Benzene-1,2,4-tricarboxylic acid 1,2-anhydride, oligomeric reaction products with ethane- l,2-diol

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

migrated information: read-across based on grouping of substances (category approach)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Scientifically valid study but predates establishment of guideline methods; not performed under GLP.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1988

Report date:

1988

Materials and methods

Objective of study:

toxicokinetics

Test guideline

Qualifier:

no guideline available

Principles of method if other than guideline:

Inhalation exposure of radiolabelled test material to rats, with time course assessment of tissue accumulation and elimination in various organs. Additionally, TMA-specific serum antibodies were quantitated for the 32 days after exposure.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

trimellitic anhydride

IUPAC Name:

trimellitic anhydride

Constituent 2

Reference substance name:

Benzene-1,2,4-tricarboxylic acid 1,2-anhydride

EC Number:

209-008-0

EC Name:

Benzene-1,2,4-tricarboxylic acid 1,2-anhydride

Cas Number:

552-30-7

Molecular formula:

C9H4O5

IUPAC Name:

1,3-dioxo-1,3-dihydro-2-benzofuran-5-carboxylic acid

Test material form:

aerosol dispenser: not specified

Remarks:

migrated information: aerosol

Details on test material:

14C-trimellitic anhydride (TMA), lot No. 2031-236 was synthesized by NE England Nuclear, Boston, MA. The radiolabel was in the 2-carbonyl position. The specific activity was 13.5 mCi/mmole and the radiochemical purity wa 97% by TLC. The test article was stored in a tightly sealed opaque jars in a ventilated cabinet, at room temperature, 22 degrees C.

Radiolabelling:

yes

Remarks:

specific activity was 13.5 mCi 14C-TMA/mmole

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories, Portage, MI
- Age at study initiation:
- Weight at study initiation: 135 g
- Fasting period before study:
- Housing: singly housed in disposable plastic cages containing San-I-Cel corn cob bedding.
- Individual metabolism cages: yes/no
- Diet (e.g. ad libitum): ad libitum, Purina Rodent Chow 5001 (Ralston Purina Co., St. Louis, MO)
- Water (e.g. ad libitum): ad libitum, from a reverse-osmosis purifier by means of water bottles
- Acclimation period: 14 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22
- Humidity (%): 40
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: To: 9 June, 1986 to 11 July 1986

Administration / exposure

Route of administration:

inhalation

Details on exposure:

A static test atmosphere of the test article was generated by periodically feeding small amounts of the test article into the chamber via a partially encased recirculating blower. As the test article entered the blower encasement, it was blown into the chamber atmosphere and any test article that remained airborn was recirculated through the blower. The remainder of the test article settled on the chamber walls and floor.
The exposure chamber was a 370-liter glass aquarium fitted with a 1/8 inch plexiglass top. The entire chamber was housed in a PVC bag which served as secondary containment. The inhalation chamber, PVC bag, rats and associated materials were contained in a large PVC tent, approximately 8x8x8 ft.

Duration and frequency of treatment / exposure:

45 minutes

Doses / concentrations

Remarks:

Doses / Concentrations:
950 µg/m3

No. of animals per sex per dose / concentration:

2 per sex per time point

Details on study design:

There were seven time points for sacrifice after the 45 minute exposure. Two males and two females were assigned to each time point.
The times were 3 h, 1 day, 2, 4, 8, 16 and 32 days after dosing.

Details on dosing and sampling:

The dose was approximately 50 µCi of 14 C per rat. The actual concentration of the 14C-TMA in the atmosphere was determined by drawing a known volume of the test atmosphere across an open-face filter. The filter was placed in a vial containing 10% (v/v) acetonitrile in water and shaken for 10 min. A portion of the resultant mixture was injected into an HPLC and compared with known standards for quantitation.

Statistics:

The elimination rate constant (Ke) was determined by plotting the natural log (Ln) of the counts per min (cpm) per gram tissue versus the time past exposure and performing a linear fit (RS/1 Statistics, FFN Software Products Corp., Cambridge, MA, USA). Linear regression of the curve yielded a straight line, the negative slope of which equaled the Ke. The half-life (t-1/2) Of the 14C was calculated for each tissue using the following equation: t-1/2 = 0.693/Ke.

Results and discussion

Preliminary studies:

The actual concentation of 14C-TMA in the exposure chamber was 950 µg/m3. The fraction of respirable particles was not determined. Preliminary estimates using assumed respiratory rates, tidal volumes and particle retention suggested that the test conditions allowed sufficiently high 14C doses for adequate in vivo detection of radiolabel.

