Androsta-1,4-diene-3,17-dione

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

176 µg/m³

Most sensitive endpoint:

effect on fertility

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

25

Modified dose descriptor starting point:

NOAEC

Value:

4.41 mg/m³

Explanation for the modification of the dose descriptor starting point:

The leading health effect after repeated exposure of androstendion is the effect on fertility, based on the substance's interference with the body's hormonal balance. For such a systemic effect extrapolation from oral to inhalation is possible. The default assumption for differences in bioavailability between the two exposure routes (50 % of the substance will be absorbed after oral compared to inhalation exposure) is employed in this extrapolation. Further uncertainties related to toxicokinetics were taken into account by the factor 2.5 for remaining interspecies uncertainties.

AF for dose response relationship:

1

Justification:

When the starting point for the DNEL delineation is a NOAEC, the default assessment factor, as a standard procedure, is 1.

AF for differences in duration of exposure:

2

Justification:

The assessment factor suggested by Guidance Document R.8 (ECHA, 2012) for exposure duration from subchronic to chronic should be 2.

AF for interspecies differences (allometric scaling):

1

Justification:

Already covered with correction of dose-descriptor.

AF for other interspecies differences:

2.5

Justification:

A factor 2.5 is suggested by Guidance Document R.8 (ECHA, 2012) for remaining interspecies differences, and is applied here for uncertainties related to toxicokinetics.

AF for intraspecies differences:

5

Justification:

For intraspecies variability, the default assessment factor for workers is 5.

AF for the quality of the whole database:

1

Justification:

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.

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:

50 µg/kg bw/day

Most sensitive endpoint:

effect on fertility

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

100

Modified dose descriptor starting point:

NOAEL

Value:

5 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

For androstendion it is not indicated that dermal absorption is higher than oral absorption, since at least acute toxicity studies reveal no findings at all after dermal exposure compared to unspecific and slight findings after oral exposure. Moreover, the leading health effect after repeated exposure is the effect on fertility, based on the substance's interference with the body's hormonal balance. For such a systemic effect extrapolation from oral to dermal route is justified.

AF for dose response relationship:

1

Justification:

When the starting point for the DNEL delineation is a NOAEL, the default assessment factor, as a standard procedure, is 1.

AF for differences in duration of exposure:

2

Justification:

The assessment factor suggested by Guidance Document R.8 (ECHA, 2012) for exposure duration from subchronic to chronic should be 2.

AF for interspecies differences (allometric scaling):

4

Justification:

For allometric scaling rat to human the standard factor is 4

AF for other interspecies differences:

2.5

Justification:

A factor 2.5 is suggested by Guidance Document R.8 (ECHA, 2012) for remaining interspecies differences, and is applied here for uncertainties related to toxicokinetics.

AF for intraspecies differences:

5

Justification:

For intraspecies variability, the default assessment factor for workers is 5.

AF for the quality of the whole database:

1

Justification:

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.

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

Androstadiendion (CAS No. 897-06-3) is an intermediate in the synthesis of different steroid hormones.

Since no repeated dose toxicity data are available for this substance, subchronic toxicity data of androstendion (CAS No.63-05 -8) were used for the DNEL derivation of androstadiendion. A search for structure-analogue substances using the QSAR Toolbox 3.3.5 recommended androstendion as one out of 11 category substances for a read-across approach (for details see QSAR OECD Toolbox Report on Androstadiendion attached in chapter 7, Endpoint Summary: Toxicological information).

In androstendion (androst-4-ene-3,17-dione) the double bound in position 1 of the target molecule androstadiendion (androsta-1,4-diene-3,17-dione) is replaced by a single bound. No other changes in the molecule occurred. No relevant toxicological effects are expected by the change of an alkene group versus an alkane group. Therefore, an identical toxicity profile of androstadiendion and androstendion is to be expected and a read-across with androstendion seems justified to fill the data gaps of androstadiendion.

