2,6-bis({[bis(2-hydroxyethyl)amino]methyl})-4-[2-(3-{[bis(2-hydroxyethyl)amino]methyl}-4-hydroxyphenyl)propan-2-yl]phenol; 2,6-bis({[bis(2-hydroxyethyl)amino]methyl})-4-[2-(4-hydroxyphenyl)propan-2-yl]phenol; 2-[(2-hydroxyethyl)amino]ethan-1-ol; 2-{[bis(2-hydroxyethyl)amino]methyl}-4-[2-(3-{[bis(2-hydroxyethyl)amino]methyl}-4-hydroxyphenyl)propan-2-yl]phenol; 2-{[bis(2-hydroxyethyl)amino]methyl}-4-[2-(4-hydroxyphenyl)propan-2-yl]phenol; 4-[2-(4-hydroxyphenyl)propan-2-yl]phenol

Endpoint summary

Additional information

For an assessment of toxicokinetics read across to the two main constituents of the substance 2,2'-iminodiethanol (DEA, CAS No 111-42-2) and 2,2-bis(4-hydroxyphenyl)propane (BPA, CAS No 80-05-7) is performed. These account for approx. 55 % of the substance (DEA ca. 40 %, BPA ca. 15 %), and information on their toxicokinetic properties is thus relevant for the toxicokinetic assessment of the substance. Two reaction products of DEA, formaldehyde and BPA (i.e. Mannich Bases) account for further 39 % of the substance (Mannich Base 1 ca. 26 %; Mannich Base 2 [two isomers] ca. 13 %). The Mannich Bases are structurally similar to BPA, but are larger molecules (i.e. BPA with one or two diethanolaminomethyl-substituents attached to the aromatic ring). Due to the higher molecular weights of the Mannich Bases (345 g/mol and 462 g/mol for Mannich Base 1 and 2, respectively) a lower absorption is expected, and toxicokinetic properties like distribution, metabolism and excretion of the substance will be dominated by the lower molecular weight-substances DEA and BPA (105 g/mol and 228 g/mol, respectively). A QSAR-analysis (OECD toolbox, version 3.3.0.132; Schlecker, 2015-04-13) revealed for the Mannich Bases no specific finding except a predicted estrogen receptor binding based on the BPA core-structure. Overall, the toxicokinetic properties of the substance is well reflected when considering the data of DEA and BPA.

For DEA and BPA summaries on the toxicokinetic properties exist based on peer-reviewed chemical risk assessments, e.g. OECD SIDS Initial Assessment Report and EU Risk Assessment Report, respectively. Summaries are given in the following.

 

Cited from OECD SIDS, 2007, with respect to toxicokinetics of DEA: "2,2'-Iminodiethanol (diethanolamine, DEA) is well absorbed following oral administration in rats (57 %) and to a lower degree after dermal administration (3-16 % in rats; 25 – 60 % in mice). When applied dermally, DEA appears to facilitate its own absorption, as higher doses were more completely absorbed than lower doses. DEA (20 mg/cm²) applied to skin preparations in vitro showed penetration rates of 6.68 % (mouse) > 2.81 % (rabbit) >0.56 % (rat) > 0.23 % (human). Distribution to the tissues was similar via all routes examined. DEA is cleared from the tissues with a half-life of approximately 6 days. The highest concentrations are observed in liver and kidney. Metabolism after oral administration revealed non-metabolized DEA and smaller proportions of N-methyl-DEA (N-MDEA), N,N-dimethyl-DEA (N’N-DMDEA) and DEA-phosphates co-eluting with phosphatidyl ethanolamine and phosphatidyl choline. After digestion, 30 % of the phospholipids were identified as ceramides and the remaining 70 % as phosphog1ycerides. DEA is excreted primarily in urine as the parent molecule (25-36 %), with lesser amounts of O-phosphorylated and N-methylated metabolites. Accumulation of DEA at high levels in liver and kidney is assumed by a mechanism that normally conserves ethanolamine, a normal constituent of phospholipids. DEA is incorporated as the head group in phospholipids, presumably via the same enzymatic pathways that normally utilize ethanolamine."

 

EU RAR, 2003, respective to BPA: "Animal data indicates that absorption of BPA from the gastrointestinal tract is rapid and extensive following oral administration, although it is not possible to reliably quantify the extent of absorption. Following dermal exposure, available data suggest limited absorption of about 10 % of the applied dose. BPA is removed rapidly from the blood and the data indicate extensive first pass metabolism following absorption from the gastrointestinal tract. In view of this first pass metabolism, the bioavailability of unconjugated BPA is probably limited following oral exposure to no more than 10 to 20 % of the administered dose. The major metabolic pathway in rats involves glucuronide conjugation, with approximately 10 % and 20 % of the administered dose recovered in urine as the glucuronide metabolite in males and females, respectively. The major route of excretion is via the faeces with the urinary route being of secondary importance. Over seven days post dosing, approximately 80 % and 70 % of the administered dose was eliminated in the faeces in male and female rats, respectively. The first pass metabolism and extensive and rapid elimination of BPA suggest that the potential for transfer to the foetus and bioaccumulation may be limited. There are no data on the toxicokinetics of BPA following inhalation exposure."

The 2008 updated EU RAR concluded: "New information on the toxicokinetics of BPA in humans and in pregnant and non-pregnant rodents of different ages provides an important contribution to the knowledge of kinetic properties of BPA. Human studies have demonstrated that at comparable exposure levels the blood concentrations of free BPA in humans are much lower than those in rodents. In rats, mice, monkeys, and humans, the available evidence suggests that following oral administration, BPA is rapidly and extensively absorbed from the gastrointestinal tract. For the purposes of risk characterisation, absorption via the oral and inhalation routes will be assumed to be 100 %; dermal absorption will be taken to be 10 %. A number of studies in rats suggest that BPA metabolites and free BPA have a limited distribution to the embryo/foetal or placental compartments following oral administration. Maternal and embryo/foetal exposure to free BPA did occur, but systemic levels were found to be low due to extensive first-pass metabolism. There are differences between humans and rodents in the distribution of BPA. After oral administration, BPA is rapidly metabolised in the gut wall and the liver to BPA-glucuronide. In humans, the glucuronide is released from the liver into the systemic circulation and cleared by urinary excretion. In contrast, BPA-glucuronide is eliminated in bile in rodents and undergoes enterohepatic recirculation after cleavage to BPA and glucuronic acid by glucuronidase in the intestinal tract."

In 2015 EFSA concluded on toxicokinetics: "The kinetic data available indicate species- and life stage-dependent differences. Such variability has to be considered when data of different species are compared. Conjugation to BPA-glucuronide, which is a biologically inactive form, is the major metabolic pathway of BPA in humans and animals. A study in humans on high BPA diets (Teeguarden et al., 2011) showed that unconjugated BPA in serum was below the LOD of 0.3 ng/mL (= 1.3 nM), confirming under the condition of the study that internal exposure to unconjugated BPA is low. The percentage of unconjugated BPA in blood is only a few percent of total BPA (sum of conjugated and unconjugated Bisphenol A)."