means: 130-135 g (males); 105-111 g (females)
- Housing: individually; stainless steel wire bottom (Lab Products, Inc. Harford Systems Division, Aberdeen, MD), changed weekly
- Diet: ad libitum, except during exposure and urine collection periods; NIH-07 open formula pelleted diet (Zeigler Brothers, Inc., Gardners, PA), changed daily
- Water: ad libitum, softened tap water (Richland municipal supply) via automatic watering system (Edstrom Industries, Waterford, WI), changed weekly
- Acclimation period: 19 to 20 days quarantine

ENVIRONMENTAL CONDITIONS
- Temperature (°C): ~23
- Humidity (%): 55 +/- 15
- Air changes: 15/hour
- Photoperiod: 12 hours dark/light cycle
No further details are given.

IN-LIFE DATES: From: 6 (males) or 7 (females) March 1989 To: 6 (males) or 7 (females) June 1989

Administration / exposure

Route of administration:
inhalation: aerosol
Vehicle:
other: air
Details on exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: the study laboratory designed the stainless-steel inhalation exposure chambers so that uniform vapour concentrations could be maintained throughout the chambers when catch pans were in place. The total active mixing volume of each chamber was 1.7 m³.
- System of generating particulates/aerosols: the gallium arsenide aerosol generation and delivery system had five basic components: a flexible-brush dust feed mechanism developed at the study laboratory, a Trost Model GEM-T air-impact mill, a cyclone separator, an aerosol charge neutraliser, and an aerosol distribution system. The flexible-brush dust feed mechanism employed a hopper into which the dry powder was poured. The hopper was reloaded with additional gallium arsenide at regular intervals throughout each day's exposure period. Aerosol passed through the charge neutraliser into the distribution line. At each chamber location, a vacuum pump drew aerosol from the distribution line into the chamber inlet, where the aerosol was further diluted with HEPA-filtered air to the appropriate concentration.
- Temperature, humidity in air chamber: 23-25°C, 55% +/- 15%
- Air change rate: 15 air changes per hour
- Method of particle size determination: the particle size distribution in each chamber was determined during pre-study testing and monthly during the 14-week study using a Mercer-style seven-stage impactor. The stages (glass coverslips lightly sprayed with silicone) were analysed by ICP/MS. The relative mass collected on each stage was analysed by probit analysis. The mass median aerodynamic particle diameter and the geometric standard deviation of each set of samples were estimated.

- Chamber aerosol concentrations were monitored with real-time aerosol monitors (RAMs) that used a pulsed-light emitting diode in combination with a silicon detector to sense light scattered over a forward angular range of 45° to 95° by particles traversing the sensing volume. The instrument responds to particles 0.1 to 20 µm in diameter; the geometric diameter of gallium arsenide aerosol approached the minimum of this range. Each RAM was calibrated by correlating the measured voltage with gallium arsenide concentrations determined by analyzing exposure chamber samples collected on fiberglass filters. Filter samples were dissolved in nitric acid and analyzed for gallium arsenide using inductively coupled plasma/mass spectroscopy (ICP/MS). RAMs were calibrated one to two times weekly during the 14-week studies. Additional filter samples were collected on days not dedicated to RAM calibration during the 14-week studies for gravimetric analysis of chamber concentrations as an additional check of monitor operation.
- Uniformity of aerosol concentration in the 14-week studies was evaluated prior to the start of the studies without animals present and once during each of the studies with animals present in the exposure chambers. Chamber concentration uniformity was acceptable throughout the studies
Duration and frequency of treatment / exposure:
90 days, 6 hours/day, 5 days /week
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 0.1, 1, 10, 37, 75 mg GaAs/m³
No. of animals per sex per dose:
Lung from male rats were evaluated at three time points.
Day 23: 10 males (o mg/m³) or 6 males (0.1, 1, 10, 37, and 75 mg/m³)
Day 45: 2 males (o mg/m³) or 4 males (0.1, 1, 10, 37, and 75 mg/m³)
Day 93: 4 males (o mg/m³) or 3 males (0.1, 1, 10, 37, and 75 mg/m³)
Control animals:
yes
Positive control:
no
Details on study design:
- Dose selection rationale: in a preceding 16-day study (range-finding), the severity of alveolar proteinosis increased with increasing exposure concentration and was considered the primary reason for the concomitant increased lung weights. The proteinosis and lung weights were markedly increased in the 75 and 150 mg/m3 groups and represented the upper exposure limits for the 14-week study. Because effects were similar between the 75 and 150 mg/m3 groups, 75 mg/m3 was selected as the high exposure concentration for the 14-week study. Because a no-effect level was not achieved for the lung and the effects observed at 37 mg/m3 were similar to but less severe than those in the 75 mg/m3 group, the three lower concentrations for the 14-week study were spaced by a factor of ten.
- Rationale for animal assignment (if not random): randomly into groups of approximately equal initial mean body weights
Details on dosing and sampling:
Lung burden study:
The lungs from male rats were evaluated at three time points.
Day 23: 10 males (o mg/m³) or 6 males (0.1, 1, 10, 37, and 75 mg/m³)
Day 45: 2 males (o mg/m³) or 4 males (0.1, 1, 10, 37, and 75 mg/m³)
Day 93: 4 males (o mg/m³) or 3 males (0.1, 1, 10, 37, and 75 mg/m³)P
- Method type(s) for identification: atomic absorption spectrometry
- Limits of detection and quantification: no data
Statistics:
Survival analyses:
- The probability of survival was estimated by the product-limit procedure of Kaplan and Meier (1958).
- Statistical analyses for possible dose-related effects on survival used Cox.s (1972) method for testing two groups for equality and Tarone.s (1975) life table test to identify dose-related trends. All reported P values for the survival analyses are two sided.