Androstendion is an endogenous intermediate in steroid hormone synthesis and as such an endogenous precursor of testosterone and estrone, which can be metabolized to estradiol. Consequently, repeated exposure to the substance interferes with the body's hormonal balance (for a discussion on health effects see FDA white paper, Health Effects of Androstendione, 2004).

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 androstadiendion or androstendion for the dermal or inhalation route.

 

Two available subchronic (90-day) toxicity studies in rats and mice with oral administration of androstendion revealed evidence that the effect on fertility is the leading health effect of androstendion (NTP, 2010; Blystone et al., 2011). Whereas the rat study revealed a NOAEL of 5 mg/kg (based on sperm investigations: decreased number of sperm), mice were shown to be less susceptiple to reproductive toxicity of androstendione (based on sperm investigations: decreased sperm motility at 50 mg/kg). Therefore, the NOAEL of the rat study was used as point of departure for the derivation of systemic long-term DNELs for workers.

 

In addition, two carcinogenicity studies with androstendion were available (NTP, 2010; Blystone et al., 2011). The one on rats showed equivocal evidence and the one on mice clear evidence for carcinogenic activity. However, it has to be taken into account that steroid hormones in general can promote the growth of specific hormone dependent tissues and tumors. Furthermore, the overall conclusion of the available genotoxicity studies support that androstendion does not act as genotoxic carcinogen (Ames test - negative (Reimann,1996); HPRT - negative ( Wollny, 2013); MNT in vivo, rat - negative, male mouse - negative, female mouse - equivocal (NTP, 2010)). Therefore, despite the evidence of carcinogenic activity a threshold effect is concluded for androstendion and this threshold has to be related to reproductive toxicity/fertility. Consequently, for workers DNELs for long-term exposure via inhalation and dermal route have to be derived.

 

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

NOAEL = 5 mg/kg for rats exposed orally to the substance for 14 weeks, 5 days/week

Modification of dose-descriptor to the correct starting point (according to Example B. 3, Guidance Document R.8, ECHA, 2012):

In case of workers 8h/day exposed:

corrected inhalatory NOAEC       =oral NOAEL * sRV_rat^-1* ABS_oral-rat/ABS_inh-human* sRV_human/wRV

= oral NOAEL * (0.38 m³/kg bw)^-1* 0.5 * 0.67 = 4.41 mg/m³

 

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

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

sRV_human= 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 Guidance Document R.8 (ECHA, 2012) a series of assessment factors (AF) were applied to the corrected NOAEC and are summarized in the table below:

Assessment	Assessment Factor
For interspecies differences rat vs. human (allometric scaling)	Already covered with correction of dose-descriptor
For remaining interspecies differences^1	2.5
For intraspecies differences (workers)^2	5
Differences in duration of exposure^3	2
Dose-response relationship^4	1
Quality of whole Database^5	1
Overall Assessment Factor	25

¹ A factor 2.5 is suggested by Guidance Document R.8 (ECHA, 2012) for remaining interspecies differences.

² For intraspecies variability, the default assessment factor for workers is 5.

³ The assessment factor suggested by Guidance Document R.8 (ECHA, 2012) for exposure duration from subchronic to chronic should be 2.

⁴ When the starting point for the DNEL delineation is a NOAEC, the default assessment factor, as a standard procedure, is 1.

⁵ 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.

 

Therefore, the overall AF (assessment factor) is 25. Corrected inhalatory NOAEC : 25 = 0.176 mg/m³ = 176 µg/m³

 

DNELsystemic, long-term for workers for hazards via inhalation route = 176 µg/m³

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

NOAEL = 5 mg/kg for rats exposed orally to the substance for 14 weeks, 5 days/week

Modification of dose-descriptor to the correct starting point (according to Example B. 5, Guidance Document R.8, ECHA, 2012):

In case of workers 8h/day exposed:

corrected dermal NOAEL = oral NOAEL * ABS_oral-rat/ABS_dermal-human = oral NOAEL * 1 = 5 mg/kg

