Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics
Type of information:
other: assessment based on available info
Adequacy of study:
key study
Study period:
April 2011
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: non-GLP assessment report

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2011
Report Date:
2011

Materials and methods

Test guideline
Qualifier:
no guideline required
Principles of method if other than guideline:
assessment of all available data
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): LIN10001:4,4’-Isopropylidenediphenol, propoxylated (BPA+2PO)
- Physical state:White powder with lumps (determined at NOTOX)
- Analytical purity:>95% in BPA 2 PO

Test animals

Species:
other: none
Strain:
other: none

Administration / exposure

Route of administration:
other: oral, dermal, inhalation
Vehicle:
unchanged (no vehicle)

Results and discussion

Main ADME results
Type:
absorption
Results:
For risk assessment purposes, the oral, dermal absorption is set at 50% and the inhalation absoption is set at 100%

Any other information on results incl. tables

The octanol/water partition coefficient of 4,4’-Isopropylidenediphenol, propoxylated (BPA+2PO) being 3.3 to 3.6, and the molecular weight of 344.44 are favourable for absorption. The water solubility of

The octanol/water partition coefficient of 4,4’-Isopropylidenediphenol, propoxylated (BPA+2PO) is moderate (109 mg/L). In general, a compound needs to be dissolved before it can be taken up from the gastro-intestinal tract after oral administration (1). Potential for ionization may result in impaired uptake since compounds need to pass the lipid membranes in the gastrointestinal wall (1). For risk assessment purposes the oral absorption of 4,4’-Isopropylidenediphenol, propoxylated (BPA+2PO) is set at 50% as a worst case assumption. The results of the toxicity studies do not provide reasons to deviate from this proposed oral absorption factor.

Absorbed 4,4’-Isopropylidenediphenol, propoxylated (BPA+2PO) might undergo biotransformation (3). Because of the moderate molecular weight of 4,4’-Isopropylidenediphenol, propoxylated (BPA+2PO), the conjugates will either be excreted via the bile or the urine.

 

Based on the particle size of 4,4’-Isopropylidenediphenol, propoxylated (BPA+2PO), particles < 100µm which have the potential to be inhaled, are present in a small amount (4.48%). Particles will predominantly settle in the nasopharyngeal region (particles with aerodynamic diameter > 1-5 µm); the particles are too large to reach the tracheobronchial or pulmonary region (no particles < 5 µm). Part of the deposits in the nasopharyngeal region will be coughed or sneezed out of the body, or swallowed, while the moderate water solubility of 4,4’-Isopropylidenediphenol, propoxylated (BPA+2PO) (0.109 g/L) indicates that a part will dissolve into the mucus lining of the respiratory tract. Next to the moderate water solubility, the log Pow > 0 (3.3 to 3.6) furthermore indicates a limited potential for absorption directly across the respiratory tract epithelium. However, for risk assessment purposes the inhalation absorption of 4,4’-Isopropylidenediphenol, propoxylated (BPA+2PO) should be set at 50% as a worst case assumption but to be compliant with Echa guidance it will be set at 100%.

4,4’-Isopropylidenediphenol, propoxylated (BPA+2PO), being a solid with a moderate water solubility (0.109 g/L) has the potential for dermal absorption. Its molecular weight (344.44) and log Pow (3.3 to 3.6) are indicative to be moderately favourable for dermal uptake. However, the criteria for 10% dermal absorption as given in the Reach Guidance on information requirements and chemical safety assessment (2) (MW>500 and -1<log Pow >4) are not met, and therefore 100% dermal absorption of 4,4’-Isopropylidenediphenol, propoxylated (BPA+2PO) should be considered for risk assessment purposes. It is, however, generally accepted that dermal absorption is not higher compared to oral absorption. The 100% dermal absorption derived from physical/chemical properties of the substance should therefore be considered as a non-realistic assumption, and for risk assessment purposes a lower dermal absorption of 50% might be considered more appropriate.

 

Based on the present available data, no additional conclusions can be drawn on the distribution, metabolism and excretion of 4,4’-Isopropylidenediphenol, propoxylated (BPA+2PO) after dermal absorption.

5. REFERENCES

1. Martinez MN, Amidon GL. Mechanistic approach to understanding the factors affecting drug absorption: a review of fundamentals. J Clin Pharmacol 2002; 42: 620-43.

2. Guidance for the implementation of REACH. Guidance on information requirements and chemical safety assessment. Chapter R.7c: Endpoint specific guidance. European Chemical Agency, May 2008.

3. A. Parkinson. In: Casarett and Doull’s Toxicology, The basic science of poisons. Sixth edition. Ed. C.D. Klaassen. Chapter 6: Biotransformation of xenobiotics. McGraw-Hill, New York, 2001.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): other: For risk assessment purposes, the oral absorption is set at 50%. For risk assessment purposes the inhalation absorption is set at 50%. For risk assessment purposes the dermal absorption is set at 50%.
The evaluation of currently available information on LIN10001:4,4’-Isopropylidenediphenol, propoxylated (BPA+2PO) led to the following toxicokinetic assessment:
For risk assessment purposes, the oral absorption is set at 50%.
For risk assessment purposes the inhalation absorption is set at 50%.
For risk assessment purposes the dermal absorption is set at 50%.