Hydroxyprogesterone

Endpoint summary

Description of key information

Acute toxicity oral: LD50 > 2000 mg/kg bw, based on a read across to hydroxyprogesterone acetate (Kurth 1995)

Acute toxicity dermal: LD50 > 2000 mg/kg bw, based on a read across to hydroxyprogesterone acetate (Kurth 1996)

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: oral

Type of information:

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

Adequacy of study:

key study

Justification for type of information:

Justification for analogue approach:
As no acute toxicity data of hydroxyprogesterone is available, a read-across to hydroxyprogesterone acetate (CAS 302-23-8) was performed. Usually esters are hydrolysed in the presence of water or in organisms due to enzymatic degradation by esterases. As a result, the respective alcohol derivative (hydroxyprogesterone (CAS 68-96-2)) and carboxylic acid are generated.

Reason / purpose for cross-reference:

read-across source

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No animal died after application of 2000 mg/kg of the test compound during the study.

Clinical signs:

other: The compound was tolerated without clinical signs.

Gross pathology:

Autopsy revealed no compound-related or suspected compound-related findings.

Executive summary:

No acute toxicity is available for the target substance Hydroxyprogesterone. Results of a study conducted with Hydroxyprogesterone acetate are regarded as representative as most likely ester cleavage occurs in vivo after administration.

In an acute oral toxicity study similar to OECD TG 423, fasted HAN: WIST rats (3/sex) were given a single oral dose by gavage of hydroxyprogesterone acetate in physiological saline with 0.085% (w/v) Myrj 53 at the limit dose 2000 mg/kg and observed for 14 days.

The administration was tolerated without mortalities, clinical effects, effects on body weight gain and gross pathological findings in both sexes.

Based on read-across, the oral LD50 of hydroxyprogesterone is therefore: LD50 > 2000 mg/kg body weight.

 

Reference 2

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

July to Aug 1995

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Qualifier:

according to guideline

Guideline:

other: Amendment to Annex VI of the Directive 67/548 EEC in the version of EEC Directive 93/21 EEC and "Gefahrstoffverordnung, Stand Oct. 94"

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Version / remarks:

study was conducted prior to implementation of OECD TG 423

Deviations:

yes

Remarks:

The application of 2000 mg/kg to three animals was repeated with three animals of a different sex.

GLP compliance:

yes

Test type:

acute toxic class method

Limit test:

yes

Species:

rat

Strain:

other: HAN: WIST (SPF)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Schering AG
- Age at study initiation: not specified
- Weight at study initiation: males: 98-113 g; females: 89-106 g
- Fasting period before study: ca. 19-20 h
- Housing: single housing
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23-24°C
- Humidity (%): 42-58%
- Air changes (per hr): not specified
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: To: males: 11. - 24. Jul 1995; females 20. Jul - 02. Aug 1995

Route of administration:

oral: gavage

Vehicle:

other: physiological saline with 0.085% (w/v) Myrj 53

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 200 mg/ml
- Amount of vehicle (if gavage): 10 ml/kg
- Lot/batch no. (if required): males: G/7160-1; females: G/7170



CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: Limit dose

Doses:

2000 mg/kg

No. of animals per sex per dose:

3 + 3 (males + females)

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of weighing: day 8 and 14
- Necropsy of survivors performed: yes

Statistics:

Not applicable.

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No animal died after application of 2000 mg/kg of the test compound during the study.

Clinical signs:

other: The compound was tolerated without clinical signs.

Gross pathology:

Autopsy revealed no compound-related or suspected compound-related findings.

Conclusions:

A single oral administration of the test substance by gavage to three male and three female rats at the limit-dose 2000 mg/kg was tolerated without mortalities, clinical effects, effects on body weight gain and gross pathological findings in both sexes. The oral LD50 of the test substance is therefore: LD50 > 2000 mg/kg body weight.

Executive summary:

In an acute oral toxicity study similar to OECD TG 423, fasted HAN: WIST rats (3/sex) were given a single oral dose by gavage of hydroxyprogesterone acetate in physiological saline with 0.085% (w/v) Myrj 53 at the limit dose 2000 mg/kg and observed for 14 days.

The administration was tolerated without mortalities, clinical effects, effects on body weight gain and gross pathological findings in both sexes.

