Trimethylgallium

Acute Toxicity: inhalation

Administrative data

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

April 21, 2004 - March 4, 2005

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: 30 minute screening study, actual exposure is theoretical

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2005

Report date:

2005

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Version / remarks:

Adopted: May 12, 1981

Deviations:

yes

Remarks:

30 minutes exposure

GLP compliance:

yes (incl. QA statement)

Test type:

traditional method

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

Trimethylgallium

EC Number:

215-897-6

EC Name:

Trimethylgallium

Cas Number:

1445-79-0

Molecular formula:

C3H9Ga

IUPAC Name:

trimethylgallane

Test material form:

liquid

Details on test material:

TrimethylgalliumHigh Purity MetalorganicCylinder No. 150VW-0470"0"Lot No. 0404115217Analytical No. 85776[WIL Log No. 6147A]1 Cylinder Gross weight: 1391.1 gThe purity of the test article was 99.9999%.

Test animals

Species:

rat

Strain:

other: Crl:CD®(SD)IGS BR

Sex:

male/female

Details on test animals or test system and environmental conditions:

ANIMAL RECEIPT AND ACCLIMATION
The Crl:CD®(SD)IGS BR rats used for this study were received in good health from
Charles River Laboratories, Raleigh, North Carolina, on May 4, 2004. The rats were
uniquely identified by an eartag displaying the animal number and were acclimated to the laboratory for a minimum of 7 days. During the acclimation period, the rats were
observed twice daily for mortality and moribundity. The animals were acclimated to
restraint in the nose-only tubes twice prior to the initiation of exposure.

ANIMAL HOUSING
Upon arrival, all animals were housed in individual suspended wire-mesh cages. The
animals were maintained by the animal husbandry staff of WIL Research Laboratories,
LLC in accordance with standard operating procedures. On the day of exposure, the
animals were placed in nose-only restraint tubes in the animal room, transported to the
exposure room, exposed for the requisite duration then returned to their home cages.

DIET, DRINKING WATER AND MAINTENANCE
The basal diet used in this study, PMI Nutrition International, LLC, Certified Rodent
LabDiet® 5002, is a certified feed with appropriate analyses performed by the
manufacturer and provided to WIL Research Laboratories, LLC. Municipal water
supplying the facility is sampled for contaminants according to the standard operating
procedures. The results of the diet and water analyses are maintained at WIL Research
Laboratories, LLC. No contaminants were present in animal feed or water at
concentrations sufficient to interfere with the objectives of this study. The basal diet and
municipal water, delivered by an automatic watering system, were provided ad libitum,
except during the exposure period.

ENVIRONMENTAL CONDITIONS
The animal room was maintained with controlled temperature, humidity and light
(12 hours light/12 hours dark). The room temperature and humidity controls were set to
maintain daily averages of 71 ± 5°F (22 ± 3°C) and 50 ± 20% relative humidity. Actual
mean daily temperature ranged from 70.7°F to 70.9°F (21.5°C to 21.6°C) and mean daily
relative humidity ranged from 33.0% to 43.6% during the study.

ASSIGNMENT OF ANIMALS TO TREATMENT GROUPS
Animals used in the study were selected from available stock and assigned to groups
using a computerized randomization procedure. A printout containing the animal
numbers, corresponding body weights and individual group assignments was generated
based on body weight stratification in a block design. The animals then were arranged
into groups according to the printout. The selected animals were approximately 8 to
11 weeks old at initiation of exposure; body weight values ranged from 270 g to 283 g for
males and from 236 g to 252 g for females. Individual body weights at randomization
were within ± 20% of the mean for each sex.

Administration / exposure

Route of administration:

inhalation: vapour

Type of inhalation exposure:

nose only

Vehicle:

other: Based on the pyrophoric property of trimethylgallium, dry compressed nitrogen was used to generate the test article flow from the sponsor-provided source.

Remarks:

Dry compressed air was mixed with the test article stream to deliver the resulting atmosphere to the exposure chamber.

Details on inhalation exposure:

A vapor atmosphere of the test article was generated. According to the sponsor, TMG produces a flame or smoke when exposed to air, but can produce an invisible aerosol containing TMG degradation products at lower concentrations. Rats were exposed once for 30 minutes in a nose-only exposure system to the highest non-smoking concentration of TMG in air.The system was setup and operated according to instructions provided by the sponsor. The test article was generated at the maximum concentration which did not produce clouding or liquid droplets in the glass generator tube or visible atmosphere in the inhalation exposure chamber. All generation and exposure equipment were contained within a walk-in laminar flow hood. The system operated as follows. The liquid test article contained within a sponsor-provided bubbler was maintained in an oil bath at approximately 5°C. The test article was delivered by a direct flow of dry nitrogen at approximately 0.20 mL/min from the bubbler to a glass mixing chamber (provided by the sponsor) and diluted with approximately 10 LPM of dry compressed air. The resulting vapor was piped to the inlet of the nose-only exposure chamber. Exhaust vapor was drawn through a scrubber containing approximately 10% (w/w) oleic acid/Isopar-H solution prior to entering the in-house exhaust system.

