Paraquat-dichloride

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

86.4 µg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

25

Dose descriptor starting point:

NOAEL

Value:

0.45 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

2.16 mg/m³

Explanation for the modification of the dose descriptor starting point:

The substance fulfils the REACH Annex VII to Annex X information requirements in accordance with ECHA guidance R7.5-7.7 (2016) for assessing long-term systemic toxicity. Since no repeated dose inhalation study is available, route-to-route extrapolation from the oral exposure route is performed. The starting point is the NOAEL from the 1-year feeding study in dogs; 15 ppm, equivalent to 0.45 mg/kg bw/day. This effect level is for the test substance cation species. The recalculated effect level for the pure test substance is (100/72.4) * 0.45 = 0.62 mg/kg bw/day. This oral dog NOAEL is converted to an inhalation NOAEC for dogs by using a default respiratory volume for the dog corresponding to 8 hours (sRVDog = 0.2 * 1.4 = 0.28 L/min/kg bw, adjustment for 8 hour worker exposure is 0.28 L/min/kg bw * 60 min * 8 hours = 134.4 L/kg bw = 0.1344 m3/kg bw). A factor for route-to-route extrapolation is included based on the default absorption values (R.7.12. June 2017). The resulting dog inhalation NOAEC is converted into inhalation worker NOAEC by correction for respiratory rate based on activity (6.7 m3 for normal light activity versus 10 m3 for worker activity) and by correction for 5 day exposure (7 days exposure per week in the study versus 5 days per week for workers): 0.62 * (1/0.1344) * (50/100) * (6.7/10) * (7/5) = 2.16 mg/m3.

AF for dose response relationship:

1

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose-response for human health, for the dose-response relationship, consideration should be given to the uncertainties in the dose descriptor (NOAEL, benchmark dose,…) as the surrogate for the true no-adverse-effect-level (NAEL). In this case the starting point for the DNEL calculation is a NOAEL, derived from a study which is of good quality and without uncertainties. Therefore the default assessment factor, as a standard procedure, is 1.

AF for differences in duration of exposure:

2

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose-response for human health, a factor allowing for differences in the experimental exposure duration and the duration of exposure for the worker and scenario under consideration needs to be considered taking into account that a) in general the experimental NOAEL will decrease with increasing exposure times and b) other and more serious adverse effects may appear with increasing exposure times. Consequently, to end up with the most conservative DNEL for repeated dose toxicity, chronic exposure is the ‘worst case’. For a sub-chronic toxicity study, an assessment factor of 2 is to be applied, as a standard procedure.

AF for interspecies differences (allometric scaling):

1

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose-response for human health, as long as route-to-route extrapolation is not needed, allometric scaling should not be applied in cases where the dose unit (original or transformed) in experimental animal studies are expressed as concentrations (e.g. in mg/m³ air, ppm in diet, or mg/L in the drinking water) as these are assumed to be already scaled according to the allometric principle, since ventilation rate and food intake directly depend on the basal metabolic rate. In this case, route-to-route extrapolation is performed form an oral feeding study. The derived NOAEL is modified according to allometric principles to a NOAEC (mg/m³), therefore additional assessment factor for allometric scaling is not needed.

AF for other interspecies differences:

2.5

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose-response for human health, interspecies differences result from variation in the sensitivity of species due to differences in toxicokinetics and toxicodynamics. Some of the toxicokinetic differences can be explained by differences in body size (and related differences in basal metabolic rate). As no substance-specific data are available, the standard procedure for threshold effects is followed. As a default, an additional factor of 2.5 for interspecies differences (other than allometric scaling), i.e. toxicokinetic differences not related to metabolic rate (small part) and toxicodynamic differences (larger part) is applied.

AF for intraspecies differences:

5

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose-response for human health, intraspecies differences in human result from a multitude of biological factors such as genetic polymorphism affecting e.g. toxicokinetics/metabolism, age, gender, health status and nutritional status. For workers, as standard procedure for threshold effects a default assessment factor of 5 is to be used, based on the fact that this sub population does not cover the very young, the very old, and the very ill.

