Tris(2-butoxyethyl) phosphate

Endpoint summary

Additional information

Assessment of the Toxicokinetic/Toxicodynamic Profile of TBEP

No specific toxicokinetic studies are available on TBEP. Its toxicokinetic profile has been assessed from general toxicity studies in animals and from exposure data in humans.

Animal Studies

Three subchronic oral toxicity studies have been chosen as key studies. Two of these studies reported effects of administration of up to 10,000 ppm TBEP to rats in the diet. Reyna (1987) administered TBEP for 18 weeks, while Saito (1994) studied effects from 5 or 14 week administration. The only significant adverse effects reported in these studies were mild effects on the liver consisting of increased serum gamma glutamyl transpeptidase, depressed plasma cholinesterase, increased liver weight, mild periportal hepatocellular hypertrophy and periportal vacuolization from dietary concentrations equivalent to a dose of 3000 ppm (approximately 200 mg/kg bw/day).

A third study (Laham, 1985) administered TBEP by gavage at 0.25 and 0.5 mL/kg/day (255 & 509 mg/kg bw/day) for 18 weeks. Effects on the liver similar to those in the dietary studies were reported from an equivalent dose (255 mg/kg/day). In addition, effects were reported on the nervous system. During the first half of the study a minority of high dose females showed temporary muscular weakness & ataxia. During the second half of the exposure period, some animals showed cholinergic effects such as breathing difficulties, ataxia, piloerection, lacrimation, increased urination. Significant dose-related reduction in caudal nerve conduction velocity and increases of refractory periods were observed in all animals. Sciatic nerve sections showed dose-related morphological changes including degeneration of myelin sheaths, swelling of axons and clumping of electrofilaments.

From these three studies it is apparent that TBEP is absorbed from the gastrointestinal tract following oral administration either in the diet or as a bolus gavage dose. The majority of the dietary dose appeared to be metabolized during the first pass through the liver, since no effects were reported in other organs by this route. The cholinergic effects reported at high dose following gavage but not dietary administration indicates that a high peak dose can be distributed throughout the body.

No studies on dermal absorption are available. In a dermal subacute study in rabbits (Daly, 185), there were no clinical signs or evidence of systemic toxicity up to a dose of 1000 mg/kg bw/day. Dermal absorption can be considered likely to be lower than that via the oral route, however no quantitative estimate can be made and the possibility of metabolism in the skin cannot be excluded.

The IPCS expert panel (EHC 218, 2000) considered that 2-butoxyethanol is a metabolite of TBEP, however no source for this information was given.

Human Information

Low concentrations of TBEP have been detected in human serum and adipose tissue. Lebel and co-workers in Canada undertook a series of investigations of levels of TBEP in human adipose tissue samples obtained from cadavers at autopsy. The results of these studies have been reported in three publications assessed as Reliability 2 and described in section 7.10.5 (exposure related observations in humans). 

From Lebel & Williams (1983) 4 of 16 human adipose tissue samples were found to contain TBEP at levels of between 4.0 - 26.8 ng/g. From Lebel & Williams (1986), out of 115 adipose tissue samples obtained at autopsy from two Canadian cities, Kingston (58)and Ottawa (57), TBEP was found in 21/68 male samples and 20/47 female samples. From Lebel et al (1989), the mean concentrations of TBEP in adipose tissue samples from Ottawa (males+females 15.8 ng/g) were 2.5-times those found in the Kingston samples (males+females 6.6 ng/g). In both cities, the TBEP level in females (28.6 ng/g forOttawaversus 8.7 ng/g forKingston) was 2-3-times that of the male samples (7.9 ng/g forOttawaversus 3.6 ng/g forKingston). The overall mean TBEP concentration in the 41 samples was 11.3 ng/g (male=6.3; female=16.6 ng/g).

Anderson et al (1984) measured peaks of TBEP determined by HPLC in spiked samples of serum during the development of an analytical refinement. There was marked inter-individual variation in peak height which correlated with serum lipoprotein concentration. This study is described in section 8 (analytical methods).

Two studies reported that TBEP interacts with beta-adrenergic transport proteins, non specific tissue binding sites and beta-adrenergic receptors coupled to the catecholamine-sensitive adenylate cyclase. These studies are described in section 7.9.3 (Specific investigations, other). TBEP displaces basic drugs from their binding sites on alpha-1-acid glycoprotein (AAG). AAG is the main binding protein for basic drugs in plasma. TBEP was considered to have a high but variable affinity for plasma proteins (Sager & Little, 1989). Devine (1984) also reported that TBEP disrupts the binding of basic drugs to AAG. When blood drawn for therapeutic monitoring is exposed to TBEP, drug-protein binding is disrupted leading to increased free drug which is taken into red blood cells, resulting in decreased serum drug levels. Units of donor blood were spiked with quinidine or lidocaine and then exposed under various conditions to stoppers with and without TBEP. Total drug levels were determined by enzyme immunoassay as were free drug levels after equilibrium dialysis. AAG levels were determined by rate nephelometry. TBEP lowered quinidine levels by 11% at 8.20 micromol/L and by 32% at 4.38 micromol/L; lidocaine levels were reduced by 10% at 32.39 micromol/L and by 18% at 12.74 micromol/L. Exposure to TBEP increased free lidocaine from 66.7% to 80.0% of total lidocaine in the serum. The effect was diminished when the AAG level was low.