Analytical verification of test atmosphere concentrations:

no

Duration of exposure:

ca. 30 min

Concentrations:

The degradation products of TMG in air have not been chemically characterized and degradant-specific collection methods and analytical methods were not available. Therefore, it was not possible to determine the actual exposure concentration of TMG in the inhalation chamber.

By utilizing the delivery conditions (5 oC, 0.2 sccm flow rate for the TMG nitrogen carrier stream, 760 torr system pressure) and the vapor pressure of TMG at the system temperature (88.59 torr), the theoretical TMG uptake rate can be calculated as follows (where MW is molecular weight, P is pressure and R is the Universal gas constant):
Uptake Rate = (MW TMG)*(PTMG)*(Flow Rate)*(60)/(Psystem-PTMG)/(R)/(273.15)
Therefore, under the conditions of this study, this gives a theoretical TMG uptake rate of 8.1 milligrams of TMG per hour (4.9 milligrams of gallium per hour). This corresponds to a stream containing 8.3 ppm gallium (= (8.3*69.72)/24.45 = 23.7 mg gallium /L.) Thus, over the course of the 30 minute study, the test subjects were exposed to 4.1 milligrams of TMG (2.5 milligrams of gallium).

No. of animals per sex per dose:

5

Control animals:

yes

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Each animal was observed for mortality at the approximate midpoint of exposure, immediately following exposure and 1 hour following exposure on day 0 and twice daily thereafter for 14 days. Each animal was observed immediately following exposure and 1 hour following exposure on day 0 and once daily thereafter for 14 days. Body weights were obtained immediately prior to exposure on study day 0 and on post-exposure days 7 and 14.
- Necropsy of survivors performed: yes
- Other examinations performed: Blood samples were collected from all animals at approximately 24 hours after exposure and just prior to the scheduled necropsy (day 14). Approximately 2 mL of blood was collected from each animal via a tail vein into tubes containing sodium heparin. Urine samples were collected for an approximate 24-hour period using metabolism cages on the day of exposure (day 0) and prior to the scheduled necropsy (day 13). The blood and urine samples were stored frozen at approximately -70°C and shipped on dry ice the Monday following collection to Baylor Toxicology Services, Baylor College of Medicine, Houston, Texas for gallium analysis. Gallium was analyzed using Inductive Coupled Plasma Mass Spectrometry.

Results and discussion

Mortality:

None of the animals died during exposure or the 14-day observation period.

Clinical signs:

other: Rapid respiration was noted for one female (no. 56284) in the TMG group 1 hour following exposure.

Body weight:

There were no remarkable changes in body weight in the trimethylgallium group.

Gross pathology:

There were no gross necropsy findings for any animal in the TMG group.

Other findings:

There were no other toxicologically relevant clinical observations during the study.

Applicant's summary and conclusion

Interpretation of results:

study cannot be used for classification

Conclusions:

The results of this screening study showed that acute inhalation exposure to trimethylgallium (TMG) for 30 minutes at the highest non-smoking concentration did not induce toxicity detectable by clinical observations, body weights or at gross necropsy. There were no significant clinical observations, body weight effects or gross necropsy findings in either the control or the exposed groups. Measurable amounts of gallium (Ga) in kidney indicated systemic uptake of Ga from the lung. Although total clearance of gallium did not occur within 14 days of the exposure, blood and urine levels of gallium decreased by approximately 80% after 14 days suggesting that the urine is an important excretion route for clearance of inhaled Ga from the body.
Since the test article was administered to a single group of five male and five female albino rats via nose-only exposure for only 30 minutes the study cannot be used for classification.

Executive summary:

Trimethylgallium (TMG) is a pyrophoric liquid used in the compound semiconductor industry. TMG produces a flame or smoke when exposed to air at high concentrations,

but can produce an invisible aerosol containing TMG degradation products at lower concentrations. There are no available inhalation data available on TMG and therefore a

screening inhalation study was performed using groups of 10 Crl:CD(SD)IGS BR rats (5/sex/group). Rats were exposed once for 30 minutes in a nose-only exposure system to either TMG (highest non-smoking concentration in air) or air only.

There were no significant clinical observations, body weight effects or gross necropsy findings in either the control or the exposed groups. Gallium (Ga) levels were measured

in blood and urine samples collected 1 and 15 days post-exposure and in lung and kidney specimens collected at necropsy. At 24 hours, exposed group blood and urine Ga levels were significantly higher than those of the control group. On study day 15, exposed group blood and urine Ga levels were still significantly higher than those of the control group; however, between study days 1 and 15, blood and urine Ga levels in the exposed group had decreased by approximately 80%. Exposed group lung and kidney samples contained measurable levels of Ga. Ga was not detected in control animal lung or kidney samples.

The results of this screening study showed that a 30-minute inhalation exposure to TMG did not induce toxicity based on clinical observations, body weights or gross necropsy

findings. Measurable amounts of Ga in kidney indicated systemic uptake of Ga from the lung; however, this study suggests that the urine may be an important excretion route for clearance of inhaled Ga from the body.