 

ABS_oral-rat/ABS_dermal-human= the absorption of rats after oral exposure is assumed to be identical to the absorption of humans after dermal exposure = 1

 

According to Guidance Document R.8 (ECHA, 2012) a series of assessment factors (AF) were applied to the NOAEL and are summarized in the table below:

Assessment	Assessment Factor
For interspecies differences rat vs. human (allometric scaling)^1	4
For remaining interspecies differences^2	2.5
For intraspecies differences (workers)^3	5
Differences in duration of exposure^4	2
Dose-response relationship^5	1
Quality of whole Database^6	1
Overall Assessment Factor	100

¹ For allometric scaling rat to human the standard factor is 4.

² A factor 2.5 is suggested by Guidance Document R.8 (ECHA, 2012) for remaining interspecies differences.

³ For intraspecies variability, the default assessment factor for workers is 5.

⁴ The assessment factor suggested by Guidance Document R.8 (ECHA, 2012) for exposure duration from subchronic to chronic should be 2.

⁵ When the starting point for the DNEL delineation is a NOAEL, the default assessment factor, as a standard procedure, is 1.

⁶ 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.

 

Therefore, the overall AF (assessment factor) is 100. Corrected dermal NOAEL : 100 = 0.05 mg/kg = 50 µg/kg

 

DNELsystemic, long-term for workers for hazards via dermal route = 50 µg/kg bw/day

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

43 µg/m³

Most sensitive endpoint:

effect on fertility

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

50

Modified dose descriptor starting point:

NOAEC

Value:

2.17 mg/m³

Explanation for the modification of the dose descriptor starting point:

The leading health effect after repeated exposure of androstendion is the effect on fertility, based on the substance's interference with the body's hormonal balance. For such a systemic effect extrapolation from oral to inhalation is possible. The default assumption for differences in bioavailability between the two exposure routes (50 % of the substance will be absorbed after oral compared to inhalation exposure) is employed in this extrapolation. Further uncertainties related to toxicokinetics were taken into account by the factor 2.5 for remaining interspecies uncertainties.

AF for dose response relationship:

1

Justification:

When the starting point for the DNEL delineation is a NOAEC, the default assessment factor, as a standard procedure, is 1.

AF for differences in duration of exposure:

2

Justification:

The assessment factor suggested by Guidance Document R.8 (ECHA, 2012) for exposure duration from subchronic to chronic should be 2.

AF for interspecies differences (allometric scaling):

1

Justification:

Already covered with correction of dose-descriptor.

AF for other interspecies differences:

2.5

Justification:

A factor 2.5 is suggested by Guidance Document R.8 (ECHA, 2012) for remaining interspecies differences, and is applied here for uncertainties related to toxicokinetics.

AF for intraspecies differences:

10

Justification:

For intraspecies variability, the default assessment factor for the general population is 10.

AF for the quality of the whole database:

1

Justification:

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.

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

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

25 µg/kg bw/day

Most sensitive endpoint:

effect on fertility

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

200

Modified dose descriptor starting point:

NOAEL

Value:

5 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

For androstendion it is not indicated that dermal absorption is higher than oral absorption, since at least acute toxicity studies reveal no findings at all after dermal exposure compared to unspecific and slight findings after oral exposure. Moreover, the leading health effect after repeated exposure is the effect on fertility, based on the substance's interference with the body's hormonal balance. For such a systemic effect extrapolation from oral to dermal route is justified.

AF for dose response relationship:

1

Justification:

When the starting point for the DNEL delineation is a NOAEL, the default assessment factor, as a standard procedure, is 1.

AF for differences in duration of exposure:

2

Justification:

The assessment factor suggested by Guidance Document R.8 (ECHA, 2012) for exposure duration from subchronic to chronic should be 2.