AF for the quality of the whole database:

1

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose-response for human health, the evaluation of the total toxicological database should include an assessment whether the available information as a whole meets the tonnage driven data requirements necessary to fulfil the REACH requirements, or whether there are data gaps (completeness of the database). Furthermore, the hazard data should be assessed for the reliability and consistency across different studies and endpoints and taking into account the quality of the testing method, size and power of the study design, biological plausibility, dose-response relationships and statistical association (adequacy of the database). When taking into account the standard information requirements and the completeness and consistency of the database the default assessment factor of 1, to be applied for good/standard quality of the database, is recommended.

AF for remaining uncertainties:

1

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose-response for human health, there are no remaining uncertainties. Since there are no further uncertainties, the default assessment factor of 1, to be applied for good/standard quality of the database, is recommended.

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

259.2 µg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

1

DNEL extrapolated from long term DNEL

Explanation for the modification of the dose descriptor starting point:

The substance fulfils the REACH Annex VII to Annex X information requirements in accordance with ECHA guidance R7.5-7.7 (2016) for acute toxicity. The substance is classified as acute toxicant category 1 (H330). According to the REACH guideline (R8, Appendix R 8-8, November, 2012), a DNEL for acute toxicity should be derived if an acute toxicity hazard (leading to C&L) has been identified and there is a potential risk for high peak exposures. For workers, there are risks for peak exposures, hence an acute DNEL is derived.

Setting a DNEL based on the lethality data involves too large uncertainties, therefore the long-term inhalation DNEL will be used as starting point for deriving an acute DNEL according to Appendix R.8.8 (November, 2012). The long-term DNEL for systemic effects upon inhalation shall then be modified by multiplying with a factor of 3, which is considered to be an appropriate factor based on potency and the dose-response relationship. 

AF for dose response relationship:

1

Justification:

The starting point for the acute DNEL for systemic effects upon inhalation is based on the long-term DNEL for systemic effects upon inhalation. Assessment factors are already included in this long-term DNEL and should therefore not be included in the derivation of the short-term DNEL.

AF for interspecies differences (allometric scaling):

1

Justification:

The starting point for the acute DNEL for systemic effects upon inhalation is based on the long-term DNEL for systemic effects upon inhalation. Assessment factors are already included in this long-term DNEL and should therefore not be included in the derivation of the short-term DNEL.

AF for other interspecies differences:

1

Justification:

The starting point for the acute DNEL for systemic effects upon inhalation is based on the long-term DNEL for systemic effects upon inhalation. Assessment factors are already included in this long-term DNEL and should therefore not be included in the derivation of the short-term DNEL.

AF for intraspecies differences:

1

Justification:

The starting point for the acute DNEL for systemic effects upon inhalation is based on the long-term DNEL for systemic effects upon inhalation. Assessment factors are already included in this long-term DNEL and should therefore not be included in the derivation of the short-term DNEL.

AF for the quality of the whole database:

1

Justification:

The starting point for the acute DNEL for systemic effects upon inhalation is based on the long-term DNEL for systemic effects upon inhalation. Assessment factors are already included in this long-term DNEL and should therefore not be included in the derivation of the short-term DNEL.

AF for remaining uncertainties:

1

Justification:

The starting point for the acute DNEL for systemic effects upon inhalation is based on the long-term DNEL for systemic effects upon inhalation. Assessment factors are already included in this long-term DNEL and should therefore not be included in the derivation of the short-term DNEL.

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

medium 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:

0.097 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):

35

Dose descriptor starting point:

NOAEL

Value:

0.45 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

3.4 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The substance fulfils the REACH Annex VII to Annex X information requirements in accordance with ECHA guidance R7.5-7.7 (2016) for assessing long-term systemic toxicity. Since no repeated dose dermal toxicity study is available, route-to-route extrapolation from the oral exposure route is performed.

