Hydroxyprogesterone

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3.53 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

75

Dose descriptor starting point:

NOAEL

Value:

300 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

264.5 mg/m³

Explanation for the modification of the dose descriptor starting point:

No repeated dose toxicity study available for the inhalative route.

AF for dose response relationship:

1

Justification:

see "Discussion"

AF for differences in duration of exposure:

6

Justification:

see "Discussion"

AF for interspecies differences (allometric scaling):

1

Justification:

see "Discussion"

AF for other interspecies differences:

2.5

Justification:

see "Discussion"

AF for intraspecies differences:

5

Justification:

see "Discussion"

AF for the quality of the whole database:

1

Justification:

see "Discussion"

AF for remaining uncertainties:

1

Justification:

see "Discussion"

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

300

Dose descriptor starting point:

NOAEL

Value:

300 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

300 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No repeated dose toxicity study available for the dermal route.

AF for dose response relationship:

1

Justification:

see "Discussion"

AF for differences in duration of exposure:

6

Justification:

see "Discussion"

AF for interspecies differences (allometric scaling):

4

Justification:

see "Discussion"

AF for other interspecies differences:

2.5

Justification:

see "Discussion"

AF for intraspecies differences:

5

Justification:

see "Discussion"

AF for the quality of the whole database:

1

Justification:

see "Discussion"

AF for remaining uncertainties:

1

Justification:

see "Discussion"

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - workers

Preliminary remarks

Hydroxyprogesterone (CAS No. 68 -96 -2) is an intermediate in the synthesis of different steroid hormones.

 

Hydroxyprogesteron is a metabolite of progesterone and as such an endogenous intermediate in steroid hormone synthesis.

 

Selection of the relevant starting point for the derivation of systemic long-term DNELs (inhalation and dermal route) for workers

 

There are no repeated dose toxicity studies available with hydroxyprogesterone for the dermal or inhalation route.

 

In a rat study according to OECD 422 with oral doses of hydroxprogesterone of up to 1000 mg/kg bw/day a NOAEL of 300 mg/kg bw was established as the lowest NOAEL (Barraclough, 2017). Rats were treated by gavage for 42 (males) and up to 64 (females; pre-pairing, throughout gestation, and during the first weeks of lactation) days, respectively. In females, microscopically, an increased incidence and/or severity of tubular basophilia and/or cortical scar of kidneys was present in test-item groups. Slightly elevated urea and creatinine, together with an increased incidence and severity of tubular basophila and/or scarring, observed for females administered 1000 mg/kg bw/day were indicative for renal injury, and as such, was considered adverse. In the low and intermediate dose group slightly lower grades of severity in regard to microscopic kidney changes compared to high dose group were observed. In the absence of any notable changes in blood creatinine and urea they were considered as not adverse. 300 mg/kg bw/day is considered the no observed adverse effect level (NOAEL) for females for systemic toxicity. No test-item related effects in males were observed up to the highest dose tested; as such, 1000 mg/kg/day is considered the no observed effect level (NOEL) for males for systemic and reproductive toxicity.

No effect on mating, fertility, or pregnancy was observed. A slightly lower number of implantation sites was observed for females administered 1000 mg/kg/day, and a slightly higher percentage post-implantation loss was observed for females administered 1000 or 300 mg/kg/day; these resulted in slightly lower mean pups/litter in these dose groups. A slightly higher percentage of male pups was noted in 1000 mg/kg/day litters. In the absence of any adverse clinical observations or higher rates of litter mortality after birth, these slight differences, compared with controls, were considered not to have represented adverse effects on the offspring. The NOAEL for females for reproductive toxicity was established at 1000 mg/kg/day.

The NOAEL for offspring development was considered to be 1000 mg/kg/day.

Therefore the relevant starting point is the systemic NOAEL established in female rats at 300 mg/kg bw/day.