AF for interspecies differences (allometric scaling):

4

Justification:

For allometric scaling rat to human the standard factor is 4

AF for other interspecies differences:

2.5

Justification:

A factor 2.5 is suggested by Guidance Document R.8 (ECHA, 2012) for remaining interspecies differences, and is applied here for uncertainties related to toxicokinetics.

AF for intraspecies differences:

10

Justification:

For intraspecies variability, the default assessment factor for the general population is 10.

AF for the quality of the whole database:

1

Justification:

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.

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

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

25 µg/kg bw/day

Most sensitive endpoint:

effect on fertility

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

200

Modified dose descriptor starting point:

NOAEL

Value:

5 mg/kg bw/day

AF for dose response relationship:

1

Justification:

When the starting point for the DNEL delineation is a NOAEL, the default assessment factor, as a standard procedure, is 1.

AF for differences in duration of exposure:

2

Justification:

The assessment factor suggested by Guidance Document R.8 (ECHA, 2012) for exposure duration from subchronic to chronic should be 2.

AF for interspecies differences (allometric scaling):

4

Justification:

For allometric scaling rat to human the standard factor is 4

AF for other interspecies differences:

2.5

Justification:

A factor 2.5 is suggested by Guidance Document R.8 (ECHA, 2012) for remaining interspecies differences, and is applied here for uncertainties related to toxicokinetics.

AF for intraspecies differences:

10

Justification:

For intraspecies variability, the default assessment factor for the general population is 10.

AF for the quality of the whole database:

1

Justification:

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.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - General Population

Preliminary remarks

Androstadiendion(CAS No. 897-06-3) is an intermediate in the synthesis of different steroid hormones.

Since norepeated dose toxicity data are available for this substance, subchronic toxicitydataof androstendion (CAS No.63-05 -8) were used for the DNEL derivation of androstadiendion.A search for structure-analogue substances using the QSAR Toolbox 3.3.5 recommended androstendion as one out of 11 category substances for a read-across approach (for details see QSAR OECD Toolbox Report on Androstadiendion attached in chapter 7, Endpoint Summary: Toxicological information).

In androstendion (androst-4-ene-3,17-dione) the double bound in position 1 of the target molecule androstadiendion (androsta-1,4-diene-3,17-dione) is replaced by a single bound. No other changes in the molecule occurred. No relevant toxicological effects are expected by the change of an alkene group versus an alkane group.Therefore, an identical toxicity profile of androstadiendion and androstendion is to be expected and a read-across with androstendion seems justified to fill the data gaps of androstadiendion.

Androstendion is an endogenous intermediate in steroid hormone synthesis and as such an endogenous precursor of testosterone and estrone, which can be metabolized to estradiol. Consequently, repeated exposure to the substance interferes with the body's hormonal balance (for a discussion on health effects see FDA white paper, Health Effects of Androstendione, 2004).

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

 

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

 

Two available subchronic (90-day) toxicity studies in rats and mice with oral administration of androstendion revealed evidence that the effect on fertility is the leading health effect of androstendion (NTP, 2010; Blystone et al., 2011). Whereas the rat study revealed a NOAEL of 5 mg/kg (based on sperm investigations: decreased number of sperm), mice were shown to be less susceptiple to reproductive toxicity of androstendione (based on sperm investigations: decreased sperm motility at 50 mg/kg). Therefore, the NOAEL of the rat study was used as point of departure for the derivation of systemic long-term DNELs for the general population.

 

In addition, two carcinogenicity studies with androstendion were available (NTP, 2010; Blystone et al., 2011). The one on rats showed equivocal evidence and the one on mice clear evidence for carcinogenic activity. However, it has to be taken into account that steroid hormones in general can promote the growth of specific hormone dependent tissues and tumors. Furthermore, the overall conclusion of the available genotoxicity studies support that androstendion does not act as genotoxic carcinogen (Ames test - negative (Reimann,1996); HPRT - negative ( Wollny, 2013); MNT in vivo, rat - negative, male mouse - negative, female mouse - equivocal (NTP, 2010)). Therefore, despite the evidence of carcinogenic activity a threshold effect is concluded for androstendion and this threshold has to be related to reproductive toxicity/fertility. Consequently, for the general population DNELs for long-term exposure via inhalation and dermal route have to be derived.

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

NOAEL = 5 mg/kg for rats exposed orally to the substance for 14 weeks, 5 days/week

Modification of dose-descriptor to the correct starting point (according to Example B. 3, Guidance Document R.8, ECHA, 2012):

In case of the general population 24h/day exposed:

corrected inhalatory NOAEC      =oral NOAEL * sRV_rat^-1* ABS_oral-rat/ABS_inh-human

=oral NOAEL * (1.15 m³/kg)^-1* 0.5 = 2.17 mg/m³

 

sRV_rat= default respiratory volume rat, 24 h exposure = 1.15 m³/kg

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

 

According to Guidance Document R.8 (ECHA, 2012) a series of assessment factors (AF) were applied to the corrected NOAEC and are summarized in the table below:

Assessment	Assessment Factor
For interspecies differences rat vs. human (allometric scaling)	Already covered with correction of dose-descriptor
For remaining interspecies differences^1	2.5
For intraspecies differences (general population)^2	10
Differences in duration of exposure^3	2
Dose-response relationship^4	1
Quality of whole Database	1
Overall Assessment Factor	50

¹ A factor 2.5 is suggested by Guidance Document R.8 (ECHA, 2012) for remaining interspecies differences.

² For intraspecies variability, the default assessment factor for the general population is 10.

³ The assessment factor suggested by Guidance Document R.8 (ECHA, 2012) for exposure duration from subchronic to chronic should be 2.

⁴ When the starting point for the DNEL delineation is a NOAEC, the default assessment factor, as a standard procedure, is 1.

⁵ 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.

 

Therefore, the overall AF (assessment factor) is 50. Corrected inhalatory NOAEC : 50 = 0.043 mg/m³ = 43.5 µg/m³

DNELsystemic, long-term for the general population for hazards via inhalation route = 43.5 µg/m³

Derivation of a systemic long-term DNEL for the general population on hazards via the dermal/oral route

NOAEL = 5 mg/kg for rats exposed orally to the substance for 14 weeks, 5 days/week

Modification of dose-descriptor to the correct starting point (according to Example B. 5, Guidance Document R.8, ECHA, 2012):

In case of the general population 24h/day exposed:

corrected dermal NOAEL = oral NOAEL * ABS_oral-rat/ABS_dermal-human= oral NOAEL * 1 = 5 mg/kg

 

ABS_oral-rat/ABS_dermal-human= the absorption of rats after oral exposure is assumed to be identical to the absorption of humans after dermal exposure = 1

According to Guidance Document R.8 (ECHA, 2012) a series of assessment factors (AF) were applied to the NOAEL and are summarized in the table below:

Assessment	Assessment Factor
For interspecies differences rat vs. human (allometric scaling)^1	4
For remaining interspecies differences^2	2.5
For intraspecies differences (general population)^3	10
Differences in duration of exposure^4	2
Dose-response relationship^5	1
Quality of whole Database^6	1
Overall Assessment Factor	200

¹ For allometric scaling rat to human the standard factor is 4.

² A factor 2.5 is suggested by Guidance Document R.8 (ECHA, 2012) for remaining interspecies differences.

³ For intraspecies variability, the default assessment factor for the general population is 10.

⁴ The assessment factor suggested by Guidance Document R.8 (ECHA, 2012) for exposure duration from subchronic to chronic should be 2.

⁵ When the starting point for the DNEL delineation is a NOAEL, the default assessment factor, as a standard procedure, is 1.

⁶ 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.

 

Therefore, the overall AF (assessment factor) is 200. Corrected dermal NOAEL or oral NOAEL : 200 = 0.025 mg/kg = 25 µg/kg

 

DNELsystemic, long-term for the general population for hazards via dermal or oral route = 25 µg/kg bw/day