The oral LD50 of hydroxyprogesterone acetate is therefore: LD50 > 2000 mg/kg body weight.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

OECD guideline study

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: dermal

Type of information:

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

Adequacy of study:

key study

Justification for type of information:

Justification for analogue approach:
As no acute toxicity data of hydroxyprogesterone is available, a read-across to hydroxyprogesterone acetate (CAS 302-23-8) was performed. Usually esters are hydrolysed in the presence of water or in organisms due to enzymatic degradation by esterases. As a result, the respective alcohol derivative (hydroxyprogesterone (CAS 68-96-2)) and carboxylic acid are generated.

Reason / purpose for cross-reference:

read-across: supporting information

Reason / purpose for cross-reference:

reference to other study

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No animal died during the study.

Clinical signs:

other: The test item was tolerated without compound-related findings.

Gross pathology:

Autopsy revealed no compound-related findings.

Executive summary:

No acute toxicity is available for the target substance Hydroxyprogesterone. Results of a study conducted with Hydroxyprogesterone acetate are regarded as representative as most likely ester cleavage occurs in vivo after administration.

In an acute dermal toxicity study similar to OECD TG 402 performed as a combined study on acute toxicity and on local tolerance HAN: WIST rats (3/sex) (3/sex) were dermally exposed to hydroxyprogesterone acetate in physiological saline for 24 hours at a limit dose of 2000 mg/kg bw under semiocclusive conditions.  Animals then were observed for 14 days.

The administration of the test substance was tolerated without mortalities, compound-related clinical findings, effects on body weight gain and gross pathological findings.

Based on read-across, the oral LD50 of hydroxyprogesterone is therefore: LD50 > 2000 mg/kg body weight

 

Reference 2

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

Aug to Sep 1995

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Reason / purpose for cross-reference:

reference to same study

Qualifier:

according to guideline

Guideline:

other: Amendment to Annex VI of the Oirective 67/548 EEC in the version of EEC Directive 93/21 EEC and "Gefahrstoffverordnung, Stand Oct. 94".

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Version / remarks:

1981

Deviations:

yes

Remarks:

3 instead of 5 animals/sex used

GLP compliance:

yes

Remarks:

- but a QA check was not performed

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

other: HAN: WIST (SPF)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Schering AG
- Age at study initiation: not specified
- Weight at study initiation: males: 112-120 g; females: 101-107 g
- Fasting period before study: ca. 16.5-19 h
- Housing: single housing
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23-24°C
- Humidity (%): 58-62%
- Air changes (per hr): not specified
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: To: males: 30. Aug - 12. Sep 1995; females 6. - 19. Sep 1995

Type of coverage:

semiocclusive

Vehicle:

other: 0.9% (w/v) NaCl-solution

Details on dermal exposure:

TEST MATERIAL
- Amount(s) applied: males 224-240 mg; females 202 - 214 mg
- For solids, paste formed: yes

VEHICLE
- Amount(s) applied: males 0.4 ml; females 0.3 ml

Duration of exposure:

24 hours

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

3

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: day 1, 7 and 14
- Necropsy of survivors performed: yes

Statistics:

not applicable

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No animal died during the study.

Clinical signs:

other: The test item was tolerated without compound-related findings.

Gross pathology:

Autopsy revealed no compound-related findings.

Conclusions:

A single dermal administration of the test substance to male and female rats at the limit-dose 2000 mg/kg was tolerated without mortalities, compound-related clinical findings, effects on body weight gain and gross pathological findings. The dermal LD50 of the test substance is therefore > 2000 mg/kg body weight.

Executive summary:

In an acute dermal toxicity study similar to OECD TG 402 performed as a combined study on acute toxicity and on local tolerance HAN: WIST rats (3/sex) (3/sex) were dermally exposed to hydroxyprogesterone acetate in physiological saline for 24 hours at a limit dose of 2000 mg/kg bw under semiocclusive conditions.  Animals then were observed for 14 days.

The administration of the test substance was tolerated without mortalities, compound-related clinical findings, effects on body weight gain and gross pathological findings.