The starting point is the NOAEL from the 1-year feeding study in dogs; 15 ppm, equivalent to 0.45 mg/kg bw/day. This effect level is for the test substance cation species. The recalculated effect level for the pure test substance is (100/72.4) * 0.45 = 0.62 mg/kg bw/day.

A factor of 3.92 for route-to-route extrapolation from oral to dermal absorption is included. This factor is based on an estimated lower worst case oral absorption in dogs at 54 h of 10.97% total oral absorption from an OECD 417 toxicokinetic study (Silcock, 2007) versus a measured higher worst case dermal absorption in humans at 54 h of 2.80% total dermal absorption from an in vitro human epidermis study (Clowes, 2000): 10.97% total oral absorption / 2.80% total dermal absorption = 3.92.

A correction for 5 day exposure versus 7 days is included (7 days exposure per week in the study versus 5 days per week for workers): 0.62 * (10.97/2.8) * (7/5) = 3.40 mg/kg bw/day.

 

Explanation route-to-route extrapolation from oral to dermal absorption

Dermal absorption in humans

Dermal absorption is calculated as the sum of dermal absorption into the receptor fluid and dermal absorption into the epidermis. The results used for dermal absorption from an OECD 428 (Clowes, 2000) are taken at the 54 h time point as the dermal absorption study was run for this period and epidermis absorption was measured only then.

1.           Dermal absorption into the receptor fluid after 54 h:

The relative absorption of test substance cation was highest for the aqueous spray dilution without wetting agent. This is used as the worst case.

The total percentage of transfer into the receptor fluid is not given as numerical value. It was estimated by calculation from the total percentage of transfer into the receptor fluid at 24 h, being 0.448%, assuming the rate of absorption stayed stable at 0.004 µg/cm²*h for the spray dilution without wetting agent:

total percentage of transfer into the receptor fluid at 54 h= 0.448% (24 h) * 54h/24h = 1.008 % (54 h)

This value is in line with the value calculated from mean amount absorbed (in µg/cm²) depicted in Figure 1 (Clowes, 2000): The absorbed amount at 54 h is estimated to be 0.20 µg/cm², the absorbed amount at 24 h is 0.093 µg/cm², which corresponds to 0.448 % of the total percentage of transfer into the receptor fluid.

total percentage of transfer into the receptor fluid at 54 h= 0.448% * 0.20 µg/cm²/0.093 µg/cm² = 0.963 % (2.07 g/L wo surf, 54 h)

The value of 1.01% is taken forward for total percentage of transfer into the receptor fluid as a worst case assumption.

2.           Dermal absorption into the epidermis after 54 h:

The relative absorption of test substance cation is highest for the spray dilution without wetting agent:1.79 % (54 h, epidermis)

 

total absorption of test substance cation via the human skin = 1.01 % (2.07 g/L wo surf, 54 h, receptor fluid) + 1.79 % (2.07 g/L wo surf., 54 h, epidermis)

                                                                                                                  = 2.80 % (2.07 g/L wo surf, 54 h, total dermal absorption)

This value is probably an overestimation compared to in vivo skin, as it is known that the integrity of skin in this in vitro model is reduced after 24 h (cf. OECD 428 guideline).

 

Oral absorption in dogs

For a comparison the oral absorption, which was measured in dogs (Silcock, 2007) was determined at 54 h as the in vitro human dermal absorption was only determined at 54 h (see above and Clowes, 2000). The oral absorption values were calculated from the percentages of radioactivity recovered in urine and cage wash following oral dose administration. These values represent an underestimation of the oral absorption in dogs, which adds to the conservatism of the approach. The oral absorption in the female dog was lower than in males, thus the values for the female dog are taken forward for calculation of the oral absorption after 54 h (Silcock, 2007, TABLE 1 Percentage recovery of radioactivity in excreta following a single oral dose of [14C]-paraquat to dogs):

 

oral absorption after 54 h as percentage recovery of dose administered within 54 h = 10.80% (urine) + 0.17% (cage wash)* = 10.97%

* This is an underestimation as only the amount between 0 – 48 h is measured as the cage was washed only after 24, 48 and 72 h. Only the values from 24 h and 48 h were added.

