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

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: EU Risk Assessment Report According to ECHA Practical Guide 6 the maximum score for read across is rel. 2

Data source

Reference

Reference Type:

review article or handbook

Title:

European Union Risk Assessment Report, CAS No 80-05-7; EINECS No 201-245-8; 4,4´-Isopropylidenediphenol (bisphenol-A)

Author:

EU

Year:

2008

Bibliographic source:

Updated European Union Risk Assessment Report on 4,4'-isopropylidenediphenol (bisphenol-A); 3rd priority list, Volume 37; EUR 24589 EN

Materials and methods

Principles of method if other than guideline:

Comprehensive Risk Assessment (Update) of Bisphenol A (CAS 80-05-7)

Test material

Test material information

Constituent 1

Reference substance name:

4,4'-isopropylidenediphenol

EC Number:

201-245-8

EC Name:

4,4'-isopropylidenediphenol

Cas Number:

80-05-7

Molecular formula:

C15H16O2

IUPAC Name:

2,2-bis(4-hydroxyphenyl)propane

Results and discussion

Any other information on results incl. tables

The substance contains approx. 15 % 2,2-bis(4-hydroxyphenyl)propane (CAS No 80-05-7), therefore data of 2,2-bis(4-hydroxyphenyl)propane are relevant for toxicological assessment and were thus included in the IUCLID.

Applicant's summary and conclusion

Executive summary:

Cited from EU RAR, 2008:

Impact of new information and summary of toxicokinetics:

"The new information on the toxicokinetics of BPA in humans and in pregnant and nonpregnant rodents of different ages provides an important contribution to our knowledge of the kinetic properties of BPA. However, the most significant impact of the new information for risk assessment purposes arises from the studies in humans. These studies have demonstrated that at comparable exposure levels the blood concentrations of free BPA in humans are much lower than those in rodents, indicating that there are important quantitative differences in the fate of BPA between humans and rodents.

The toxicokinetics of BPA have been well studied in rats both in vivo and in vitro, and have been investigated to a lesser extent in mice and cynomolgus monkeys. Two studies have investigated the toxicokinetics and fate of an oral dose of labelled BPA in human volunteers."

Absorption

"In the species studied (rats, mice, monkeys, humans), the available evidence suggests that following oral administration, BPA is rapidly and extensively absorbed from the gastrointestinal tract. Analysis of plasma AUC values suggests that the extent of absorption from the GI tract is up to 86 % in rats and up to 85 % in monkeys. The only relevant human studies suggest that, on the basis of the recovery of labelled BPA-glucuronide from the urine, a relatively low dose of BPA (54-88 μg/kg) was completely absorbed after oral dosing. An in vitro dermal absorption study using human skin found limited absorption of BPA at millimolar concentrations; the extent of absorption was in the region of 10 % of the applied dose.

There are no data on the toxicokinetics of BPA following inhalation exposure. However, on the basis of the observed absolute organ weight changes in a repeat inhalation study and the high partition coefficient, it would be prudent to assume that absorption via the inhalation route can occur, but the data do not allow a quantitative estimation of absorption to be made. Furthermore, because first-pass metabolism would not take place following exposure by this route, or by the dermal route, the systemic bioavailability is likely to be substantially greater for these routes than is associated with the oral route.

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 %."

Metabolism

"The available data indicate that BPA is subject to extensive first-pass metabolism following absorption from the gastrointestinal tract. In all species studied, the major metabolic pathway involves conjugation of BPA to BPA-glucuronide. Studies conducted in rats suggest that in neonates the glucuronidation pathway is more susceptible to saturation than in adults indicating an age-dependent increase in metabolic capacity. In vitro studies with microsomal preparations also suggest species differences, with the rank order for the metabolic clearance rate per unit weight of tissue being mice > rats > humans. When the total clearance rates for the whole liver were calculated, the rank order was reversed (humans > rats > mice).

In addition to the glucuronidation pathway, in vivo and in vitro studies suggest that in the rat, BPA may be subject to limited oxididation to bisphenol O-quinone by cytochrome P450, and also to conjugation to BPA-sulphate and 5-hydroxy-BPA.

A study in pregnant mice given subcutaneous doses of BPA also found that glucuronidation was the major pathway for the metabolism of BPA, although dehydrated, sulphated and methoxylated conjugates of BPA were also produced. Some minor metabolites were double conjugates, such as a double conjugate of BPA with glucuronide and N-acetyl galactosamine which was found in the intestine, placenta, amniotic fluid and foetal tissue. A study in cynomolgus monkeys showed that BPA-glucuronide was the major metabolite, although there was evidence for production of a minor metabolite, possibly BPA-sulphate or 5 -hydroxy-BPA. Studies conducted in humans provide evidence for the glucuronidation of BPA in man; some studies also found evidence for the sulphation of BPA."

