tris[3-bromo-2,2-bis(bromomethyl)propyl] phosphate

Endpoint summary

Description of key information

Short description of key information on bioaccumulation potential result: 
Absorption: only about 1% of an oral dose of 14C FR 370 administered as a suspension in corn oil was absorbed by rats. Metabolism: Chromatographic analysis revealed that essentially all of the radioactivity excreted in faeces was unchanged FR 370, with one minor unidentified metabolite (RM7), representing ca 2% of the sample radioactivity detected. Excretion: The excretion results obtained in this study therefore suggest that less than 1% of an oral dose of 14C FR 370 was absorbed by rats, this being the proportion of the radioactive dose excreted in urine. Overall: no obvious side effects were observed in any of the rats dosed orally with 14C-FR-370 at target dose levels of either 50 mg/kg or 1000 mg/kg.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

The toxicokinetics of ¹⁴C‑FR‑370 was investigated in a study with Sparague- Dowley CD rats. The plasma and whole-blood levels of radioactivity, excretion of radioactivity and metabolite profiles were investigated following single oral applications of¹⁴C‑FR‑370 50mg/kg and 1000mg/kg to male and female rats.

Absorption: At 50mg/kg in male rats, the maximum mean concentrations of radioactivity in plasma occurred 12 hours after oral administration of¹⁴C‑FR‑370 (representing 1821 ng equivalents FR-370/ml). Concentrations declined thereafter to 215.2 ng equivalents/ml at 120hours and were not detectable at 168 hours post-dose. In female rats, the maximum mean concentrations of radioactivity in plasma occurred 6 hours after the oral dose of¹⁴C‑FR‑370 (745.2 ng equivalents FR-370/ml). Thereafter, mean concentrations declined to 251.4 ng equivalents FR-370/ml) at 72 hours post-dose and were not detectable after this time. Total radioactivity concentrations in plasma were greater than those in whole-blood at all times. This observation is supportive of lack of affinity of FR-370 with blood cells. No relationship with dose was found for absorption.

In the high dose group (1000mg/kg), concentrations of radioactivity in plasma and whole blood-cell, were generally bellow the limit of detection due to the much reduced specific activity of the test substance. The available data indicate that plasma concentrations were only 2-3 times higher than those obtained at the 50mg/kg dose level at 3 and 6 hours post administration, respectively. These limited data suggest that the absorption rate is significantly lower than that might have been expected based upon a 20-fold increase in dose level.

Excretion:Following 50 mg/kg oral administration of¹⁴C‑FR‑370, radioactivity was rapidly excreted by both male and female rats. 85% (male) and 81% (female) of the total faecal radioactivity was recovered by 24 hours post-dose, increasing to >99% (male and female) by 48 hours. For both males and females, excretion of radioactivity was essentially complete by 120 hours post- administration. The mean total radioactivity recovered in excreta and expired air at 120 hours was 99.4% (male) and 100.9% (female). Radioactivity in the animal carcass and gastrointestinal tract provided an additional 0.7% and 0.52% (male and female respectively). The faeces were the major excretory route in rats with mean totals of 89.33% and 99.74%of the dose in males and females respectively. The corresponding values in urine were 0.76% and 0.87%, in expired air 0.12% and 0.09% and that associate with cage washing being 0.19% and 0.2% for males and females respectively.

Following administration of high dose (1000mg/kg)¹⁴C‑FR‑370, the mean total radioactivity recovered was in excreta at 120 hours was 98.9% (male) and 97.49% (female). Radioactivity in the animal carcass and gastrointestinal tract provided an additional 0.05% dose (male), whereas in females both were below the limit of detection. 

The faeces was the major excretory route with mean total of 98.70% and 97.30% for males and females respectively. The corresponding values in urine were 0.14% and 0.11%, and associated with cage washing being 0.09% and 0.07%. Radioactivity levels in the expired air were below the limit of detection for males and 0.01% for females. For both males and females, excretion of radioactivity was essentially complete by 120 hours post- administration, less than 0.02% of the dose were present in the final daily samples taken.  

Distribution:After a single oral administration of¹⁴C‑FR‑370 at 50 mg/kg to male and female rats, radioactivity was widely distributed throughout the animal body. Greatest concentrations in most systemic tissues occurred at times consistent with the pharmacokinetic T_max,i. e.either 12 or 6 hours post-administration for male and female rats respectively. Highest concentrations of radioactivity at these times were present in the gastrointestinal tract and liver (the principle excretory organs for this compound), although high levels were also detected in fat at later sacrifice times, presumably reflecting the lipophilic nature of the parent compound and/or its metabolites. Lowest tissue radioactivity concentrations were associated with brain, indicating that test-compound related material did not readily penetrate the blood-brain barrier. In addition, whole-blood radioactivity concentrations were generally only about half of those in plasma, and only low levels of radioactivity were detected in blood cells, indicating that association of test-compound related material with the blood cells was not extensive.

 Metabolism: Chromatographic analysis revealed that essentially all of the radioactivity excreted in faeces was unchanged FR‑370, with one minor unidentified metabolite (RM7), representingca2% of the sample detected. Onlyca1% of the dose was recovered in urine following low dose (50 mg/kg) administration, although up to eight metabolites were detected, indicating that the small amount of¹⁴C‑FR‑370 that was absorbed had gone extensive metabolism, but no individual metabolite accounted for greater than 0.29% of the recovered dose. Following enzyme hydrolysis, FR-513 was tentatively identified.

In summary, approximately 98% of the test substance was excreted via faeces within 5 days. Maximum absorption was considered to be 2% at the dose level of 50mg/kg and 0.2% at the dose level of 1000mg/kg. Only 1% of the initial dose was recovered in urine.