 

Route-to-route extrapolation factor

Route-to-route extrapolation from oral (dogs) to dermal (human) absorption = 10.97% total oral absorption / 2.80% total dermal absorption = 3.92.

Interspecies differences between human and dog is accounted for later in DNEL derivation by using the standard assessment factor for interspecies differences (allometric scaling).

AF for dose response relationship:

1

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose-response for human health, for the dose-response relationship, consideration should be given to the uncertainties in the dose descriptor (NOAEL, benchmark dose,…) as the surrogate for the true no-adverse-effect-level (NAEL). In this case the starting point for the DNEL calculation is a NOAEL, derived from a study which is of good quality and without uncertainties. Therefore the default assessment factor, as a standard procedure, is 1.

AF for differences in duration of exposure:

2

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose-response for human health, a factor allowing for differences in the experimental exposure duration and the duration of exposure for the worker and scenario under consideration needs to be considered taking into account that a) in general the experimental NOAEL will decrease with increasing exposure times and b) other and more serious adverse effects may appear with increasing exposure times. Consequently, to end up with the most conservative DNEL for repeated dose toxicity, chronic exposure is the ‘worst case’. For a sub-chronic toxicity study, an assessment factor of 2 is to be applied, as a standard procedure.

AF for interspecies differences (allometric scaling):

1.4

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose-response for human health, differences in metabolic rate (allometric scaling) should be accounted for by extrapolation of doses according to an overall assumption that equitoxic doses (when expressed in mg/kg bw/day) scale with body weight to the power of 0.75. This results in different default allometric scaling factors for the different animal species when compared with humans. For dogs, the default assessment factor, as a standard procedure, is 1.4.

AF for other interspecies differences:

2.5

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose-response for human health, interspecies differences result from variation in the sensitivity of species due to differences in toxicokinetics and toxicodynamics. Some of the toxicokinetic differences can be explained by differences in body size (and related differences in basal metabolic rate). As no substance-specific data are available, the standard procedure for threshold effects is followed. As a default, an additional factor of 2.5 for interspecies differences (other than allometric scaling), i.e. toxicokinetic differences not related to metabolic rate (small part) and toxicodynamic differences (larger part) is applied.

AF for intraspecies differences:

5

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose-response for human health, intraspecies differences in human result from a multitude of biological factors such as genetic polymorphism affecting e.g. toxicokinetics/metabolism, age, gender, health status and nutritional status. For workers, as standard procedure for threshold effects a default assessment factor of 5 is to be used, based on the fact that this sub population does not cover the very young, the very old, and the very ill.

AF for the quality of the whole database:

1

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose-response for human health, the evaluation of the total toxicological database should include an assessment whether the available information as a whole meets the tonnage driven data requirements necessary to fulfil the REACH requirements, or whether there are data gaps (completeness of the database). Furthermore, the hazard data should be assessed for the reliability and consistency across different studies and endpoints and taking into account the quality of the testing method, size and power of the study design, biological plausibility, dose-response relationships and statistical association (adequacy of the database). When taking into account the standard information requirements and the completeness and consistency of the database the default assessment factor of 1, to be applied for good/standard quality of the database, is recommended.

AF for remaining uncertainties:

1

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose-response for human health, there are no remaining uncertainties. Since there are no further uncertainties, the default assessment factor of 1, to be applied for good/standard quality of the database, is recommended.

