Hydroxyprogesterone

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics, other

Type of information:

other: Toxicokinetic Assessment

Adequacy of study:

other information

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Toxicokinetic assessment based on physical-chemical properties of the compound and toxicological data. Experimental toxicokinetic was not performed.

Data source

Reference

Reference Type:

other: TK Assessment

Title:

Unnamed

Year:

2017

Report date:

2017

Materials and methods

Principles of method if other than guideline:

TK assessment based on based on physico-chemical properties the compound and on toxicological data

Test material

Test material information

Constituent 1

Reference substance name:

Hydroxyprogesterone

EC Number:

200-699-4

EC Name:

Hydroxyprogesterone

Cas Number:

68-96-2

Molecular formula:

C21H30O3

IUPAC Name:

17-hydroxypregn-4-ene-3,20-dione

Results and discussion

Any other information on results incl. tables

Toxicokinetic assessment based on physical-chemical properties of the compound and toxicological data. Experimental toxicokinetic was not performed.

Applicant's summary and conclusion

Executive summary:

The following remarks on the toxicokinetics of 17α-Hydroxyprogesterone are based on physico-chemical properties of the compound and on toxicological data. Experimental toxicokinetic studies were not performed.

Hydroxyprogesterone is an organic solid with a very low vapour pressure under normal ambient conditions (< 0.001 Pa at 25°C), therefore inhalation exposure to the vapour is expected to be negligible.

The log Pow of 2.82 at 25°C and the molecular weight of 330.46 g/mol point to a good gastrointestinal absorption, although the water solubility is quite low, 0.014 g/L at 20 – 30 °C. An acute oral toxicity study with esterified 17α-Hydroxyprogesterone acetate was conducted and did not result in any clinical or toxicological signs up to the highest dose tested (2000 mg/kg bw). However, a combined repeated dose toxicity study with a reproduction toxicity screening conducted according to OECD 422 resulted in effects on the kidneys of female rats at the highest dose tested (1000 mg/kg bw/day), which can be regarded as a sign of any systemic exposure.

Because of the considerable lipophilicity of the substance, accumulation of the unchanged compound in fatty tissues might be possible depending on the efficiency of metabolic and excretory processes. However, with a log P value below 3 hydroxyprogesterone would be unlikely to accumulate.

The molecular weight below 500 and the lipohilicity indicate that the substance may be absorbed to some amount by the stratum corneum. However, based on the low water solubility (0.014 g/L at 20 – 30°C) the systemic bioavailability after dermal exposure will be low as the transfer from the stratum corneum to the epidermis will be limited. This is supported by a study on skin sensitisation (LLNA; Buchmann, 2016) in which no signs of systemic toxicity were observed.

Based on the results of three in vitro genotoxicity tests (negative with and without metabolic activation in an Ames test (Wollny, 1995; with Hydroxyprogesterone acetate), in a HPRT test (Wollny, 2016) as well as in a mammalian cell micronucleus test (Chang, 2016) it is concluded that DNA-reactive metabolites of the substance will most probably not be generated in mammals in the course of hepatic biotransformation.