Main ADME results

Type:

absorption

Results:

Peak absorption was evident at 3 h after dosing. Half-lives ranged from 3 to 46 days for various organs.

Toxicokinetic / pharmacokinetic studies

Details on absorption:

The peak concentrations of 14C in the tissues were found at the first time point (3 h after exposure). The concentration rapidly decreased in all tissues in an approximately exponential fashion. Linear regression of the natural log of the concentration vs. time yielded straight lines, indicating exponential decline. The concentration of 14C (cpm/g tissue) generally throughout the time course was found in feces and urine, and the following tissues: popliteal lymph nodes, esophagus, kidneys, intestines, urinary bladder and abdominal skin. Abdominal skin showed the highest consistent radiolabel content of all tissues. Lung tissue did not show a high concentration of radiolabel at 3 h after dosing (comparable to testes, spinal cord and bone marrow).

The half-life values ranged from 4-23 days in males and from 3-46 days in females. Half-lives were lowest for feces and intestines, stomachs and esophagi, and highest for popliteal and lung-associated lymph nodes, spleen, heart, adrenals, brais and bone marrow. The exponential decline was apparent in all tissues except the lung-associated lymph nodes (LALN), where, after an initial decline, there was a second influx of 14C peaking at day 8 and then declining again. This second peak was particularly apparent in male rats.

Details on distribution in tissues:

Distribution occurred to all organs examined. Radiolabel showed particular accumulation occurring in the kidneys, urine, bladder, feces and esophagus. Half-lives were lowest for feces, intestines, stomachs and esophagi, and highest for popliteal and lung-associated lymph nodes, spleens, hearts, adrenals, brains and bone marrow.

Details on excretion:

Almost all tissues exhibited an exponential elimination of 14C. The elimination rate constant (Ke) ranged from 0.015 to 0.214 in female rats. Total urinary and fecal elimination was not reported.

Metabolite characterisation studies

Metabolites identified:

no

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): low bioaccumulation potential based on study results
Groups of rats exposed to inhaled 14C-TMA exhibited typical first order exponential decays of 14C with half-lives ranging from 3 to 46 days. C14 was distributed to all tissues examined with particular accumulation occurring in the kidneys, urine, bladder, feces and esophagus.

Executive summary:

Groups of two male and two female Sprague Dawley rats were exposed for 45 minutes to an atmospher of 14C-trimellitic anhydride aerosol (950 µg/m³) with a specific activity of 13.5 mCi/mmole. Exposure was in a sealed 370 -liter chamber wrapped ina PVC bag, and animals and excretia were appropriately handled as radioactive material. Animals were weighed prior to exposure and weekly thereafter, and prior to sacrifice. Daily observations were made for clinical effects. Animals were euthanized at 3 hours, 1 day and 2,4,8,16 and 32 days after exposure and subjected to an extensive necropsy. Organs were removed, weighed, homogenized and aliquots were prepared and counted for radioactivity. Tissues/fluids/excretia were collected and include popliteal lymph nodes, lung-associated lymph nodes (LALN), lungs, trachea, thymus, whole blood, serum, brain, heart, spleen, liver, kidneys, intestines, stomach, urinary bladder, gonads, urine, feces, skin, abdominal skin and fat, bone marrow, pancreas, esophagus, adrenals, spinal cord, bone marrow and leg muscle. The findings were that 14C was distributed to all tissues examined with particularly high counts in the kidneys, urine, bladder, feces and esophagus. The highest radioactivity level was at 3 hours in all tissues and exretia examined. Half-lives ranged from 3 to 46 days and showed exponential decay in most tissues.

In males, the lung-associated lymph nodes showed a different clearance pattern of radiolabel compared to other tissues: two peaks of radioactivity, one at 3 h and one at 8 days. Hence, males showed no exponential decay of radiolabel. This was not evident in females, and is consistent with results in other studies showing higher and more severe lung lesions after TMA exposure as compared with females. Serum antibody analysis, specific against TMA but not isotype specific, showed there was no significant antibody present until 4 -8 days after exposure. Between 8 and 32 days after exposure, 2 of 12 rats developed antibody and were presumably sensitized to TMA. Therefore, the sensitization incidence was 17%. The conclusion from this study is that TMA does not show signs of bioaccumulation or bioconcentration. Most tissue elimination is exponential. There is toxicokinetic evidence of immunological activity against TMA>