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Administrative data

Endpoint:
basic toxicokinetics
Type of information:
other: Toxicokinetic assessment
Adequacy of study:
supporting study
Study period:
15. Aug. 2006 - 15. Aug. 2006
Rationale for reliability incl. deficiencies:
other: Assessment based on results of GLP toxicology studies, well documented

Data source

Reference
Reference Type:
other: Expert assessment
Title:
Unnamed
Report date:
2006

Materials and methods

Principles of method if other than guideline:
Assessment based on results of GLP toxicology studies.

Test material

Constituent 1
Chemical structure
Reference substance name:
-
EC Number:
480-680-7
EC Name:
-
Cas Number:
120128-90-7
Molecular formula:
Hill formula: C8H16N2O3 CAS formula: C8H16N2O3
IUPAC Name:
480-680-7

Results and discussion

Any other information on results incl. tables

Absorption : Although the relatively small molecular size and the high water solubility of the substance indicates that uptake can take place through aqueous pores, the hydrophilic character of the substance (log Po/w: -3.3) will limit this passive diffusion. Furthermore, the ionization of FORMAMIDOPROPYLBETAINE will impair the uptake since compounds need to pass the lipid membranes in the gastrointestinal wall (1). It is therefore unlikely that FORMAMIDOPROPYLBETAINE will be absorbed to a high extent from the gastro-intestinal tract. For risk assessment purposes the oral absorption of FORMAMIDOPROPYLBETAINE is set at 10%. The results of the toxicity studies do not provide reasons to deviate from this proposed oral absorption factor. The high water solubility of FORMAMIDOPROPYLBETAINE indicates that the substance will dissolve in the mucus lining of the respiratory tract and subsequently be absorbed through aqueous pores (taking the molecular weight <200 into account). The hydrophilic character of the substance (log Po/w: -3.3) indicates a limited potential for absorption directly across the respiratory tract epithelium. Although it is unlikely that FORMAMIDOPROPYLBETAINE will be absorbed to a high extent after inhalation via the lungs, for risk assessment purposes the inhalation absorption of FORMAMIDOPROPYLBETAINE is set at 100% as a worst case assumption. FORMAMIDOPROPYLBETAINE being a substance in solution has the potential to be dermally absorbed. The substance however is expected to be too hydrophilic to cross the lipid rich environment of the stratum corneum (miscible with water; log Po/w: -3.3). As the criteria for 10% dermal absorption as given in the TGD (2) (MW > 500 and log Po/w < -1) are not met, 50% dermal absorption of FORMAMIDOPROPYLBETAINE is proposed for risk assessment purposes. The results of the toxicity studies do not provide reasons to deviate from this proposed dermal absorption factor.

Distribution : FORMAMIDOPROPYLBETAINE will show a relatively small volume of distribution. Distribution of FORMAMIDOPROPYLBETAINE will be limited to the extracellular space, because of the ionization in plasma. Therefore, a volume of distribution equaling that of the extracellular space (approx. 12 L) is expected. Accumulation in fatty tissues is not anticipated.

Metabolism and excretion : Absorbed FORMAMIDOPROPYLBETAINE will largely be eliminated in the unchanged form via renal excretion. Renal excretion will be in the non-ionized form only via glomerular filtration. Hence, the flow of urine is important for the maintenance of a concentration gradient, favoring excretion of the non-ionized forms. Glucuronidation and/or sulphation may take place on the carboxylic acid group (3). Because of the small size of the molecule, the conjugates will probably be excreted via the urine.

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. ECB EU Technical Guidance Document on Risk Assessment, 2003.

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-Hili,

New York, 2001.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): other: No bioaccumulation potential anticipated based on expert judgement
Based on the expected kinetic behavior in the body, FORMAMIDOPROPYLBETAINE will show reduced absorption after oral or dermal administration or after inhalation. FORMAMIDOPROPYLBETAINE will be eliminated from the body via the urine. Accumulation of FORMAMIDOPROPYLBETAINE during prolonged exposure is highly unlikely. Accumulation in fatty tissues is not anticipated.
Executive summary:

TOXICOKINETIC ASSESSMENT OF FORMAMIDOPROPYLBETAINE

Absorption: Although the relatively small molecular size and the high water solubility of the substance indicates that uptake can take place through aqueous pores, the hydrophilic character of the substance (log Po/w: -3.3) will limit this passive diffusion. Furthermore, the ionization of FORMAMIDOPROPYLBETAINE will impair the uptake since compounds need to pass the lipid membranes in the gastrointestinal wall (1). It is therefore unlikely that FORMAMIDOPROPYLBETAINE will be absorbed to a high extent from the gastro-intestinal tract. For risk assessment purposes the oral absorption of FORMAMIDOPROPYLBETAINE is set at 10%. The results of the toxicity studies do not provide reasons to deviate from this proposed oral absorption factor. The high water solubility of FORMAMIDOPROPYLBETAINE indicates that the substance will dissolve in the mucus lining of the respiratory tract and subsequently be absorbed through aqueous pores (taking the molecular weight <200 into account). The hydrophilic character of the substance (log Po/w: -3.3) indicates a limited potential for absorption directly across the respiratory tract epithelium. Although it is unlikely that FORMAMIDOPROPYLBETAINE will be absorbed to a high extent after inhalation via the lungs, for risk assessment purposes the inhalation absorption of FORMAMIDOPROPYLBETAINE is set at 100% as a worst case assumption. FORMAMIDOPROPYLBETAINE being a substance in solution has the potential to be dermally absorbed. The substance however is expected to be too hydrophilic to cross the lipid rich environment of the stratum corneum (miscible with water; log Po/w: -3.3). As the criteria for 10% dermal absorption as given in the TGD (2) (MW > 500 and log Po/w < -1) are not met, 50% dermal absorption of FORMAMIDOPROPYLBETAINE is proposed for risk assessment purposes. The results of the toxicity studies do not provide reasons to deviate from this proposed dermal absorption factor.

Distribution: FORMAMIDOPROPYLBETAINE will show a relatively small volume of distribution. Distribution of FORMAMIDOPROPYLBETAINE will be limited to the extracellular space, because of the ionization in plasma. Therefore, a volume of distribution equaling that of the extracellular space (approx. 12 L) is expected. Accumulation in fatty tissues is not anticipated.

Metabolism and excretion: Absorbed FORMAMIDOPROPYLBETAINE will largely be eliminated in the unchanged form via renal excretion. Renal excretion will be in the non-ionized form only via glomerular filtration. Hence, the flow of urine is important for the maintenance of a concentration gradient, favoring excretion of the non-ionized forms. Glucuronidation and/or sulphation may take place on the carboxylic acid group (3). Because of the small size of the molecule, the conjugates will probably be excreted via the urine.

Conclusion : Based on the expected kinetic behavior in the body, FORMAMIDOPROPYLBETAINE will show reduced absorption after oral or dermal administration or after inhalation. FORMAMIDOPROPYLBETAINE will be eliminated from the body via the urine. Accumulation of FORMAMIDOPROPYLBETAINE during prolonged exposure is highly unlikely. Accumulation in fatty tissues is not anticipated.

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. ECB EU Technical Guidance Document on Risk Assessment, 2003.

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-Hili, New York, 2001.

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