The dermal LD50 of the test substance is therefore > 2000 mg/kg body weight.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

comparable to guidelinestudy

Additional information

No acute toxicity studies were conducted with 17-OHP. Instead, data of its ester OHPA from rat acute oral and acute dermal studies are used for the toxicological characterization of 17-OHP; this can be regarded as worst-case scenario due to its qualitatively identical but quantitatively stronger biological activity (on the progesterone receptor). Additionally, adverse effects following systemic exposure are expected to be driven by the pharmacological activity of the substances (activity on the PR); no other toxicity effects are expected below the pharmacological threshold for a substance representing an endogenous metabolite.

 

Acute oral toxicity study:

A single oral administration of the test substance, hydroxyprogesterone acetate, by gavage to three male and three female rats at the limit-dose 2000 mg/kg was tolerated without mortalities, clinical effects, effects on body weight gain and gross pathological findings in both sexes. According to OECD TG 423 the oral LD50 of hydroxyprogesterone acetate is therefore: LD50 > 2000 mg/kg body weight. (Kurth/ Treher, 1995)

A read-across approach from hydroxyprogesterone acetate to hydroxyprogesterone is justified as described in the document "Justification for a read-across between 17-Hydroxyprogesterone acetate (CAS 302-23-8, EC 206-119-6) as source and 17-Hydroxyprogesterone (CAS 68-96-2, EC 200-699-4) as target".

 

Acute dermal toxicity study:

A single dermal administration of hydroxyprogesterone acetate, to male and female rats at the limit-dose 2000 mg/kg was tolerated without mortalities, compound-related clinical findings, effects on body weight gain and gross pathological findings. According to OECD TG 402 the dermal LD50 of the hydroxyprogesterone acetate is therefore > 2000 mg/kg body weight. (Kurth/ Treher, 1996)

A read-across approach from hydroxyprogesterone acetate to hydroxyprogesterone is justified as described in the document "Justification for a read-across between 17-Hydroxyprogesterone acetate (CAS 302-23-8, EC 206-119-6) as source and 17-Hydroxyprogesterone (CAS 68-96-2, EC 200-699-4) as target".

 

Acute toxicity studies for OHPA

	Hydroxyprogesterone acetate OHPA (CAS 302-23-8)
Study type	Acute oral	Comb. acute dermal & local tolerance
Study no./ Report no.	TX95191/ X053 (draft version) Kurth/ Treher, 1995	TX95187/ X058 (draft version) Kurth/ Treher, 1996
GLP/ OECD TG/ deviations	GLP, equivalent to OECD 423 (limit study) Dev.: 2 sexes instead of 1; no individual animal reporting but means per sex with low & acceptable standard deviations	GLP, comparable to OECD 402 & 404 Dev.: 2 sexes instead of 1, with n=3 animals per sex; no individual animal reporting but means per sex with low & acceptable standard deviations; scope of report limited according to actual TG 402 (2017) and TG 404 (July 2015); no scoring of erythema or oedema
Species; animals/ group	Rat (Wistar), n=3 female/ male	Rat (Wistar), n=3 female/ male
Doses/ route/ schedule	2000 mg/kg (200 mg/ml) p.o., single treatment	2000 mg/kg, dermal (semi-occlusive), 24h-exposure, single treatment
Formulation	· Microcrystalline suspension · pH 5.7 (batch I) & 6.1 (batch II) · Vehicle: 900 mg NaCI + 85 mg Myrj® 53 ad 1 00 ml bidist. Water; freshly prepared · Compound concentrations of 100% and 106% confirmed by HPLC and UV analysis (report SFR-KI 95116)	· Paste · Vehicle: 900 mg NaCI ad 100 ml bidest. water; freshly prepared · Compound purity 98.3%
observation period	14d; intervals unspecified	14d; intervals unspecified
Results	· Compound tolerated without any clinical signs · Increasing BW (mean values per sex) over time · No animal died · No findings within gross necropsy · LD50 > 2000 mg/kg	· No local findings on skin at the application sites · Compound tolerated without any clinical signs · Increasing BW (mean values per sex) over time · No animal died · No findings within gross necropsy · LD50 > 2000 mg/kg

 

 

Justification for classification or non-classification

Based on the data available (no effects occurred in dermal and oral acute toxicity studies up to the highest dose tested) no classification is warranted for acute toxicity according to Regulation (EC) 1272/2008 (CLP).