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:

medium hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

15.4 µg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

50

Dose descriptor starting point:

NOAEL

Value:

0.45 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

0.77 mg/m³

Explanation for the modification of the dose descriptor starting point:

The substance fulfils the REACH Annex VII to Annex X information requirements in accordance with ECHA guidance R7.5-7.7 (2016) for assessing long-term systemic toxicity. Since no repeated dose inhalation study is available, route-to-route extrapolation from the oral exposure route is performed. The starting point is the NOAEL from the 1-year feeding study in dogs; 15 ppm, equivalent to 0.45 mg/kg bw/day. This effect level is for the test substance cation species. The recalculated effect level for the pure test substance is (100/72.4) * 0.45 = 0.62 mg/kg bw/day. This oral dog NOAEL is converted to an inhalation NOAEC for dogs by using a default respiratory volume for the dog corresponding to 24 hours (sRVDog = 0.2 * 1.4 = 0.28 L/min/kg bw, adjustment for 24 hour consumer exposure is 0.28 L/min/kg bw * 60 min * 24 hours = 403.2 L/kg bw = = 0.4032 m3/kg bw). A factor for route-to-route extrapolation is included based on the default absorption values (R.7.12. June 2017): 0.62 * (1/0.4032) * (50/100) = 0.77 mg/m3.

AF for dose response relationship:

1

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose-response for human health, for the dose-response relationship, consideration should be given to the uncertainties in the dose descriptor (NOAEL, benchmark dose,…) as the surrogate for the true no-adverse-effect-level (NAEL). In this case the starting point for the DNEL calculation is a NOAEL, derived from a study which is of good quality and without uncertainties. Therefore the default assessment factor, as a standard procedure, is 1.

AF for differences in duration of exposure:

2

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose-response for human health, a factor allowing for differences in the experimental exposure duration and the duration of exposure for the consumer and scenario under consideration needs to be considered taking into account that a) in general the experimental NOAEL will decrease with increasing exposure times and b) other and more serious adverse effects may appear with increasing exposure times. Consequently, to end up with the most conservative DNEL for repeated dose toxicity, chronic exposure is the ‘worst case’. For a sub-chronic toxicity study, an assessment factor of 2 is to be applied, as a standard procedure.

AF for interspecies differences (allometric scaling):

1

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose-response for human health, as long as route-to-route extrapolation is not needed, allometric scaling should not be applied in cases where the dose unit (original or transformed) in experimental animal studies are expressed as concentrations (e.g. in mg/m³ air, ppm in diet, or mg/L in the drinking water) as these are assumed to be already scaled according to the allometric principle, since ventilation rate and food intake directly depend on the basal metabolic rate. In this case, route-to-route extrapolation is performed form an oral feeding study. The derived NOAEL is modified according to allometric principles to a NOAEC (mg/m³), therefore additional assessment factor for allometric scaling is not needed.

AF for other interspecies differences:

2.5

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose-response for human health, interspecies differences result from variation in the sensitivity of species due to differences in toxicokinetics and toxicodynamics. Some of the toxicokinetic differences can be explained by differences in body size (and related differences in basal metabolic rate). As no substance-specific data are available, the standard procedure for threshold effects is followed. As a default, an additional factor of 2.5 for interspecies differences (other than allometric scaling), i.e. toxicokinetic differences not related to metabolic rate (small part) and toxicodynamic differences (larger part) is applied.

AF for intraspecies differences:

10

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose-response for human health, intraspecies differences in human result from a multitude of biological factors such as genetic polymorphism affecting e.g. toxicokinetics/metabolism, age, gender, health status and nutritional status. For consumers, as standard procedure for threshold effects a default assessment factor of 10 is to be used, based on the fact that the all sub-populations are covered in this population: the very young, the very old, and the very ill.

AF for the quality of the whole database:

1

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose-response for human health, the evaluation of the total toxicological database should include an assessment whether the available information as a whole meets the tonnage driven data requirements necessary to fulfil the REACH requirements, or whether there are data gaps (completeness of the database). Furthermore, the hazard data should be assessed for the reliability and consistency across different studies and endpoints and taking into account the quality of the testing method, size and power of the study design, biological plausibility, dose-response relationships and statistical association (adequacy of the database). When taking into account the standard information requirements and the completeness and consistency of the database the default assessment factor of 1, to be applied for good/standard quality of the database, is recommended.