Analysis of neoplasm and non-neoplastic lesion incidences:
- The Poly-k test (Bailer and Portier, 1988; Portier and Bailer, 1989; Piegorsch and Bailer, 1997) was used to assess neoplasm and nonneoplastic lesion prevalence.

Analysis of continuous variables:
- Organ and body weight data, which historically have approximately normal distributions, were analyzed with the parametric multiple comparison procedures of Dunnett (1955) and Williams (1971, 1972).
- Blood and bone marrow hematology, clinical chemistry, urinalysis, spermatid, and epididymal spermatozoal data, were analyzed using the nonparametric multiple comparison methods of Shirley (1977) and Dunn (1964). Jonckheere.s test (Jonckheere, 1954) was used to assess the significance of the dose-related trends and to determine whether a trend-sensitive test (Williams. or Shirley.s test) was more appropriate for pairwise comparisons than a test that does not assume a monotonic dose-related trend (Dunnett.s or Dunn.s test).
- Average severity values were analyzed for significance with the Mann-Whitney U test (Hollander and Wolfe, 1973). Treatment effects were investigated by applying a multivariate analysis of variance (Morrison, 1976) to the transformed data to test for simultaneous equality of measurements across exposure concentrations.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Lung weights increased with increasing exposure concentrations in males exposed to 1 mg/m³ and greater on days 23 and 45 and in all exposed groups at week 14.
In addition, lung weights in exposed rats continued to increase to a greater extent throughout the study than did chamber control lung weights. The percentages of gallium and arsenic in the lung relative to the total lung burden of gallium arsenide were similar at all exposure concentrations throughout the study because the deposition and clearance rates in the lung for gallium and arsenic were similar within the exposed groups.
Lung burden for gallium and arsenic increased with increasing exposure concentration, and each increased thoughout the study; therefore, steady state lung burdens were not achieved for any exposure concentration. When lung burdens were normalized to exposure concentration, they were inversely proportional to the exposure concentration.
Although lung deposition rates increased proportionally to exposure concentration, lung clearance half-times actually decreased as exposure concentration increased, indicating a possible increase in lung clearance mechanisms at the higher concentrations. Thus the more rapid elimination rate at higher exposure concentrations accounts for the subproportional retained lung burdens that were observed as exposure concentration increased.

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
no data

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): no bioaccumulation potential based on study results The percentages of gallium and arsenic in the lung were similar at all exposure concentrations throughout the study. Lung clearance half-times decreased as exposure concentration increased, indicating a possible increase in lung clearance mechanisms.
In a 90-day toxicity study with inhalative administration of GaAs to male rats, additional animals were treated for the characterisation of the lung burden.
Lung weights increased with increasing exposure concentrations in males exposed to 1 mg/m³ and greater on days 23 and 45 and in all exposed groups at week 14.
In addition, lung weights in exposed rats continued to increase to a greater extent throughout the study than did chamber control lung weights. The percentages of gallium and arsenic in the lung relative to the total lung burden of gallium arsenide were similar at all exposure concentrations throughout the study because the deposition and clearance rates in the lung for gallium and arsenic were similar within the exposed groups.
Lung burden for gallium and arsenic increased with increasing exposure concentration, and each increased thoughout the study; therefore, steady state lung burdens were not achieved for any exposure concentration. When lung burdens were normalized to exposure concentration, they were inversely proportional to the exposure concentration.
Although lung deposition rates increased proportionally to exposure concentration, lung clearance half-times actually decreased as exposure concentration increased, indicating a possible increase in lung clearance mechanisms at the higher concentrations. Thus the more rapid elimination rate at higher exposure concentrations accounts for the subproportional retained lung burdens that were observed as exposure concentration increased.
Executive summary:

In a 90-day toxicity study with inhalation exposure of male rats to concentrations of 0, 0.1, 1, 10, 37, 75 mg GaAs/m³, additional animals were treated for the characterisation of the lung burden.

Lung weights increased with increasing exposure concentrations in males exposed to 1 mg/m³ and above on days 23 and 45 and in all exposed groups at week 14 (day 90) including the lowest exposure concentration of 0.1 mg/m³.

In addition, lung weights in exposed rats continued to increase to a greater extent throughout the study than did chamber control lung weights.

The percentages of gallium and arsenic in the lung relative to the total lung burden of gallium arsenide were similar at all exposure concentrations throughout the study because the deposition and clearance rates in the lung for gallium and arsenic were similar within the exposed groups.

Lung burden for gallium and arsenic increased with increasing exposure concentration, and each increased thoughout the study; therefore, steady state lung burdens were not achieved for any exposure concentration.

When lung burdens were normalized to exposure concentration, they were inversely proportional to the exposure concentration. Although lung deposition rates increased proportionally to exposure concentration, lung clearance half-times actually decreased as exposure concentration increased, indicating a possible increase in lung clearance mechanisms at the higher concentrations.Thus, the more rapid elimination rate at higher exposure concentrations accounts for the subproportional retained lung burdens that were observed as exposure concentration increased.

Lung burden analysis indicated that the percentages of gallium and arsenic in the lung were similar at all exposure concentrations throughout the study. Deposition and clearance rates in the lung for both gallium and arsenic were similar.