Distribution

"Most studies investigating the distribution of BPA measured tissue radioactivity levels after giving labelled BPA to experimental animals. An oral dosing study in rats found that the tissue concentrations of BPA-derived-radioactivity were highest in the liver, kidney and carcass, and lowest in the brain and testes, and there were no large differences between adult and neonatal animals. A number of studies in rats suggest that BPA metabolites and especially free BPA have a limited distribution to the embryo/foetal or placental compartments following oral administration. No selective affinity of either yolk sac/placenta or embryo/foetus for BPA or BPA metabolites relative to maternal plasma or tissues was observed in a recent study in rats after oral dosing. However, maternal and embryo/foetal exposure to free BPA did occur, but systemic levels were found to be low due to extensive first-pass metabolism.

Regarding the distribution of free, unconjugated BPA to tissues after oral dosing, since free BPA is removed rapidly from the blood after absorption by first pass metabolism, it has been suggested that in animals the availability of free BPA to extrahepatic tissues is likely to be limited following oral exposure. In adult rats it has been estimated that no more than 5-10 % of the administered dose of free BPA is available to the tissues, although this figure may be higher in neonates. In humans, the systemic availability of free BPA is very low as enterohepatic recirculation of BPA does not occur.

In summary, 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. This metabolite is devoid of endocrine activity. In humans, the glucuronide is released from the liver into the systemic circulation and cleared by urinary excretion. Due to the rapid biotransformation and excretion (t1/2 = 5 hours) and plasma protein binding, peak free BPA concentrations in humans after oral exposure that are available for estrogen receptor binding are very low. 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. The enterohepatic recirculation results in slow excretion (t1/2 = 15-22 hours) and increased systemic availability of free BPA in rodents.

This conclusion is supported by the observation that in urine of rats dosed orally with BPA, a part of the dose was excreted as free BPA in urine (1 -4 % of applied dose, whereas BPA-glucuronide in urine accounted for 20-40 % of applied dose). In both of the human studies and the monkey study free BPA was below the limit of detection in all urine and blood samples (equivalent to a ratio of free BPA to BPA-glucuronide of < 0.5 %). Since free BPA found in urine is translocated from blood to urine in the kidney, these observations of higher free BPA levels in urine of rats compared with primates further support the existence of species differences in blood levels of free BPA between rodents and humans with higher AUCs for free BPA in rats."

Excretion

"The major route of elimination in the rat is via the faeces. The available data indicate that the percentage of the administered dose recovered in the faeces is in the range 50 % to 83 %. Urinary excretion is of secondary importance in the rat, with 13 % to 42 % of the administered dose being recovered in the urine. Over 7 days post-dosing approximately 80 % and 70 % of the administered dose was eliminated in the faeces in males and females, respectively. Elimination was rapid; the majority of the dose was excreted by 72 hours post-dosing. A sex difference was also observed for urinary elimination, with females excreting approximately twice as much radioactivity (24-28 %) than males (14-16 %). A study in female SD rats found that excretion was not affected by pregnancy at 3 different stages of gestation. Data from a number of studies suggest limited excretion of BPA in the milk. However, the data do not allow a reliable quantitative determination to be made.

Following oral administration to rats, a high proportion of the administered dose (45-66 %) was rapidly excreted in the bile in the form of BPA-glucuronide, with the rate of biliary excretion tending to be higher in males than females. Most of the faecal radioactivity was found to be in the form of free BPA. Since BPA has a high oral bioavailability in the rat, the free BPA found in the faeces is more likely to be derived from BPA-glucuronide excreted in the bile and hydrolysed to free BPA in the gastrointestinal tract rather than representing unabsorbed BPA which might have passed along the gastrointestinal tract into the faeces unchanged. Most of the urinary radioactivity was found to be in the form of BPA-glucuronide (82 %) with free BPA and BPA-sulphate making minor contributions (14 % and 4 % respectively).

In contrast to the findings in rodents, in cynomolgus monkeys given BPA orally most of the administered dose (82–85 %) was recovered in the urine, with only 2-3 % of the dose being recovered in the faeces. In two studies in human volunteers given a low dose of BPA orally, the administered dose was completely recovered in the urine as BPA-glucuronide. No free BPA was detected and no gender differences in the kinetics of BPA-glucuronide in plasma and urine were reported."