AF for remaining uncertainties:

1

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose-response for human health, there are no remaining uncertainties. Since there are no further uncertainties, the default assessment factor of 1, to be applied for good/standard quality of the database, is recommended.

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:

medium hazard (no threshold derived)

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.03 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):

70

Dose descriptor starting point:

NOAEL

Value:

0.45 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

2.42 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The substance fulfils the REACH Annex VII to Annex X information requirements in accordance with ECHA guidance R7.5-7.7 (2016) for assessing long-term systemic toxicity. Since no repeated dose dermal toxicity study is available, route-to-route extrapolation from the oral exposure route is performed.

The starting point is the NOAEL from the 1-year feeding study in dogs; 15 ppm, equivalent to 0.45 mg/kg bw/day. This effect level is for the test substance cation species. The recalculated effect level for the pure test substance is (100/72.4) * 0.45 = 0.62 mg/kg bw/day.

A factor of 3.92 for route-to-route extrapolation from oral to dermal absorption isincluded. This factor is based on an estimated lower worst case oral absorption in dogs at 54 h of 10.97% total oral absorption from an OECD 417 toxicokinetic study (Silcock, 2007) versus a measured higher worst case dermal absorption in humans at 54 h of 2.80% total dermal absorption from anin vitrohuman epidermis study (Clowes, 2000): 10.97% total oral absorption / 2.80% total dermal absorption = 3.92.

The modified dose descriptor starting point is therefore 0.62 * (10.97/2.8) = 2.42 mg/kg bw/day.

Explanation route-to-route extrapolation from oral to dermal absorption

Dermal absorption in humans

Dermal absorption is calculated as the sum of dermal absorption into the receptor fluid and dermal absorption into the epidermis. The results used for dermal absorption from an OECD 428 (Clowes, 2000) are taken at the 54 h time point as the dermal absorption study was run for this period and epidermis absorption was measured only then.

1.           Dermal absorption into the receptor fluid after 54 h:

The relative absorption of test substance cation was highest for the aqueous spray dilution without wetting agent. This is used as the worst case.

The total percentage of transfer into the receptor fluid is not given as numerical value. It was estimated by calculation from the total percentage of transfer into the receptor fluid at 24 h, being 0.448%, assuming the rate of absorption stayed stable at 0.004 µg/cm²*h for the spray dilution without wetting agent:

total percentage of transfer into the receptor fluid at 54 h= 0.448% (24 h) * 54h/24h = 1.008 % (54 h)

This value is in line with the value calculated from mean amount absorbed (in µg/cm²) depicted in Figure 1 (Clowes, 2000): The absorbed amount at 54 h is estimated to be 0.20 µg/cm², the absorbed amount at 24 h is 0.093 µg/cm², which corresponds to 0.448 % of the total percentage of transfer into the receptor fluid.

total percentage of transfer into the receptor fluid at 54 h= 0.448% * 0.20 µg/cm²/0.093 µg/cm² = 0.963 % (2.07 g/L wo surf, 54 h)

The value of 1.01% is taken forward fortotal percentage of transfer into the receptor fluid as a worst case assumption.

2.           Dermal absorption into the epidermis after 54 h:

The relative absorption of test substance cation is highest for the spray dilution without wetting agent:1.79 % (54 h, epidermis)

total absorption of test substance cation via the human skin = 1.01 % (2.07 g/L wo surf, 54 h, receptor fluid) + 1.79 % (2.07 g/L wo surf., 54 h, epidermis)

                                                                                                                  = 2.80 % (2.07 g/L wo surf, 54 h, total dermal absorption)

This value is probably an overestimation compared toin vivoskin, as it is known that the integrity of skin in thisin vitromodel is reduced after 24 h (cf. OECD 428 guideline).

Oral absorption in dogs

For a comparison the oral absorption, which was measured in dogs (Silcock, 2007) was determined at 54 h as thein vitrohuman dermal absorption was only determined at 54 h (see above and Clowes, 2000). The oral absorption values were calculated from the percentages of radioactivity recovered in urine and cage wash following oral dose administration. These values represent an underestimation of the oral absorption in dogs, which adds to the conservatism of the approach. The oral absorption in the female dog was lower than in males, thus the values for the female dog are taken forward for calculation of the oral absorption after 54 h (Silcock, 2007, TABLE 1 Percentage recovery of radioactivity in excreta following a single oral dose of [14C]-paraquat to dogs):

oral absorption after 54 h as percentage recovery of dose administered within 54 h = 10.80% (urine) + 0.17% (cage wash)* = 10.97%

* This is an underestimation as only the amount between 0 – 48 h is measured as the cage was washed only after 24, 48 and 72 h. Only the values from 24 h and 48 h were added.

Route-to-route extrapolation factor

Route-to-route extrapolation from oral (dogs) to dermal (human) absorption = 10.97% total oral absorption / 2.80% total dermal absorption = 3.92.

Interspecies differences between human and dog is accounted for later in DNEL derivation by using the standard assessment factor for interspecies differences (allometric scaling).

AF for dose response relationship:

1

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose-response for human health, for the dose-response relationship, consideration should be given to the uncertainties in the dose descriptor (NOAEL, benchmark dose,…) as the surrogate for the true no-adverse-effect-level (NAEL). In this case the starting point for the DNEL calculation is a NOAEL, derived from a study which is of good quality and without uncertainties. Therefore the default assessment factor, as a standard procedure, is 1.

AF for differences in duration of exposure:

2

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose-response for human health, a factor allowing for differences in the experimental exposure duration and the duration of exposure for the consumer and scenario under consideration needs to be considered taking into account that a) in general the experimental NOAEL will decrease with increasing exposure times and b) other and more serious adverse effects may appear with increasing exposure times. Consequently, to end up with the most conservative DNEL for repeated dose toxicity, chronic exposure is the ‘worst case’. For a sub-chronic toxicity study, an assessment factor of 2 is to be applied, as a standard procedure.

AF for interspecies differences (allometric scaling):

1.4

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose-response for human health, differences in metabolic rate (allometric scaling) should be accounted for by extrapolation of doses according to an overall assumption that equitoxic doses (when expressed in mg/kg bw/day) scale with body weight to the power of 0.75. This results in different default allometric scaling factors for the different animal species when compared with humans. For dogs, the default assessment factor, as a standard procedure, is 1.4.

AF for other interspecies differences:

2.5

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose-response for human health, interspecies differences result from variation in the sensitivity of species due to differences in toxicokinetics and toxicodynamics. Some of the toxicokinetic differences can be explained by differences in body size (and related differences in basal metabolic rate). As no substance-specific data are available, the standard procedure for threshold effects is followed. As a default, an additional factor of 2.5 for interspecies differences (other than allometric scaling), i.e. toxicokinetic differences not related to metabolic rate (small part) and toxicodynamic differences (larger part) is applied.

AF for intraspecies differences:

10

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose-response for human health, intraspecies differences in human result from a multitude of biological factors such as genetic polymorphism affecting e.g. toxicokinetics/metabolism, age, gender, health status and nutritional status. For consumers, as standard procedure for threshold effects a default assessment factor of 10 is to be used, based on the fact that the all sub-populations are covered in this population: the very young, the very old, and the very ill.

AF for the quality of the whole database:

1

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose-response for human health, the evaluation of the total toxicological database should include an assessment whether the available information as a whole meets the tonnage driven data requirements necessary to fulfil the REACH requirements, or whether there are data gaps (completeness of the database). Furthermore, the hazard data should be assessed for the reliability and consistency across different studies and endpoints and taking into account the quality of the testing method, size and power of the study design, biological plausibility, dose-response relationships and statistical association (adequacy of the database). When taking into account the standard information requirements and the completeness and consistency of the database the default assessment factor of 1, to be applied for good/standard quality of the database, is recommended.

