Hydroxyprogesterone

Endpoint summary

Link to relevant study record(s)

Reference

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.

Principles of method if other than guideline:

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

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

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.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

Biosynthesis and Metabolism of 17-Hydroxyprogesterone

 

Biosynthesis of 17-Hydroxyprogesterone (17-OHP) is predominantly located within the adrenal glands via hydroxylation of progesterone by 17α-hydroxylase[i]. (Progesterone itself is produced at a relatively high level in the adrenal glands, the corpus luteum (ovaries) and the placenta during pregnancy[ii].) 17-OHP is therefore an endogenous a metabolic intermediate and used for the anabolism of 11-deoxycortisol and androstendione and other steroids in the human body. In the organism 17-OHP is detectable at typical serum concentrations in women of 15–70 ng/dl (pre-luteal) and 35–290 ng/dl (luteal phase) and in children of 3-90 ng/dl. It is commonly used for diagnostic (biomarker) purposes e.g. for the indication of congenital adrenal hyperplasia which typically shows accumulation of 17-OHP in the serum[iii]. Bound to serum albumins 17-OHP is predominantly excreted via the liver. Unbound 17-OHP can be detected in the urine at low levels[iv].

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

• 17-OHP 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-OHPA 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 the 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 17-OHP would be unlikely to accumulate.


• The molecular weight below 500 and the lipophilicity 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 OHPA), 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.

 

 

[i] WikiJournal of Medicine, 2014, 1 (1) doi: 10.15347/wjm/2014.005 Figure Article

[ii] Aufrere and Benson, J Pharma Sci 1976; Vol. 65(6):783-800

[iii] Kamrath et al., Horm Metab Res, 2013 Feb;45(2):86-9

[iv] Lim et al. J. Paediatr. Child Health, 1995, 31:47-50