Androst-4-ene-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

Dose descriptor starting point:

NOAEL

Value:

5 mg/kg bw/day

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 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

Dose descriptor starting point:

NOAEL

Value:

5 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

5 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

For androstendione 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

Andostendione 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).

 

Subchronic (90-day) animal studies revealed evidence that the effect on fertility is the leading health effect of androstendione (NTP Technical Report 560, NIH Publication No. 10-5901, 2010). The single dermal exposure to the substance at 2000 mg/kg was tolerated without any findings (Schering, 1995), whereas the single oral exposure of 500 mg/kg led to unspecific and slight effects (LD50 > 500 and < 1000 mg/kg; Schering, 1989, 1994). No potential for skin or eye irritation or skin sensitization was concluded based on experimental studies (Schering AG, 1987 and 1995). For androstendione two carcinogenicity studies were available (NTP Technical Report 560, NIH Publication No. 10-5901, September 2010). 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 androstendione does not act as genotoxic carcinogen (Ames neg., Cytotest Cell Research GmbH, 1996; HPRT neg., Harlan Cytotest Cell Research GmbH, 2013; MNT in vivo, rat - neg., male mouse - neg, female mouse - equivocal, see NTP Technical Report 560, NIH Publication No. 10-5901, 2010). Therefore, despite the evidence of carcinogenic activity a threshold effect is concluded for androstendione 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.

 

The two available subchronic (90-day) studies that confirmed the effect on fertility as the leading health effect after repeated oral exposure were on rats and mice (NTP Technical Report 560, NIH Publication No. 10-5901, 2010). 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 delineation of the NOAEL.

 

DNEL_{systemic, long-term} for workers for hazard via 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
^1For remaining interspecies differences	2.5
^2For intraspecies differences (workers)	5
^3Differences in duration of exposure	2
^4Dose-response relationship	1
^5Quality of whole Database	1
Overall Assessment Factor	25

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

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

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

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

⁵The 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

 

DNEL_{systemic, long-term} for workers for hazards via inhalation route = 176 µg/m³

 

DNEL_{systemic, long-term} for workers for hazard via 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
^1For interspecies differences rat vs. human (allometric scaling)	4
^2For remaining interspecies differences	2.5
^3For intraspecies differences (workers)	5
^4Differences in duration of exposure	2
^5Dose-response relationship	1
^6Quality of whole Database	1
Overall Assessment Factor	100

 

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

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

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

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

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

⁶The 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

 

DNEL_{systemic, 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

Dose descriptor starting point:

NOAEL

Value:

5 mg/kg bw/day

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 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

Dose descriptor starting point:

NOAEL

Value:

5 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

5 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

For androstendione 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

Dose descriptor starting point:

NOAEL

Value:

5 mg/kg bw/day

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

Andostendione 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).

Subchronic (90-day) animal studies revealed evidence that the effect on fertility is the leading health effect of androstendione (NTP Technical Report 560, NIH Publication No. 10-5901, 2010). The single dermal exposure to the substance at 2000 mg/kg was tolerated without any findings (Schering, 1995), whereas the single oral exposure of 500 mg/kg led to unspecific and slight effects (LD50 > 500 and < 1000 mg/kg; Schering, 1989, 1994). No potential for skin or eye irritation or skin sensitization was concluded based on experimental studies (Schering AG, 1987 and 1995). For androstendione two carcinogenicity studies were available (NTP Technical Report 560, NIH Publication No. 10-5901, September 2010). 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 androstendione does not act as genotoxic carcinogen (Ames neg., Cytotest Cell Research GmbH, 1996; HPRT neg., Harlan Cytotest Cell Research GmbH, 2013; MNT in vivo, rat - neg., male mouse - neg, female mouse - equivocal, see NTP Technical Report 560, NIH Publication No. 10-5901, 2010). Therefore, despite the evidence of carcinogenic activity a threshold effect is concluded for androstendione and this threshold has to be related to reproductive toxicity/fertility. Consequently, for the general population DNELs for long term exposure via inhalation/dermal/oral route have to be derived. 

The two available subchronic (90-day) studies that confirmed the effect on fertility as the leading health effect after repeated oral exposure were on rats and mice (NTP Technical Report 560, NIH Publication No. 10-5901, 2010). 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 delineation of the NOAEL.

 

DNEL_{systemic, long-term} for the general population for hazard via 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/d 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
^1For remaining interspecies differences	2.5
^2For intraspecies differences (general population)	10
^3Differences in duration of exposure	2
^4Dose-response relationship	1
^5Quality of whole Database	1
Overall Assessment Factor	50

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

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

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

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

⁵The 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

 

DNEL_{systemic, long-term} for workers for hazards via inhalation route = 43.5 µg/m³

 

DNEL_{systemic, long-term} for the general population for hazard via 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
^1For interspecies differences rat vs. human (allometric scaling)	4
^2For remaining interspecies differences	2.5
^3For intraspecies differences (general population)	10
^4Differences in duration of exposure	2
^5Dose-response relationship	1
^6Quality of whole Database	1
Overall Assessment Factor	200

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

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

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

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

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

⁶The 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.

 

DNEL_{systemic, long-term} for workers for hazards via dermal or oral route = 25 µg/kg bw/day.