Ferrocene

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.02 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

75

Modified dose descriptor starting point:

LOAEC

Value:

1.51 mg/m³

Explanation for the modification of the dose descriptor starting point:

In the absence of any data to the contrary, the same bioavailability is assumed for humans and laboratory animals.

Workers are assumed to be exposed for 8 h/day. Converting rat inhalation data to a corresponding air concentration in the human is required. The inhalation dose for the rat is converted to the corresponding air concentration using a standard breathing volume for the human worker and to account for the presumed light activity of workers, this value is corrected for an increase in breathing volume. Thus 3mg/m3 x ((6h/8h) x (6.7m3/ 10m3)) = 1.51 mg/m3 (8-h exposure of workers, light activity).

AF for dose response relationship:

3

Justification:

Default ECHA AF; human health relevant LOAEC from peer-reviewed well-conducted 90day inhalation study.

AF for differences in duration of exposure:

2

Justification:

ECHA AF for subchronic (90-day) exposure

AF for interspecies differences (allometric scaling):

1

Justification:

Allometric scaling already considered in correcting starting point above

AF for other interspecies differences:

2.5

Justification:

Default ECHA AF for remaining toxicokinetic differences (not related to metabolic rate) and toxicodynamic differences

AF for intraspecies differences:

5

Justification:

Default ECHA AF for (healthy) worker

AF for the quality of the whole database:

1

Justification:

Default ECHA AF; the health effects data are reliable and consistent, the available information meets the tonnage driven data requirements, and confidence in the database is high.

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.04 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

37.5

DNEL extrapolated from long term DNEL

Modified dose descriptor starting point:

LOAEC

Value:

1.51 mg/m³

AF for dose response relationship:

3

Justification:

Default ECHA AF; human health relevant LOAEC from peer-reviewed well-conducted 90day inhalation study.

AF for interspecies differences (allometric scaling):

1

Justification:

Allometric scaling already considered in correcting starting point above

AF for other interspecies differences:

2.5

Justification:

Default ECHA AF for remaining toxicokinetic differences (not related to metabolic rate) and toxicodynamic differences

AF for intraspecies differences:

5

Justification:

Default ECHA AF for remaining toxicokinetic differences (not related to metabolic rate) and toxicodynamic differences

AF for the quality of the whole database:

1

Justification:

Default ECHA AF; the health effects data are reliable and consistent, the available information meets the tonnage driven data requirements, and confidence in the database is high.

Local effects

Long term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.025 mg/kg bw/day

Most sensitive endpoint:

developmental toxicity / teratogenicity

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:

In the absence of any data to the contrary, the same bioavailability is assumed for humans and laboratory animals.

Route-to-route extrapolation to calculate a dermal DNEL (development) from oral studies was considered suitable. In the absence of route-specific information on absorption the end route (dermal), a conservative assumption equal to the oral absorption will be made. Therefore, the starting point is 5mg/kg/bw/day. Workers are assumed to be exposed for 8 h/day.

AF for dose response relationship:

2

Justification:

ECHA AF; NOAEL for development in a well-conducted to GLP screening study. Adverse effects seen at higher doses. However as the positive result was seen in a screening study a higher AF has been applied

AF for differences in duration of exposure:

2

Justification:

ECHA AF for positive result in a screening study

AF for interspecies differences (allometric scaling):

4

Justification:

Default ECHA AF for rat for toxicokinetic differences in metabolic rate (allometric scaling)

AF for other interspecies differences:

2.5

Justification:

Default ECHA AF for remaining toxicokinetic differences (not related to metabolic rate) and toxicodynamic differences

AF for intraspecies differences:

5

Justification:

Default ECHA AF for (healthy) worker

AF for the quality of the whole database:

1

Justification:

Default ECHA AF; the health effects data are reliable and consistent, the available information meets the tonnage driven data requirements, and confidence in the database is high.

Acute/short term exposure

Hazard assessment conclusion:

no DNEL required: short term exposure controlled by conditions for long-term

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

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.005 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

150

Modified dose descriptor starting point:

LOAEC

Value:

0.75 mg/m³

Explanation for the modification of the dose descriptor starting point:

In the absence of any data to the contrary, the same bioavailability is assumed for humans and laboratory animals.

General population exposure via the environment is assumed to be continuous (24 h/day, 7 d/wk). Converting rat inhalation data to a corresponding in the human general population exposure is required. Thus 3mg/m3 x (6h/24h) = 0.75mg/m3 (24-h exposure of general population).

AF for dose response relationship:

3

Justification:

ECHA AF; human health relevant LOAEC from well-conducted peer reviewed 90day inhalation study.

AF for differences in duration of exposure:

2

Justification:

ECHA AF for subchronic (90day) exposure

AF for interspecies differences (allometric scaling):

1

Justification:

Allometric scaling already considered in correcting starting point above

AF for other interspecies differences:

2.5

Justification:

Default ECHA AF for remaining toxicokinetic differences (not related to metabolic rate) and toxicodynamic differences

AF for intraspecies differences:

10

Justification:

Default ECHA AF for general population

AF for the quality of the whole database:

1

Justification:

Default ECHA AF; the health effects data are reliable and consistent, the available information meets the tonnage driven data requirements, and confidence in the database is high.

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:

0.013 mg/kg bw/day

Most sensitive endpoint:

developmental toxicity / teratogenicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

400

Modified dose descriptor starting point:

NOAEL

Value:

5 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

In the absence of any data to the contrary, the same bioavailability is assumed for humans and laboratory animals.

Route-to-route extrapolation to calculate a dermal DNEL (development) from oral studies was considered suitable. In the absence of route-specific information on absorption the end route (dermal), a conservative assumption equal to the oral absorption will be made. Therefore, the starting point is 5 mg/kg/bw/day.

AF for dose response relationship:

2

Justification:

ECHA AF; NOAEL for development in well-conducted to GLP screening study. Adverse effects seen at higher doses. . However as the positive result was seen in a screening study an higher AF has been applied

AF for differences in duration of exposure:

2

Justification:

ECHA AF for positive result in a screening study

AF for interspecies differences (allometric scaling):

4

Justification:

Default ECHA AF for rat for toxicokinetic differences in metabolic rate (allometric scaling)

AF for other interspecies differences:

2.5

Justification:

Default ECHA AF for remaining toxicokinetic differences (not related to metabolic rate) and toxicodynamic differences

AF for intraspecies differences:

10

Justification:

Default ECHA AF for general population

AF for the quality of the whole database:

1

Justification:

Default ECHA AF; the health effects data are reliable and consistent, the available information meets the tonnage driven data requirements, and confidence in the database is high.

Acute/short term exposure

Hazard assessment conclusion:

no DNEL required: short term exposure controlled by conditions for long-term

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:

0.013 mg/kg bw/day

Most sensitive endpoint:

developmental toxicity / teratogenicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

400

Modified dose descriptor starting point:

NOAEL

Value:

5 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Modification of starting point In the absence of any data to the contrary, the same bioavailability is assumed for humans and laboratory animals Therefore, the starting point is 5 mg/kg/bw/day

AF for dose response relationship:

2

Justification:

ECHA AF; NOAEL for development in well-conducted to GLP screening study. Adverse effects seen at higher doses. . However as the positive result was seen in a screening study an higher AF has been applied

AF for differences in duration of exposure:

2

Justification:

Default ECHA AF for positive result in a screening study

AF for interspecies differences (allometric scaling):

4

Justification:

Default ECHA AF for rat for toxicokinetic differences in metabolic rate (allometric scaling

AF for other interspecies differences:

2.5

Justification:

Default ECHA AF for remaining toxicokinetic differences (not related to metabolic rate) and toxicodynamic differences

AF for intraspecies differences:

10

Justification:

Default ECHA AF for general population

AF for the quality of the whole database:

1

Justification:

Default ECHA AF; the human health effects data are reliable and consistent, the available information meets the tonnage driven data requirements, and confidence in the database is high

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

JUSTIFICATION FOR ENDPOINT SELECTION

General Population

Acute toxicity

No acute toxicity data in humans is available. Animal data is however available. In a study performed to OECD guideline 401, Ferrocene had an LD50 1320mg/kg bw. In a study performed to OECD guideline 402, Ferrocene had an NOEC 3000mg/kg bw. Based on the available data, Ferrocene is classified as harmful by acute oral exposure but not by dermal routes according to the EU CLP or DSD regulations and is classified. DNELs for acute toxicity should be derived if an acute toxicity hazard has been identified, leading to classification and labelling and there is a potential for high peak exposures (this is only usually relevant for inhalation exposures).A DNEL for acute toxicity is unnecessary as the long-term DNEL for systemic effects is expected to be sufficient to ensure that adverse effects do not occur. Therefore, a DNEL for such effects is not considered necessary as the long-term systemic general population DNEL will be sufficient to ensure that adverse effects do not occur.

Irritation/ corrosivity

In a reliable study performed to OECD Guideline 404, Ferrocene is non-irritating on the skin of male rabbits. This is based on the irritation index value of 0.5. In a reliable study performed to OECD Guideline 405, Ferrocene is non-irritating for the eye and ocular mucosa of a rabbit. This is based on the overall score of 0.02 There is no data in relation to respiratory tract irritation in humans or laboratory animals. However, due to its low skin and eye irritation potential, it is unlikely that Ferrocene would cause such an effect. Based on the available data, Ferrocene would not be classified as an eye, skin or respiratory tract irritant under the EU CLP or DSD regulations. Acute and repeated dose toxicity studies, where available, provide no relevant (dose-response) information for irritant or corrosive effects. Consequently, no general population-DNEL for irritation/ corrosivity has been calculated.

One good quality study is available for skin sensitisation of Ferrocene. In a study performed to OECD Guideline 406, Ferrocene was found to be non-sensitising (Innospec, 1987)

There are no data relating to respiratory tract sensitisation in humans or laboratory animals. However, due to the lack of sensitisation on Ferrocene on the skin it’s unlikely that it would cause any respiratory sensitisation

Oral DNEL (repeated dose toxicity, systemic effects)

Dose descriptor

There is no data available in humans relating to repeated oral exposure to ferrocene. However, studies have investigated the repeated dose oral toxicity of ferrocene in rodents and this has allowed the identification of the lowest, relevant LOAEL of 30mg/kg bw/day from a reliable peer reviewed 180day dietary study of ferrocene in dogs (Yeary, 1969).

Mode-of-action

Ferrocene is considered to have only threshold effects, as the weight-of-evidence indicates that it does not possess genotoxic potential.

Modification of starting point

In the absence of any data to the contrary, the same bioavailability is assumed for humans and laboratory animals.

General population are assumed to be exposed for 24h/day

The starting point is30mg/kg bw/day

ECHA AFs for general population – oral DNEL (repeated dose toxicity, systemic effects)

Uncertainty	AF	Justification for AF
Interspecies differences	1.4     2.5	Default ECHA AF for dog for toxicokinetic differences in metabolic rate (allometric scaling)
		Default ECHA AF for remaining toxicokinetic differences (not related to metabolic rate) and toxicodynamic differences
Intraspecies differences	10	Default ECHA AF for general population
Differences in duration of exposure	1	Default ECHA AF for chronic (180day) exposure
Dose response and endpoint specific/severity issues	3	Default ECHA AF; human health relevant LOAEL from well-conducted 180day dietary study
Quality of whole database	1	Default ECHA AF; health effects data are reliable and consistent, the available information meets the tonnage driven data requirements, and confidence in the database is high.
Overall AF for worker	105

 

General population -DNEL (long-term for oral route-systemic) = 30 (mg/kg/bw/day) / 105 =0.29mg/kg/bw/day

Inhalation DNEL (repeated dose toxicity, systemic effects)

Dose descriptor

There is no data available in humans or relating to repeated inhalation exposure to ferrocene. However, studies have investigated the repeated dose inhalation toxicity of ferrocene in rodents and this has allowed the identification of the lowest, relevant LOAEC of 3mg/m3 from a reliable 90day study in rats (Nikula, 1993).

Mode-of-action

Ferrocene is considered to have only threshold effects, as the weight-of-evidence indicates that it does not possess genotoxic potential.

Modification of starting point

In the absence of any data to the contrary, the same bioavailability is assumed for humans and laboratory animals.General population exposure via the environment is assumed to be continuous (24 h/day, 7 d/wk). Converting rat inhalation data to a corresponding in the human general population exposure is required. Thus 3mg/m³x (6h/24h) =0.75mg/m³(24-h exposure of general population).

 

ECHA AFs for general population – inhalation DNEL (repeated dose toxicity, systemic effects)

Uncertainty	AF	Justification for AF
Interspecies differences	1     2.5	Allometric scaling already considered in correcting starting point above
		Default ECHA AF for remaining toxicokinetic differences (not related to metabolic rate) and toxicodynamic differences
Intraspecies differences	10	Default ECHA AF for general population
Differences in duration of exposure	2	ECHA AF for subchronic (90day) exposure
Dose response and endpoint specific/severity issues	3	ECHA AF; human health relevant LOAEC from well-conducted peer reviewed 90day inhalation study.
Quality of whole database	1	Default ECHA AF; the health effects data are reliable and consistent, the available information meets the tonnage driven data requirements, and confidence in the database is high.
Overall AF for worker	150

General population-DNEL(long-term for inhalation route-systemic) = 0.75 mg/m³/ 150= 0.005mg/m³

Dermal DNEL(repeated dose toxicity, systemic effects)

Dose descriptor

There is no data available in humans or laboratory animals relating to repeated dermal exposure to ferrocene.

Therefore, the use of the repeated dose oral data will be considered. Studies have investigated the repeated dose oral toxicity of ferrocene and this has allowed the identification of the lowest, relevant LOAEL of 30mg/kg bw/day from a reliable peer reviewed 180day dietary study of ferrocene in dogs (Yeary, 1969).

Mode-of-action

Ferrocene is considered to have only threshold effects, as the weight-of-evidence indicates that it does not possess genotoxic potential.

Modification of starting point

In the absence of any data to the contrary, the same bioavailability is assumed for humans and laboratory animals.

As no relevant study data on effects of repeated dermal exposure to ferrocene humans or laboratory animals are available, route-to-route extrapolation to calculate a dermal DNEL from repeated dose oral toxicity studies is a suitable alternative.

In the absence of route-specific information on absorption the end route (dermal), a conservative dermal absorption assumption equal to the oral absorption will be made.

Therefore, the starting point is30mg/kg/bw/day.

Workers are assumed to be exposed for 8 h/day.

ECHA AFs for general population – dermal DNEL (repeated dose toxicity, systemic effects)

Uncertainty	AF	Justification for AF
Interspecies differences	1.4     2.5	Default ECHA AF for dog for toxicokinetic differences in metabolic rate (allometric scaling)
		Default ECHA AF for remaining toxicokinetic differences (not related to metabolic rate) and toxicodynamic differences
Intraspecies differences	10	Default ECHA AF for general population
Differences in duration of exposure	1	Default ECHA AF for chronic (180day) exposure
Dose response and endpoint specific/severity issues	3	Default ECHA AF; human health relevant LOAEL from well-conducted 180day dietary study.
Quality of whole database	1	Default ECHA AF; the human health effects data are reliable and consistent, the available information meets the tonnage driven data requirements, and confidence in the database is high
Overall AF for general population	105

General population-DNEL (long-term for dermal route-systemic) = 30mg/kg bw/day / 105 =0.29mg/kg bw/day

Genotoxicity

In Vitro: there are 8 studies in the dossier; 4 AMES, 2 gene mutation mouse lymphoma assay (MLA) and 2 Chromosome abberations are included. In Vivo; there are 2 studies in the dossier; a mammalian erthrocyte micronucleus test and a Drosophila SLRL and reciprocal translocation tests

Under the REACh testing strategy the 3 test in vitro test battery is required. Adequate negative AMES data addresses the bacterial gene mutation end point. A recent MLA study conducted in accordance with the relevant OECD guidance and published recommendations, confirms a lack of mammalian gene mutation potential. No acceptable in vitro cytogenicity data has been generated, but the negative data from the in vivo mouse bone marrow micronucleus study is seen as an adequate substitute.

Therefore, given the available data under the requirements of REACh it is concluded that ferrocene is devoid of any genotoxic potential. Under EU CLP and DSD regulations, ferrocene would not be classified as mutagenic. Consequently, no worker-DN(M)ELs for genotoxicity have been calculated.

Reproductive toxicity (fertility impairment and developmental toxicity)

 

Fertility DNEL

No information is available on fertility effects of ferrocene in humans.

Ferrocene was assessed to investigate the systemic toxicity and its potential adverse effects on reproduction (including offspring development). The study was performed according to OECD Guideline 422. As effects of treatment were apparent at dosages as low as 5 mg/kg bw/day it was not possible to establish a No Observed Effect Level (NOEL) for systemic toxicity. A dosage of 10 mg/kg bw/day was considered to be a No Observed Adverse Effect Level (NOAEL) effects on fertility, with a LOAEL of 25mg/kg bw/day.

Development DNEL

The study also assessed Ferrocene and the potential for adverse effects on reproduction (including offspring development). As effects of treatment were apparent at dosages as low as 5 mg/kg bw/day it was not possible to establish a No Observed Effect Level (NOEL) for systemic toxicity. The study achieved a NOAEL for offspring survival, growth and development of 5mg/kg bw/day

There is clear indication of developmental toxicity in the ferrocene study and there is also evidence for concern on fertility. This concern is considered sufficient enough to trigger classification in Category 1B for reproductive toxicity (developmental/ fertility)

Oral DNEL (fertility)

Dose descriptor

There is no data available in humans to fertility effects following repeated oral exposure to ferrocene. r laboratory animals relating to fertility effects following repeated inhalation exposure. Overall therefore, the NOAEL of 10mg/kg bw/day (fertility) from the oral reproduction/ developmental screening study on ferrocene will be used for the calculation of the fertility DNEL.

Mode-of-action

Ferrocene is considered to have only threshold effects, as the weight-of-evidence indicates that it does not possess genotoxic potential.

Modification of starting point

In the absence of any data to the contrary, the same bioavailability is assumed for humans and laboratory animals

Therefore, the starting point is10mg/kg/bw/day

General population exposure via the environment is assumed to be continuous (24h/day, 7day/wk)

ECHA AFs for general population – oral DNEL (fertility)

Uncertainty	AF	Justification for AF
Interspecies differences	4     2.5	Default ECHA AF for rat for toxicokinetic differences in metabolic rate (allometric scaling)
		Default ECHA AF for remaining toxicokinetic differences (not related to metabolic rate) and toxicodynamic differences
Intraspecies differences	10	Default ECHA AF for general population
Differences in duration of exposure	2	Default ECHA AF for positive result in a screening study
Dose response and endpoint specific/severity issues	2	ECHA AF; NOAEL for fertility in well-conducted to GLP screening study. Adverse effects seen at higher doses. . However as the positive result was seen in a screening study an higher AF has been applied
Quality of whole database	1	Default ECHA AF; health effects data are reliable and consistent, the available information meets the tonnage driven data requirements, and confidence in the database is high.
Overall AF for worker	400

 

General population -DNEL (long-term for oral route-systemic) = 10 (mg/kg/bw/day) / 400 =0.025mg/kg/bw/day. This oral DNEL(fertility) is lower than the oral DNEL for repeated dose effects (0.29 mg/kg bw/day), the long-term oral general population-DNEL for systemic effects

Inhalation DNEL (fertility)

 

Dose descriptor

There are no data available in humans or laboratory animals relating to fertility effects following repeated inhalation exposure. Overall therefore, the NOAEL of 10mg/kg bw/day (fertility) from the oral reproduction/ developmental screening study on ferrocene will be used for the calculation of the fertility DNEL.

Mode-of-action

Ferrocene is considered to have only threshold effects, as the weight-of-evidence indicates that it does not possess genotoxic potential.

Modification of starting point

In the absence of any data to the contrary, the same bioavailability is assumed for humans and laboratory animals.

Route-to-route extrapolation to calculate an inhalation DNEL (fertility) from oral studies was considered suitable.

As explained previously, a health precautionary approach is to assume 100% absorption following inhalation exposure. Therefore, the starting point has been corrected to reflect 40% oral absorption (Golberg, Martin, 1964) and 100% inhalation absorption.

Thus, 10 mg/kg bw/day / (100/40) =4mg/kg bw/day.

General population exposure via the environment is assumed to be continuous (24 h/day, 7 d/wk). The oral dose for the rat is converted to the corresponding air concentration using a standard breathing volume for the rat of 1.15 m³/kg bw/ day for 24 h/day. Thus 4mg/m³/ 1.15 m³/kg bw/ day =3.48mg/m³(24-h exposure of general population).

ECHA AFs for general population – inhalation DNEL (fertility)

Uncertainty	AF	Justification for AF
Interspecies differences	1     2.5	Allometric scaling already considered in correcting starting point above
		Default ECHA AF for remaining toxicokinetic differences (not related to metabolic rate) and toxicodynamic differences
Intraspecies differences	10	Default ECHA AF for general population
Differences in duration of exposure	2	Default ECHA AF for positive result in a screening study
Dose response and endpoint specific/severity issues	2	ECHA AF; NOAEL for fertility in well-conducted to GLP screening study. Adverse effects seen at higher doses. . However as the positive result was seen in a screening study an higher AF has been applied
Quality of whole database	1	Default ECHA AF; the health effects data are reliable and consistent, the available information meets the tonnage driven data requirements, and confidence in the database is high.
Overall AF for general population	100

General population-DNEL inhalation (fertility)long-term for inhaltion route-systemic= 3.48mg/m³/ 100 =0.035mg/m^3. This inhalation DNEL (fertility) is lower than the inhalation DNEL for repeated dose effects, the long-term inhalation general population-DNEL for systemic effects

Dermal DNEL (fertility)

Dose descriptor

There are no data available in humans or laboratory animals relating to fertility effects following repeated dermal exposure. Therefore, the NOAEL of 10mg/kg bw/day (fertility) from the oral reproduction/ developmental screening study on ferrocene will be used for the calculation of the fertility DNEL.

Mode-of-action

Ferrocene is considered to have only threshold effects, as the weight-of-evidence indicates that it does not possess genotoxic potential.

Modification of starting point

In the absence of any data to the contrary, the same bioavailability is assumed for humans and laboratory animals. Route-to-route extrapolation to calculate a dermal DNEL (fertility) from oral studies was considered suitable. In the absence of route-specific information on absorption the end route (dermal), a conservative assumption equal to the oral absorption will be made. Therefore, the starting point is 10mg/kg/bw/day.

General population exposure via the environment is assumed to be continuous (24 h/day, 7 d/wk). Only limited consumer exposure is expected.

ECHA AFs for general population – dermal DNEL (fertility)

Uncertainty	AF	Justification for AF
Interspecies differences	4     2.5	Default ECHA AF for rat for toxicokinetic differences in metabolic rate (allometric scaling)
		Default ECHA AF for remaining toxicokinetic differences (not related to metabolic rate) and toxicodynamic differences
Intraspecies differences	10	Default ECHA AF for general population
Differences in duration of exposure	2	ECHA AF for positive result in a screening study
Dose response and endpoint specific/severity issues	2	ECHA AF; NOAEL for fertility in a well-conducted to GLP screening study. Adverse effects seen at higher doses. . However as the positive result was seen in a screening study an higher AF has been applied
Quality of whole database	1	Default ECHA AF; the health effects data are reliable and consistent, the available information meets the tonnage driven data requirements, and confidence in the database is high.
Overall AF for general population	400

General population-DNEL (fertility)long-term for dermal route-systemic= 10 mg/kg bw/day / 400 =0.025mg/kg bw/day.

This dermal DNEL(fertility) is the lower than the dermal DNEL for repeated dose effects, the long-term dermal general population-DNEL for systemic effects (0.29mg/kg/bw/day)

Oral DNEL (development)

Dose descriptor

There is no data available in humans to development effects following repeated oral exposure to ferrocene. There is however data relating to laboratory animals relating to fertility effects following repeated oral exposure. Overall therefore, the NOAEL of 5mg/kg bw/day (development) from the oral reproduction/ developmental screening study on ferrocene will be used for the calculation of the fertility DNEL.

 

Mode-of-action

Ferrocene is considered to have only threshold effects, as the weight-of-evidence indicates that it does not possess genotoxic potential.

Modification of starting point

In the absence of any data to the contrary, the same bioavailability is assumed for humans and laboratory animals

Therefore, the starting point is5mg/kg/bw/day

General population exposure via the environment is assumed to be continuous (24h/day, 7day/wk). Only limited consumer exposure is expected.

ECHA AFs for general population – oral DNEL (development)

Uncertainty	AF	Justification for AF
Interspecies differences	4     2.5	Default ECHA AF for rat for toxicokinetic differences in metabolic rate (allometric scaling)
		Default ECHA AF for remaining toxicokinetic differences (not related to metabolic rate) and toxicodynamic differences
Intraspecies differences	10	Default ECHA AF for general population
Differences in duration of exposure	2	Default ECHA AF for positive result in a screening study
Dose response and endpoint specific/severity issues	2	ECHA AF; NOAEL for development in a well-conducted to GLP screening study. Adverse effects seen at higher doses. . However as the positive result was seen in a screening study an higher AF has been applied
Quality of whole database	1	Default ECHA AF; the human health effects data are reliable and consistent, the available information meets the tonnage driven data requirements, and confidence in the database is high
Overall AF for general population	400

General population-DNEL (development)long-term for oral route-systemic= 5mg/kg bw/day / 400 =0.013mg/kg bw/day.

Overall, as this oral DNEL(development) is lower than the oral DNEL for repeated dose effects (0.29mg/kg bw/day), the long-term oral general population-DNEL for systemic effects, and the oral DNEL(fertility), this DNEL will be used for protection against repeated oral exposure and fertility impairment.

Inhalation DNEL (development)

 

Dose descriptor

There are no data available in humans or laboratory animals relating to development effects following repeated inhalation exposure. Overall therefore, the NOAEL of 5mg/kg bw/day (development) from the oral reproduction/ developmental screening study on ferrocene will be used for the calculation of the fertility DNEL.

Mode-of-action

Ferrocene is considered to have only threshold effects, as the weight-of-evidence indicates that it does not possess genotoxic potential. 

Modification of starting point

In the absence of any data to the contrary, the same bioavailability is assumed for humans and laboratory animals.

Route-to-route extrapolation to calculate an inhalation DNEL (development) from oral studies was considered suitable.

As explained previously, a health precautionary approach is to assume 100% absorption following inhalation exposure. Therefore, the starting point has been corrected to reflect 40% oral absorption (Golberg, Martin, 1964) and 100% inhalation absorption.

Thus, 5mg/kg bw/day / (100/40) =2mg/kg bw/day.

General population exposure via the environment is assumed to be continuous (24 h/day, 7 d/wk). Only limited consumer exposure is expected. The oral dose for the rat is converted to the corresponding air concentration using a standard breathing volume for the rat of 1.15 m³/kg bw for 24 h/day.

Thus, 2mg/kg bw/day / 1.15 m³/kg bw/day= 1.74mg/m³(24-h exposure of the general population).

ECHA AFs for general population – inhalation DNEL (development)

Uncertainty	AF	Justification for AF
Interspecies differences	1       2.5	Default ECHA AF for rats for toxicokinetic differences in metabolic rate (allometric scaling); already considered in correcting starting point above
		Default ECHA AF for remaining toxicokinetic differences (not related to metabolic rate) and toxicodynamic differences
Intraspecies differences	10	Default ECHA AF for general population
Differences in duration of exposure	2	Default ECHA AF for positive result in a screening study
Dose response and endpoint specific/severity issues	2	ECHA AF; NOAEL for development in well-conducted to GLP screening study. Adverse effects seen at higher doses. . However as the positive result was seen in a screening study an higher AF has been applied
Quality of whole database	1	Default ECHA AF; the health effects data are reliable and consistent, the available information meets the tonnage driven data requirements, and confidence in the database is high.
Overall AF for general population	100

General population-DNEL (development)long-term for inhalation route-systemic= 1.74mg/m³/ 100 =0.017mg/m³.

Overall, as this inhalation DNEL(development) is higher than the inhalation DNEL for repeated dose effects (0.005mg/m³), the long-term inhalation general population-DNEL for systemic effects is considered protective of developmental effects.

Dermal DNEL (development)

Dose descriptor

There are no data available in humans or laboratory animals relating to development effects following repeated dermal exposure. Overall therefore, the NOAEL of 5mg/kg bw/day (development) from the oral reproduction/ developmental screening study on ferrocene will be used for the calculation of the development dermal DNEL.

 

Mode-of-action

Ferrocene is considered to have only threshold effects, as the weight-of-evidence indicates that it does not possess genotoxic potential.

 

Modification of starting point

In the absence of any data to the contrary, the same bioavailability is assumed for humans and laboratory animals. Route-to-route extrapolation to calculate a dermal DNEL (development) from oral studies was considered suitable.

In the absence of route-specific information on absorption the end route (dermal), a conservative assumption equal to the oral absorption will be made. Therefore, the starting point is 5mg/kg/bw/day. General population exposure via the environment is assumed to be continuous (24 h/day, 7 d/wk). Only limited consumer exposure is expected.

ECHA AFs for general population – dermal DNEL (development)

Uncertainty	AF	Justification for AF
Interspecies differences	4     2.5	Default ECHA AF for rat for toxicokinetic differences in metabolic rate (allometric scaling)
		Default ECHA AF for remaining toxicokinetic differences (not related to metabolic rate) and toxicodynamic differences
Intraspecies differences	10	Default ECHA AF for general population
Differences in duration of exposure	2	ECHA AF for positive result in a screening study
Dose response and endpoint specific/severity issues	2	ECHA AF; NOAEL for development in well-conducted to GLP screening study. Adverse effects seen at higher doses. . However as the positive result was seen in a screening study an higher AF has been applied
Quality of whole database	1	Default ECHA AF; the health effects data are reliable and consistent, the available information meets the tonnage driven data requirements, and confidence in the database is high.
Overall AF for general population	400

General population-DNEL (development)long-term for dermal route-systemic= 5mg/kg bw/day / 400 =0.013mg/kg bw/day.

Overall, as this oral DNEL(development) is lower than the dermal DNEL for repeated dose effects (0.29mg/kg bw/day), the long-term dermal general population-DNEL for systemic effects, and the dermal DNEL(fertility), so this DNEL will be used for protection against repeated oral exposure and fertility impairment.

Workers

Acute toxicity

No acute toxicity data in humans is available. Animal data is however available. In a study performed to OECD guideline 401, Ferrocene had an LD50 1320mg/kg bw. In a study performed to OECD guideline 402, Ferrocene had an NOEC 3000mg/kg bw. Based on the available data, Ferrocene is classified as harmful by acute oral exposure but not by dermal routes according to the EU CLP or DSD regulations and is classified. DNELs for acute toxicity should be derived if an acute toxicity hazard has been identified, leading to classification and labelling and there is a potential for high peak exposures (this is only usually relevant for inhalation exposures). a DNEL’s calculations for acute toxicity are unnecessary as the long-term DNEL for systemic effects is expected to be sufficient to ensure that adverse effects do not occur. Consequently, no worker-DNEL’s for acute toxicity have been calculated.

Irritation/ corrosivity

In a reliable study performed to OECD Guideline 404, Ferrocene is non-irritating on the skin of male rabbits. This is based on the irritation index value of 0.5. In a reliable study performed to OECD Guideline 405, Ferrocene is non-irritating for the eye and ocular mucosa of a rabbit. This is based on the overall score of 0.02 There is no data in relation to respiratory tract irritation in humans or laboratory animals. However, due to its low skin and eye irritation potential, it is unlikely that Ferrocene would cause such an effect. Based on the available data, Ferrocene would not be classified as an eye, skin or respiratory tract irritant under the EU CLP or DSD regulations. Acute and repeated dose toxicity studies, where available, provide no relevant (dose-response) information for irritant or corrosive effects. Consequently, no worker-DNEL for irritation/ corrosivity has been calculated.

Sensitisation

One good quality study is available for skin sensitisation of Ferrocene. In a study performed to OECD Guideline 406, Ferrocene was found to be non-sensitising (Innospec, 1987)

There are no data relating to respiratory tract sensitisation in humans or laboratory animals. However, due to the lack of sensitisation on Ferrocene on the skin it’s unlikely that it would cause any respiratory sensitisation.

Oral DNEL (repeated dose toxicity)

Not considered applicable for workers.

Inhalation DNEL (repeated dose toxicity, systemic effects)

Dose descriptor

There is no data available in humans relating to repeated inhalation exposure to ferrocene. However, studies have investigated the repeated dose inhalation toxicity of ferrocene in rodents and this has allowed the identification of the lowest, relevant LOAEC of 3mg/m3 from a reliable 90day study in rats (Nikula, 1993).

 Mode-of-action

Ferrocene is considered to have only threshold effects, as the weight-of-evidence indicates that it does not possess genotoxic potential.

 Modification of starting point

In the absence of any data to the contrary, the same bioavailability is assumed for humans and laboratory animals.

Workers are assumed to be exposed for 8 h/day.

Converting rat inhalation data to a corresponding air exposure in the human worker is required. The inhalation dose for the rat is converted to the corresponding air concentration using a standard breathing volume for the human worker and to account for the presumed light activity of workers, this value is corrected for an increase in breathing volume.

Thus 3mg/m³x ((6h/8h) x (6.7m³/ 10m³)) =1.51 mg/m³(8-h exposure of workers, light activity).

 

ECHA AFs for workers – inhalation DNEL (repeated dose toxicity, systemic effects)

Uncertainty	AF	Justification for AF
Interspecies differences	1     2.5	Allometric scaling already considered in correcting starting point above
		Default ECHA AF for remaining toxicokinetic differences (not related to metabolic rate) and toxicodynamic differences
Intraspecies differences	5	Default ECHA AF for (healthy) worker
Differences in duration of exposure	2	Default ECHA AF for subchronic (90-day) exposure
Dose response and endpoint specific/ severity issues	3	Default ECHA AF; human health relevant LOAEC from peer-reviewed well-conducted 90day inhalation study.
Quality of whole database	1	Default ECHA AF; the health effects data are reliable and consistent, the available information meets the tonnage driven data requirements, and confidence in the database is high.
Overall AF for worker	75

 

Worker (light activity) - DNEL (long-term for inhalation route-systemic) = 1.51 (mg/m³) / 75 =0.02mg/m³

Dermal DNEL(repeated dose toxicity, systemic effects)

Dose descriptor

There is no data available in humans or laboratory animals relating to repeated dermal exposure to ferrocene.

Therefore, the use of the repeated dose oral data will be considered. Several studies have investigated the repeated dose oral toxicity of ferrocene and this has allowed the identification of the lowest, relevant LOAEL of 30mg/kg bw/day from a reliable peer reviewed 180day dietary study of ferrocene in dogs (Yeary, 1969).

 

Mode-of-action

Ferrocene is considered to have only threshold effects, as the weight-of-evidence indicates that it does not possess genotoxic potential.

 

Modification of starting point

In the absence of any data to the contrary, the same bioavailability is assumed for humans and laboratory animals.

As no relevant study data on effects of repeated dermal exposure to ferrocene humans or laboratory animals are available, route-to-route extrapolation to calculate a dermal DNEL from repeated dose oral toxicity studies was considered a suitable alternative.

In the absence of route-specific information on absorption the end route (dermal), a cautionary assumption of dermal absorption equal to the oral absorption will be made. Therefore, the starting point is30mg/kg/bw/day.

Workers are assumed to be exposed for 8 h/day.

 

ECHA AFs for workers – dermal DNEL (repeated dose toxicity)

Uncertainty	AF	Justification for AF
Interspecies differences	1.4     2.5	Default ECHA AF for dog for toxicokinetic differences in metabolic rate (allometric scaling)
		Default ECHA AF for remaining toxicokinetic differences (not related to metabolic rate) and toxicodynamic differences
Intraspecies differences	5	Default ECHA AF for (healthy) worker
Differences in duration of exposure	1	Default ECHA AF for chronic (180day) exposure
Dose response and endpoint specific/severity issues	3	Default ECHA AF; human health relevant LOAEL from a peer reviewed well-conducted 180day dietary study.
Quality of whole database	1	Default ECHA AF; the human health effects data are reliable and consistent, the available information meets the tonnage driven data requirements, and confidence in the database is high
Overall AF for worker	52.5

 

Worker-DNEL (long-term for dermal route-systemic) = 30mg/kg bw/day / 52.5 =0.57mg/kg bw/day

Genotoxicity

In Vitro: there are 8 studies in the dossier; 4 AMES, 2 gene mutation mouse lymphoma assay (MLA) and 2 Chromosome abberations are included. In Vivo; there are 2 studies in the dossier; a mammalian erthrocyte micronucleus test and a Drosophila SLRL and reciprocal translocation tests

Under the REACh testing strategy the 3 test in vitro test battery is required. Adequate negative AMES data addresses the bacterial gene mutation end point. A recent MLA study conducted in accordance with the relevant OECD guidance and published recommendations, confirms a lack of mammalian gene mutation potential. No acceptable in vitro cytogenicity data has been generated, but the negative data from the in vivo mouse bone marrow micronucleus study is seen as an adequate substitute.

Therefore, given the available data under the requirements of REACh it is concluded that ferrocene is devoid of any genotoxic potential. Under EU CLP and DSD regulations, ferrocene would not be classified as mutagenic. Consequently, no worker-DN(M)ELs for genotoxicity have been calculated.

 

Reproductive toxicity (fertility impairment and developmental toxicity)

 

Fertility DNEL

No information is available on fertility effects of ferrocene in humans.

Ferrocene was assessed to investigate the systemic toxicity and its potential adverse effects on reproduction (including offspring development). The study was performed according to OECD Guideline 422. As effects of treatment were apparent at dosages as low as 5 mg/kg bw/day it was not possible to establish a No Observed Effect Level (NOEL) for systemic toxicity. A dosage of 10 mg/kg bw/day was considered to be a No Observed Adverse Effect Level (NOAEL) effects on fertility, with a LOAEL of 25mg/kg bw/day.

Development DNEL

The study also assessed Ferrocene and the potential for adverse effects on reproduction (including offspring development). As effects of treatment were apparent at dosages as low as 5 mg/kg bw/day it was not possible to establish a No Observed Effect Level (NOEL) for systemic toxicity. The study acheieved a NOAEL for offspring survival, growth and development of 5mg/kg bw/day

There is clear indication of developmental toxicity in the ferrocene study and there is also evidence for concern on fertility. This concern is considered sufficient enough to trigger classification in Category 1B for reproductive toxicity (developmental/ fertility

 

Inhalation DNEL (fertility)

 

Dose descriptor

There are no data available in humans or laboratory animals relating to fertility effects following repeated inhalation exposure. Overall therefore, the NOAEL of 10mg/kg bw/day (fertility) from the oral reproduction/ developmental screening study on ferrocene will be used for the calculation of the fertility DNEL.

 Mode-of-action

Ferrocene is considered to have only threshold effects, as the weight-of-evidence indicates that it does not possess genotoxic potential.

 Modification of starting point

In the absence of any data to the contrary, the same bioavailability is assumed for humans and laboratory animals.

Route-to-route extrapolation to calculate an inhalation DNEL (fertility) from oral studies was considered suitable.

As explained previously, a health precautionary approach is to assume 100% absorption following inhalation exposure

Therefore, the starting point has been corrected to reflect 40% oral absorption (Golberg, Martin, 1964) and 100% inhalation absorption.

Thus, 10 mg/kg bw/day / (100/40) =4mg/kg bw/day.

 

Workers are assumed to be exposed for 8 h/day.

The dose for the rat is converted to the corresponding air concentration, using a standard breathing volume for the rat, of 0.38 m³/kg bw for 8 h/day (exposure of workers). To account for the presumed light activity of workers, this value has been corrected for an increase in breathing volume.

Thus (4mg/kg bw/day / 0.38 m³/kg bw/day) x 0.67 m³=7.05mg/m³(8-h exposure of workers, light activity).

 

ECHA AFs for workers – inhalation DNEL (fertility)

Uncertainty	AF	Justification for AF
Interspecies differences	1     2.5	Allometric scaling already considered in correcting starting point above
		Default ECHA AF for remaining toxicokinetic differences (not related to metabolic rate) and toxicodynamic differences
Intraspecies differences	5	Default ECHA AF for (healthy) worker
Differences in duration of exposure	2	ECHA AF for positive result in a screening study
Dose response and endpoint specific/severity issues	2	ECHA AF; NOAEL for fertility in well-conducted to GLP screening study. Adverse effects seen at higher doses. . However as the positive result was seen in a screening study an higher AF has been applied
Quality of whole database	1	Default ECHA AF; the health effects data are reliable and consistent, the available information meets the tonnage driven data requirements, and confidence in the database is high
Overall AF for worker	50

 Worker (light activity)-DNEL (fertility)long-term for inhalation route-systemic= 7.05 mg/m³/ 50 =0.14mg/m³

 

This inhalation DNEL(fertility) is higher than the inhalation DNEL for repeated dose effects (0.02mg/m³), the long-term inhalation worker-DNEL for systemic effects. That DNEL is therefore considered protective against fertility impairment in workers.

Dermal DNEL (fertility)

Dose descriptor

There are no data available in humans or laboratory animals relating to fertility effects following repeated dermal exposure. Therefore, the NOAEL of 10mg/kg bw/day (fertility) from the oral reproduction/ developmental screening study on ferrocene will be used for the calculation of the dermal fertility DNEL.

 Mode-of-action

Ferrocene is considered to have only threshold effects, as the weight-of-evidence indicates that it does not possess genotoxic potential.

 Modification of starting point

In the absence of any data to the contrary, the same bioavailability is assumed for humans and laboratory animals. Route-to-route extrapolation to calculate a dermal DNEL (fertility) from oral studies was considered suitable.

In the absence of route-specific information on absorption the end route (dermal), a conservative dermal absorption assumption equal to the oral absorption will be made. Therefore, the starting point is 10mg/kg/bw/day. Workers are assumed to be exposed for 8 h/day.

ECHA AFs for workers – dermal DNEL (fertility)

Uncertainty	AF	Justification for AF
Interspecies differences	4     2.5	Default ECHA AF for rat for toxicokinetic differences in metabolic rate (allometric scaling)
		Default ECHA AF for remaining toxicokinetic differences (not related to metabolic rate) and toxicodynamic differences
Intraspecies differences	5	Default ECHA AF for (healthy) worker
Differences in duration of exposure	2	ECHA AF for positive result in a screening study
Dose response and endpoint specific/severity issues	2	ECHA AF; NOAEL for fertility in well-conducted to GLP screening study. Adverse effects seen at higher doses. . However as the positive result was seen in a screening study an higher AF has been applied
Quality of whole database	1	Default ECHA AF; the health effects data are reliable and consistent, the available information meets the tonnage driven data requirements, and confidence in the database is high
Overall AF for worker	200

Worker-DNEL (fertility)long-term for dermal route-systemic= 10 mg/kg bw/day / 200 =0.05mg/kg bw/day This dermal DNEL(fertility) is lower than the dermal DNEL for repeated dose effects (0.57mg/kg bw/day), the long-term dermal worker-DNEL for systemic effects.

Inhalation DNEL (development)

 

Dose descriptor

There are no data available in humans or laboratory animals relating to development effects following repeated inhalation exposure. Overall therefore, the NOAEL of 5mg/kg bw/day (development) from the oral reproduction/ developmental screening study on ferrocene will be used for the calculation of the development inhalation DNEL.

 

Mode-of-action

Ferrocene is considered to have only threshold effects, as the weight-of-evidence indicates that it does not possess genotoxic potential.

Modification of starting point

In the absence of any data to the contrary, the same bioavailability is assumed for humans and laboratory animals. Route-to-route extrapolation to calculate an inhalation DNEL (development) from oral studies is suitable.

As explained previously, a health precautionary approach is to assume 100% absorption following inhalation exposure. Therefore, the starting point has been corrected to reflect 40% oral absorption (Golberg, Martin, 1964) and 100% inhalation absorption.

Thus, 5mg/kg bw/day / (100/40) =2mg/kg bw/day.

 Workers are assumed to be exposed for 8 h/day.

 

The oral dose for the rat is converted to the corresponding air concentration, using a standard breathing volume for the rat, of 0.38 m³/kg bw for 8 h/day (exposure of workers). To account for the presumed light activity of workers, this value has been corrected for an increase in breathing volume.

Thus (2mg/kg bw/day / 0.38 m³/kg bw/day) x 0.67 m³=3.53mg/m³(8-h exposure of workers, light activity).

 

ECHA AFs for workers – inhalation DNEL (development)

Uncertainty	AF	Justification for AF
Interspecies differences	1     2.5	Allometric scaling already considered in correcting starting point above
		Default ECHA AF for remaining toxicokinetic differences (not related to metabolic rate) and toxicodynamic differences
Intraspecies differences	5	Default ECHA AF for (healthy) worker
Differences in duration of exposure	2	ECHA AF for positive result in a screening study
Dose response and endpoint specific/severity issues	2	ECHA AF; NOAEL for development in a well-conducted to GLP screening study. Adverse effects seen at higher doses. . However as the positive result was seen in a screening study an higher AF has been applied
Quality of whole database	1	Default ECHA AF; the health effects data are reliable and consistent, the available information meets the tonnage driven data requirements, and confidence in the database is high
Overall AF for worker	50

 

Worker (light activity)-DNEL (development)long-term for inhalation route-systemic= 3.53mg/m³/ 50 =0.07mg/m³

 Overall, this inhalation DNEL (development) is higher than the inhalation DNEL for repeated dose effects (0.02mg/m³), the long-term inhalation worker-DNEL for systemic effects. That DNEL is therefore considered protective against development toxicity in workers.

Dermal DNEL (development)

Dose descriptor

There are no data available in humans or laboratory animals relating to development effects following repeated dermal exposure. Therefore, the NOAEL of 5mg/kg bw/day (development) from the oral reproduction/ developmental screening study on ferrocene will be used for the calculation of the development dermal DNEL.

 Mode-of-action

Ferrocene is considered to have only threshold effects, as the weight-of-evidence indicates that it does not possess genotoxic potential.

 Modification of starting point

In the absence of any data to the contrary, the same bioavailability is assumed for humans and laboratory animals. Route-to-route extrapolation to calculate a dermal DNEL (development) from oral studies was considered suitable. In the absence of route-specific information on absorption of the end route (dermal), a conservative assumption equal to the oral absorption will be made.

Therefore, the starting point is 5mg/kg/bw/day. Workers are assumed to be exposed for 8 h/day.

ECHA AFs for workers – dermal DNEL (development)

Uncertainty	AF	Justification for AF
Interspecies differences	4     2.5	Default ECHA AF for rat for toxicokinetic differences in metabolic rate (allometric scaling)
		Default ECHA AF for remaining toxicokinetic differences (not related to metabolic rate) and toxicodynamic differences
Intraspecies differences	5	Default ECHA AF for (healthy) worker
Differences in duration of exposure	2	ECHA AF for positive result in a screening study
Dose response and endpoint specific/severity issues	2	ECHA AF; NOAEL for development in well-conducted to GLP screening study. Adverse effects seen at higher doses. . However as the positive result was seen in a screening study an higher AF has been applied
Quality of whole database	1	Default ECHA AF; the health effects data are reliable and consistent, the available information meets the tonnage driven data requirements, and confidence in the database is high
Overall AF for worker	200

Worker-DNEL (development)long-term for dermal route-systemic= 5 mg/kg bw/day / 200 =0.025mg/kg bw/day

Overall, as this dermal DNEL(development) is lower than the long-term dermal worker-DNEL (fertility) (0.05mg/kg bw/day) and more than the dermal DNEL for repeated dose effects (0.57mg/kg bw/day), the long-term dermal worker-DNEL for systemic effects, this DNEL will be used for protection against repeated dose dermal exposure.