 

Derivation of a systemic long-term DNEL for workers on hazard via the inhalation route

 

Relevant starting point from oral OECD422 study in rats with hydroxyprogesterone:

NOAEL: 300 mg/kg bw /day

 

Modification of dose-descriptor to the correct starting point (according to ECHA Guidance on Information Requirements and Chemical Safety Assessment - Chapter R.8, Example B.3 (Version 2.1, Nov. 2012):

 

corrected inhalatory NOAEC (in case of workers 8 hours/day exposed)

= oral NOAEL * sRVrat-1* ABSoral-rat/ABSinh-human* sRVhuman/wRV

= 300 mg/kg bw * (0.38 m³ /kg bw)-1 * 0.5 * 0.67 = 264.5 mg/m³

 

sRVrat = default respiratory volume rat, 8 h exposure = 0.38 m³ /kg bw

ABSoral-rat/ABSinh-human = the absorption of rats after oral exposure is assumed to be 50 % of the human absorption after inhalation = 0.5

sRVhuman = standard respiratory volume human, 8 h exposure = 6.7 m³/person

wRV = respiratory volume light activity for worker, 8 h exposure = 10 m³/person

 

According to ECHA Guidance on Information Requirements and Chemical Safety Assessment - Chapter R.8 (Version 2.1, Nov. 2012) a series of

assessment factors (AF) were applied to the corrected NOAEC and are summarized in the table below:

 

Type of assessment	Assessment factor (AF)	Justification
Dose-response relationship	1	When the starting point for the DNEL derivation is a NOAEC, the default assessment factor, as a standard procedure, is 1.
Differences in duration of exposure	6	The assessment factor suggested by ECHA Guidance, Chapter R.8 (Nov. 2012) for subacute exposure duration is 6.
Interspecies differences rat vs. human (allometric scaling)	1	No allometric scaling factor required according to ECHA Guidance, Chapter R.8, Table R.8-4 (Nov. 2012) since already covered by correction of starting point.
Other interspecies differences	2.5	A factor of 2.5 is suggested by the ECHA Guidance, Chapter R.8 (Nov. 2012) for remaining interspecies differences.
Intraspecies differences (workers)	5	For intraspecies variability, the default assessment factor for workers is 5.
Quality of whole database	1	The default assessment factor to be applied for good/standard quality of the database, taking into account completeness, consistency and the standard information requirements, is 1.
Overall assessment factor	75

 

Therefore, the overall assessment factor (AF) is 75. Corrected inhalatory NOAEC of 264.5 mg/m³ : 75 = 3.53 mg/m³

 

Worker DNELsystemic, long-term for inhalation route = 3.53 mg/m³

 

 

Derivation of a systemic long-term DNEL for workers on hazards via the dermal route

 

Relevant starting point from OECD422 study in rats with hydroxyprogesterone:

NOAEL: 300 mg/kg bw /day

 

Modification of dose-descriptor to the correct starting point (according to ECHA Guidance on Information Requirements and Chemical Safety Assessment - Chapter R.8, Example B.5 (Version 2.1, Nov. 2012):

 

corrected dermal NOAEL (in case of workers 8 hours/day exposed)

= oral NOAEL * ABS_oral-rat/ABS_dermal-human

= 300 mg/kg bw * 1 = 300 mg/kg

 

ABS_oral-rat/ABS_dermal-human = no specific data available; the absorption of rats after oral exposure is assumed to be identical to the absorption of humans after dermal exposure (worst case) = 1

 

According to ECHA Guidance on Information Requirements and Chemical Safety Assessment - Chapter R.8 (Version 2.1, Nov. 2012) a series of

assessment factors (AF) were applied to the NOAEL and are summarized in the table below:

                                                                                                                                                                                                                                                

Type of assessment	Assessment factor (AF)	Justification
Dose-response relationship	1	When the starting point for the DNEL derivation is a NOAEL, the default assessment factor, as a standard procedure, is 1.
Differences in duration of exposure	6	The assessment factor suggested by ECHA Guidance, Chapter R.8 (Nov. 2012) for subacute exposure duration is 6.
Interspecies differences rat vs. human (allometric scaling)	4	For allometric scaling rat to human the standard factor is 4.
Other interspecies differences	2.5	A factor of 2.5 is suggested by the ECHA Guidance, Chapter R.8 (Nov. 2012).
Intraspecies differences (workers)	5	For intraspecies variability, the default assessment factor for workers is 5.
Quality of whole database	1	The default assessment factor to be applied for good/standard quality of the database, taking into account completeness, consistency and the standard information requirements, is 1.
Overall assessment factor	300

 

Therefore, the overall assessment factor (AF) is 300. Corrected dermal NOAEL of 300 mg/kg bw /day : 300 = 1 mg/kg bw /day

 

Worker DNELsystemic, long-term for dermal route = 1 mg/kg bw /day

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected