Fenamiphos

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.023 mg/m³

Most sensitive endpoint:

neurotoxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

12.5

Dose descriptor starting point:

NOAEL

Value:

0.083 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

0.29 mg/m³

Explanation for the modification of the dose descriptor starting point:

Standard human bodyweight: 70 kg

 

Allometric scaling factor (ASF) dog: 1.4

 

Worker respiratory volume (wRV) for 8 hours with light physical activity per person: 10 m³

 

Oral absorption of the dog/ inhalation absorption of humans (ABS oral-dog / ABS inh.-human): 1/2

No correction for oral absorption is indicated as the test substance was shown to be completely absorbed from the gastro-intestinal tract (section 7.1). For inhalation absorption of humans a default value according to ECHA Guidance R.8 Dose- or concentration-response characterisation (2012) is used.

 

Correction for difference between human and experimental exposure conditions: 7 d dog/5 d worker

 

 

Corrected NOAEC (inhalation) for workers:

 

NOAECcorr = NOAELoral /ASF x 70 kg/10 m³ x 7d/5d x ABSoral/ABSinh

 

NOAECcorr = 0.083 mg/kg bw/day / 1.4 x 70 kg / 10m³ x 7d / 5d x ½

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

1

Justification:

As a dose descriptor starting point is used from a chronic repeated dose toxicity study, no further extrapolation regarding duration is required.

AF for interspecies differences (allometric scaling):

1

Justification:

An assessment factor for allometric scaling has already been used for the modification of the dose descriptor starting point (NOAEC). No additional allometric scaling factor is required.

AF for other interspecies differences:

2.5

Justification:

The recommended AF for other interspecies differences is applied.

AF for intraspecies differences:

5

Justification:

The default value for the relatively homogenous group "worker" is used.

AF for the quality of the whole database:

1

Justification:

The chronic toxicity study according to OECD No. 452 is considered to be conducted according to regulatory standards and not considered to contribute to uncertainty, hence it is not necessary to apply an additional factor.

AF for remaining uncertainties:

1

Justification:

DNEL Derivation is considered conservative, reflecting reasonable worst case assumptions. Therefore, no further AF for remaining uncertainties is applied.

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.53 mg/m³

Most sensitive endpoint:

neurotoxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

12.5

Dose descriptor starting point:

NOAEL

Value:

0.25 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

6.64 mg/m³

Explanation for the modification of the dose descriptor starting point:

Standard human bodyweight: 70 kg

 

Allometric scaling factor (ASF) dog: 1.4

 

Correction for difference between human and experimental exposure conditions: 1

 

Worker respiratory volume (wRV) for 15 min: 0.31 m³

 

Oral absorption of the dog/ inhalation absorption of humans (ABS oral-dog / ABS inh.-human): 1/2

No correction for oral absorption is indicated as the test substance was shown to be completely absorbed from the gastro-intestinal tract (section 7.1). For inhalation absorption of humans a default value according to ECHA Guidance R.8 Dose- or concentration-response characterisation (2012) is used.

 

Corrected NOAEC (inhalation) for workers:

 

NOAECcorr = NOAELoral /ASF x  70 kg / 0.31 m³ x ABSoral/ABSinh

 

NOAECcorr = 0.083 mg/kg bw/day / 1.4 x 70 kg / 0.31 m³ x ½

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for interspecies differences (allometric scaling):

1

Justification:

An assessment factor for allometric scaling has already been used for the modification of the dose descriptor starting point (NOAEC). No additional allometric scaling factor is required.

AF for other interspecies differences:

2.5

Justification:

The recommended AF for other interspecies differences is applied.

AF for intraspecies differences:

5

Justification:

The default value for the relatively homogenous group "worker" is used.

AF for the quality of the whole database:

1

Justification:

The acute neurotoxicity study is considered to be conducted according to regulatory standards and not considered to contribute to uncertainty, hence it is not necessary to apply an additional factor.

AF for remaining uncertainties:

1

Justification:

DNEL Derivation is considered conservative, reflecting reasonable worst case assumptions. Therefore, no further AF for remaining uncertainties is applied.

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

skin irritation/corrosion

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

skin irritation/corrosion

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.664 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

17.5

Dose descriptor starting point:

NOAEL

Value:

0.083 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

11.62 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Oral absorption of the dog/ dermal absorption of humans (ABS oral-dog / ABS derm-human): 1/0.01

The human dermal absorption of 1% based on an in vitro model as given in the EFSA conclusion (2019) is used in the following calculation. No correction for oral absorption is indicated as the test substance was shown to be completely absorbed from the gastro-intestinal tract (section 7.1).

 

Correction for difference between human and experimental exposure conditions: 7 d dog/5 d worker

 

Corrected NOAEL (dermal) for workers:

 

NOAELcorr = NOAELoral x 7d/5d x ABSoral/ABSderm

 

NOAELcorr = 0.083 mg/kg bw/day x 7d/5d x 1/0.01

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

1

Justification:

As a dose descriptor starting point is used from a chronic repeated dose toxicity study, no further extrapolation regarding duration is required.

AF for interspecies differences (allometric scaling):

1.4

Justification:

The default allometric scaling factor for the differences between dogs and humans is applied.

AF for other interspecies differences:

2.5

Justification:

The recommended AF for other interspecies differences is applied. The recommended AF for other interspecies differences is applied.

AF for intraspecies differences:

5

Justification:

The default value for the relatively homogenous group "worker" is used.

AF for the quality of the whole database:

1

Justification:

The chronic toxicity study according to OECD No. 452 is considered to be conducted according to regulatory standards and not considered to contribute to uncertainty, hence it is not necessary to apply an additional factor.

AF for remaining uncertainties:

1

Justification:

DNEL Derivation is considered conservative, reflecting reasonable worst case assumptions. Therefore, no further AF for remaining uncertainties is applied.

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.43 mg/kg bw/day

Most sensitive endpoint:

neurotoxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

17.5

Dose descriptor starting point:

NOAEL

Value:

0.25 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

25 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Oral absorption of the dog/ dermal absorption of humans (ABS oral-dog / ABS derm-human): 1/0.01

The human dermal absorption of 1% based on an in vitro model as given in the EFSA conclusion (2019) is used in the following calculation. No correction for oral absorption is indicated as the test substance was shown to be completely absorbed from the gastro-intestinal tract (section 7.1).

 

Correction for difference between human and experimental exposure conditions: 1

 

Corrected NOAEL (dermal) for workers:

 

NOAELcorr = NOAELoral x ABSoral/ABSderm

 

NOAELcorr = 0.25 mg/kg bw/day x 1/0.01

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for interspecies differences (allometric scaling):

1.4

Justification:

The default allometric scaling factor for the differences between dogs and humans is applied.

AF for other interspecies differences:

2.5

Justification:

The recommended AF for other interspecies differences is applied.

AF for intraspecies differences:

5

Justification:

The default value for the relatively homogenous group "worker" is used.

AF for the quality of the whole database:

1

Justification:

The acute neurotoxicity study is considered to be conducted according to regulatory standards and not considered to contribute to uncertainty, hence it is not necessary to apply an additional factor.

AF for remaining uncertainties:

1

Justification:

DNEL Derivation is considered conservative, reflecting reasonable worst case assumptions. Therefore, no further AF for remaining uncertainties is applied.

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

sensitisation (skin)

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

sensitisation (skin)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

low hazard (no threshold derived)

Additional information - workers

Systemic long-term DNEL for inhalation exposure

The respective NOAEC is based on a NOAEL of 0.083 mg/kg bw/day from a chronic oral dog (1 year feeding) study according to OECD No. 452, considering an oral bioavailability of 100%. No correction for oral absorption is indicated as the test substance was shown to be completely absorbed from the gastro-intestinal tract (section 7.1). It was modified using a standard human bodyweight of 70 kg, an allometric scaling factor (ASF) for the dog of 1.4, a worker respiratory volume (wRV) of 10 m³ for 8 hours with light physical activity, the default quotient of ½ for oral absorption of the rat and inhalation absorption of humans (ABS oral-rat / ABS inh-human) and a correction for difference between human and experimental exposure conditions (7 days exposure of the rats/5 days exposure of worker per week) to 0.29 mg/m³ using the equation provided in the Guidance Document on Information Requirement, Chapter R8:

NOAECcorr = NOAELoral /ASF x 70 kg/10 m³ x 7d/5d x ABSoral/ABSinh

Using assessment factors of (i) 2.5 for remaining species differences and (ii) 5 for intraspecies extrapolation, a DNEL of 0.023 mg/m³ for long-term, systemic inhalative exposure was calculated.

 

Systemic acute DNEL for inhalation exposure

In an acute inhalation toxicity study, the LC50 was 65 – 79 mg/m³ for 4 h (aerosol) exposure in male and female rats. Therefore, hazard could be identified and the determination of a DNEL for acute inhalation toxicity triggered. The DNEL was derived on the basis of an acute oral neurotoxicity study covering the test substance’s most relevant adverse effect (erythrocyte ChE inhibition) with a NOAEL of 0.25 mg/kg bw/d, considering an oral bioavailability of 100% (no correction for oral absorption is indicated as the test substance was shown to be completely absorbed from the gastro-intestinal tract (section 7.1)), and in accordance with ECHA Guidance R.8 Dose- or concentration-response characterisation (2012). The NOAEL was modified using a standard human bodyweight of 70 kg, an allometric scaling factor (ASF) for the dog of 1.4, a worker respiratory volume (wRV) of 0.31 m³ for 15 min with light physical activity and the default quotient of ½ for oral absorption of the rat and inhalation absorption of humans (ABS oral-rat / ABS inh-human) to 6.64 mg/m³ using the equation provided in the Guidance Document on Information Requirement, Chapter R8:

NOAECcorr = NOAELoral /ASF x  70 kg / 0.31 m3 x ABSoral/ABSinh

Using assessment factors of (i) 2.5 for remaining species differences and (ii) 5 for intraspecies extrapolation, a DNEL of 0.53 mg/m³ for acute systemic inhalation exposure was calculated.

 

Local long-term and acute DNELs for inhalation exposure

No study on respiratory irritation is available, but, due to the negative outcomes in in vitro skin irritation and no indication of respiratory irritation in available in vivo acute and subacute toxicity inhalation studies, long-term and acute local effects in the respiratory tract are not expected.

 

Systemic long-term DNEL for dermal exposure

The NOAEL of 0.083 mg/kg bw/day from a chronic oral dog (1 year feeding) study according to OECD No. 452 was used as POD, considering an oral bioavailability of 100%. No correction for oral absorption is indicated as the test substance was shown to be completely absorbed from the gastro-intestinal tract (section 7.1). The human dermal absorption of 1% based on an in vitro model as given in EFSA conclusion (2019) was used.

The POD was modified using a correction for difference between human and experimental exposure conditions (7 days exposure of the rats/5 days exposure of worker per week) and a dermal absorption of 1% to 11.62 mg/kg bw/day using the equation provided in the Guidance Document on Information Requirement, Chapter R8:

NOAEL_corr = NOAEL_dermal x 7d/5d x ABSoral/ABSdermal

Using assessment factors of (i) 14 for interspecies differences (allometric scaling), (ii) 2.5 for remaining interspecies differences and (iii) 5 for intraspecies extrapolation, a DNEL of 0.664 mg/kg bw/day for long-term, systemic dermal exposure was calculated.

 

Systemic acute DNEL for dermal exposure

In an acute dermal toxicity study, the dermal LD50 was 72 – 92 mg/kg bw in male and female rats. Therefore, hazard could be identified and the determination of a DNEL for acute dermal toxicity triggered. The DNEL was derived on the basis of an acute oral neurotoxicity study covering the test substance’s most relevant adverse effect (erythrocyte ChE inhibition) with a NOAEL of 0.25 mg/kg bw/d, considering an oral bioavailability of 100%, and in accordance with ECHA Guidance R.8 Dose- or concentration-response characterisation (2012). No correction for oral absorption is indicated as the test substance was shown to be completely absorbed from the gastro-intestinal tract (section 7.1). The human dermal absorption of 1% based on an in vitro model as given in EFSA conclusion (2019) was used. The NOAEL was modified using the dermal absorption of 1% to 25 mg/kg bw/d with the equation provided in the Guidance Document on Information Requirement, Chapter R8:

NOAELcorr = NOAELoral x ABSoral/ABSderm

Using assessment factors of (i) 2.5 for remaining species differences and (ii) 5 for intraspecies extrapolation and (iii) for allometric scaling of 1.4, a DNEL of 1.43 mg/kg bw/d for acute systemic dermal exposure was calculated.

 

Local long-term and acute DNELs for dermal exposure

No hazards were identified in skin sensitisation and skin irritation studies. Thus, long-term and acute local dermal effects are not likely to occur.

 

Hazard to the eyes:

The test item is classified as eye damage Cat. 2. according to Regulation (EC) No 1272/2008 (CLP) and associated to the low hazard band. A qualitative risk assessment is conducted.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

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

Acute/short term exposure

Hazard assessment conclusion:

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

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

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

Acute/short term exposure

Hazard assessment conclusion:

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

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

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

Acute/short term exposure

Hazard assessment conclusion:

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

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

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

Acute/short term exposure

Hazard assessment conclusion:

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

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

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

Acute/short term exposure

Hazard assessment conclusion:

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

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

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