Benzophenone-3,3':4,4'-tetracarboxylic dianhydride

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

other: review article

Adequacy of study:

key study

Study period:

2012-2013

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Thorough review of existing literature and data according to ECHA technical guidance

Data source

Reference

Reference Type:

review article or handbook

Title:

Unnamed

Year:

2013

Report date:

2013

Materials and methods

Objective of study:

toxicokinetics

Test guideline

Qualifier:

no guideline available

Principles of method if other than guideline:

The assessment of toxicokinetic behavior was based on available data and information provided by the client and found in a search of the published literature.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Benzophenone-3,3':4,4'-tetracarboxylic dianhydride

EC Number:

219-348-1

EC Name:

Benzophenone-3,3':4,4'-tetracarboxylic dianhydride

Cas Number:

2421-28-5

Molecular formula:

C17H6O7

IUPAC Name:

5-(1,3-dioxo-1,3-dihydro-2-benzofuran-5-carbonyl)-1,3-dihydro-2-benzofuran-1,3-dione

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

The acute oral LD50 value, with material administered in methylcellulose in the rat model is > 12.8 g/kg indicating a very low order of acute toxicity. The effects seen at high dose levels included direct gastrointestinal irritation and hemorrhage with no reported systemic toxicity. The low water solubility, low order of acute oral toxicity and lack of systemic effects following high acute doses of BTDA suggest very low potential for absorption across the gastrointestinal tract. The LC50 in rainbow trout following a 96 hour exposure was 5592 mg/L further indicating low systemic absorption resulting in a low order of acute toxicity.

In an acute dermal toxicity and primary skin irritation study in the rabbit model the dermal LD50 was estimated to be > 3160 mg/kg and BTDA did not produce any signs of irritation or systemic toxicity when applied to intact or abraded skin. BTDA is not significantly absorbed dermally. Similarly in the rabbit model 3 mg of BTDA instilled into one eye produced slight irritation in one of six animals and no signs of systemic toxicity were reported indicating no significant ocular absorption. When BTDA was administered intradermally to guinea pigs at a dose level of 0.05 ml of a 0.1% BTDA solution on day 1 and 0.1 ml of a 0.1% BTDA solution every other day for 10 days, 6 of 7 animals were shown to be sensitized to BTDA when subsequently challenged with an intradermal injection of 0.05 ml. There have been no reports of dermatoses associated with contact exposure to BTDA in the workplace, indicating that intradermal penetration is necessary in order to achieve sensitization.

Aerosolized dust of BTDA was administered (whole body) to mice, rats and guinea pigs at a concentration of 4.44 mg/L (1400 ppm, no particle/droplet size given) for six hours followed by a 14-day observation period. No mortality and no signs of systemic toxicity were seen during the exposure or subsequent follow-up period in any of the three species. Necropsy findings in all three species including hemorrhage, congestion and foci of consolidation indicate BDTA dust caused slight pulmonary irritation and toxicity. Older studies of BTDA fume (generated at 227-289oC and assumed to be smaller particles) and dust (larger particles) provide estimates of inhalation toxicity behavior. A 6 hour exposure to dust in guinea pigs resulted in an LC50 of 135mg/m3 indicating that this form of BTDA is highly toxic upon inhalation. In a respiratory sensitization screening study rats were given whole-body exposures to BTDA as a particulate aerosol at a concentration of 50 µg/m3, 6 hours/day for 5 days. Following a 3 week rest period the rats were challenged with the same concentration of BTDA for 6 hours. None of the rats died and no significant clinical signs of toxicity were seen in any rat during the study. Serum IgG antibody levels were significantly elevated in the BTDA-exposed male rats but not female rats. No other associated changes indicative of an immunologic response due to respiratory sensitization were detected. BTDA as fume was also shown to cause chronic pneumonitis in guinea pigs exposed at 3.5 to 7.0 mg/m3 hours/day, 5 days/week for 2 weeks. BTDA has been suggested to cause lung sensitization in susceptible people following brief exposures to low, non-irritating levels of BTDA. The weight of evidence indicates that BTDA may be absorbed in the respiratory tract at low levels. Location of the absorption may vary according to particle size with fine BTDA particles absorbed to a greater extent in the upper airways and microfine particles absorbed in the lower airways.

Details on distribution in tissues:

Based on the lack of systemic toxicity and the presence of slight irritation in the GI and respiratory tract, distribution following oral or inhalation exposure is limited to the primary organ of contact. A negative in vivo cytogenetics assay in rats indicates no distribution to bone marrow cells. Given the lack of systemic toxicity it is unlikely that significant quantities of BTDA are distributed to or expressed in breast milk. Increased serum IgG levels follow inhalation exposure to BTDA, while an indication of an immunologic response, does not support a conclusion of the presence of BTDA in serum.

Details on excretion:

Fecal excretion is likely the major route of elimination of unabsorbed and unchanged BTDA.

Metabolite characterisation studies

Details on metabolites:

BTDA administered to rats via inhalation at 1, 55 and 3000 mg/m3 for 5 consecutive days did not cause a significant increase in the frequency of cytogenetic abnormalities in bone marrow cells indicating that no metabolism to potentially clastogenic species occurred in this animal model. BTDA is negative in the Ames Salmonella/mammalian microsome assay for mutagenicity when tested both with and without S9 metabolic activation, indicating that BTDA is not metabolized to form mutagenic species. BTDA did not produce DNA damage in the unscheduled DNA synthesis assay in primary rat hepatocytes. The S9 metabolic activation system consisted of a microsomal preparation derived from Aroclor-1254-induced rat liver.

BTDA hydrolysis to acid may be the cause of the slight level of irritation seen following direct contact with the moist environment of GI tract, eyes and respiratory tract.

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): low bioaccumulation potential based on study results
1,3-Isobenzofurandione, 5,5'-carbonylbis- (BTDA) is a solid low molecular weight anhydride, susceptible to hydrolysis in water. BTDA is not toxic by the oral, dermal or inhalation routes in animal studies. Low water solubility and lack of systemic toxicity would suggest relatively low potential for absorption across the skin, gastrointestinal tract and respiratory tract. Particulates may be absorbed in the lung and have increased potential to cause local toxicity. Distribution to organs is not significant and there is no evidence that BTDA is metabolized. Excretion of unchanged BTDA is likely via fecal elimination however the database is limited. Future opportunities to undertake selected in vivo studies on BTDA will provide additional knowledge, useful for risk assessment, on the toxicokinetic behavior.