AF for remaining uncertainties:

1

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose-response for human health, there are no remaining uncertainties. Since there are no further uncertainties, the default assessment factor of 1, to be applied for good/standard quality of the database, is recommended.

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:

medium hazard (no threshold derived)

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

8.9 µg/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):

70

Dose descriptor starting point:

NOAEL

Value:

0.45 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

0.62 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The substance fulfils the REACH Annex VII to Annex X information requirements in accordance with ECHA guidance R7.5-7.7 (2016) for assessing long-term systemic toxicity. The starting point is the NOAEL from the 1-year feeding study in dogs; 15 ppm, equivalent to 0.45 mg/kg bw/day. This effect level is for the test substance cation species. The recalculated effect level for the pure test substance is (100/72.4) * 0.45 = 0.62 mg/kg bw/day.

AF for dose response relationship:

1

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose-response for human health, for the dose-response relationship, consideration should be given to the uncertainties in the dose descriptor (NOAEL, benchmark dose,…) as the surrogate for the true no-adverse-effect-level (NAEL). In this case the starting point for the DNEL calculation is a NOAEL, derived from a study which is of good quality and without uncertainties. Therefore the default assessment factor, as a standard procedure, is 1.

AF for differences in duration of exposure:

2

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose-response for human health, a factor allowing for differences in the experimental exposure duration and the duration of exposure for the consumer and scenario under consideration needs to be considered taking into account that a) in general the experimental NOAEL will decrease with increasing exposure times and b) other and more serious adverse effects may appear with increasing exposure times. Consequently, to end up with the most conservative DNEL for repeated dose toxicity, chronic exposure is the ‘worst case’. For a sub-chronic toxicity study, an assessment factor of 2 is to be applied, as a standard procedure.

AF for interspecies differences (allometric scaling):

1.4

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose-response for human health, differences in metabolic rate (allometric scaling) should be accounted for by extrapolation of doses according to an overall assumption that equitoxic doses (when expressed in mg/kg bw/day) scale with body weight to the power of 0.75. This results in different default allometric scaling factors for the different animal species when compared with humans. For dogs, the default assessment factor, as a standard procedure, is 1.4.

AF for other interspecies differences:

2.5

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose-response for human health, interspecies differences result from variation in the sensitivity of species due to differences in toxicokinetics and toxicodynamics. Some of the toxicokinetic differences can be explained by differences in body size (and related differences in basal metabolic rate). As no substance-specific data are available, the standard procedure for threshold effects is followed. As a default, an additional factor of 2.5 for interspecies differences (other than allometric scaling), i.e. toxicokinetic differences not related to metabolic rate (small part) and toxicodynamic differences (larger part) is applied.

AF for intraspecies differences:

10

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose-response for human health, intraspecies differences in human result from a multitude of biological factors such as genetic polymorphism affecting e.g. toxicokinetics/metabolism, age, gender, health status and nutritional status. For consumers, as standard procedure for threshold effects a default assessment factor of 10 is to be used, based on the fact that the all sub-populations are covered in this population: the very young, the very old, and the very ill.

AF for the quality of the whole database:

1

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose-response for human health, the evaluation of the total toxicological database should include an assessment whether the available information as a whole meets the tonnage driven data requirements necessary to fulfil the REACH requirements, or whether there are data gaps (completeness of the database). Furthermore, the hazard data should be assessed for the reliability and consistency across different studies and endpoints and taking into account the quality of the testing method, size and power of the study design, biological plausibility, dose-response relationships and statistical association (adequacy of the database). When taking into account the standard information requirements and the completeness and consistency of the database the default assessment factor of 1, to be applied for good/standard quality of the database, is recommended.

AF for remaining uncertainties:

1

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose-response for human health, there are no remaining uncertainties. Since there are no further uncertainties, the default assessment factor of 1, to be applied for good/standard quality of the database, is recommended.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)