Registration Dossier

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

7 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

25

Modified dose descriptor starting point:

NOAEC

Value:

175.9 mg/m³

Explanation for the modification of the dose descriptor starting point:

In the absence of a repeated dose inhalation study, a corrected inhalation starting point (NOAEC) is derived from the oral repeated dose (90 -day) dietary study in the rat. Inhalation absorption is assumed to be 100%, oral absorption is 86% (determined experimentally). The NOAEL of 116 mg/kg bw/d obtained in the oral rat study is corrected for oral and inhalation absorption (86%/100%), standard respiratory volume for the rat (0.38 m³/kg/d, 8 h exposure) and respiratory volume of the worker assuming light activity (6.7 m³/10 m³, 8 h exposure):

Corrected inhalation NOAEC = oral NOAEL * oral absorption / rat respiratory volume * worker respiratory volume

= 116 mg/kg bw/d * (86%/100%) / 0.38 m³/kg/d * (6.7 m³/10 m³)

= 175.9 mg/m³

AF for dose response relationship:

1

Justification:

Default value: starting point is NOAEL/NOAEC

AF for differences in duration of exposure:

2

Justification:

Extrapolation from sub-chronic study to chronic exposure

AF for interspecies differences (allometric scaling):

1

Justification:

The application of a factor for allometric scaling is not required when the starting point is a NOAEC (allometric scaling is already taken into account when deriving the corrected starting point from the NOAEL).

AF for other interspecies differences:

2.5

Justification:

Default factor

AF for intraspecies differences:

5

Justification:

Default factor (workers)

AF for the quality of the whole database:

1

Justification:

Default factor

AF for remaining uncertainties:

1

Justification:

Default factor

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.16 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

100

Modified dose descriptor starting point:

NOAEL

Value:

116 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

In the absence of a repeated dose dermal toxicity study, a corrected dermal starting point is derived from the oral repeated dose (90 -day) dietary study in the rat. The NOAEL of 116 mg/kg bw/d is corrected for oral and dermal absorption. Oral absorption is 86%; no suitable dermal absorption data are available therefore dermal absorption is assumed to be the same as oral absorption according to the ECHA REACH guidance.

Corrected dermal NOAEL = oral NOAEL * (oral absorption %/dermal absorption %)

= 116 mg/kg bw/d * (86%/86%)

= 116 mg/kg bw/d

AF for dose response relationship:

1

Justification:

Starting point is NOAEL

AF for differences in duration of exposure:

2

Justification:

Extrapolation from sub-chronic study to chronic exposure

AF for interspecies differences (allometric scaling):

4

Justification:

Starting point is derived from a study in the rat

AF for other interspecies differences:

2.5

Justification:

Default factor

AF for intraspecies differences:

5

Justification:

Default factor (workers)

AF for the quality of the whole database:

1

Justification:

Default factor

AF for remaining uncertainties:

1

Justification:

Default factor

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Toxicokinetics

The oral and dermal absorption, toxicokinetics and metabolism of cloquintocet acid can be adequately characterised based on the available experimental data.

Cloquintocet acid is rapidly and extensively absorbed following oral exposure and is likely to be rapidly and extensively absorbed following inhalation exposure. Oral absorption was determined to be 86%. Absorption following dermal exposure to a formulated plant protection product and in-use spray dilutions containing cloquintocet acid was found to be minimal, and reached the plateau of absorption by the 24 hour point with the remainder of the substance becoming not absorbable.

Cloquintocet acid is not widely distributed and is only slightly metabolised. Unchanged cloquintocet acid is rapidly and extensively excreted mainly in the urine but also in the faeces, indicating bioaccumulation is unlikely.

Acute toxicity

Cloquintocet acid was demonstrated to be of low acute toxicity: the acute oral LD50 was > 2000 mg/kg bw; the acute dermal LD50 was > 5000 mg/kg bw; and the acute inhalation 4 hour LC50 was > 6.11 mg/L.

Irritation/corrosion

Cloquintocet acid caused slight irritation to rabbit skin and eyes in in vivo guideline studies, however effects were fully reversible and not sufficient to trigger classification.

Skin sensitisation

No evidence of skin sensitisation was seen in a local lymph node assay with cloquintocet acid.

Repeated dose toxicity

In a 90-day repeated dose dietary toxicity study in rats (OECD 408) the NOAEL was the highest dose tested, 2100 ppm, which corresponded to time-weighted average concentrations of 116.0 and 127.0 mg/kg bw/day in males and females, respectively. On this basis, low toxicity is also predicted for the inhalation and dermal routes of exposure. The repeated dose toxicity of the substance is adequately elucidated by the oral route. Further testing via the dermal and inhalation routes is not required.

Genetic toxicity

No evidence of mutagenicity was seen in a bacterial reverse mutation assay (Ames test). In studies in mammalian cells in vitro, cloquintocet acid did not induce chromosomal aberrations when tested in human peripheral blood lymphocytes and was not clastogenic when tested in Chinese hamster ovary cells in either the absence or the presence of metabolic activation.

Toxicity to reproduction

No reproductive or developmental effects were observed in a dietary reproduction/developmental toxicity screening test (OECD 421) at the highest dose tested (2100 ppm, equivalent to 123 mg/kg/day for males and 125 mg/kg/day for females during pre-breeding and 143 mg/kg/day for females during the gestation and 227 mg/kg/day for females during lactation). The substance is not therefore predicted to be a reproductive toxicant.

No study of developmental toxicity is available; however a study is not considered necessary because no adverse effects on reproductive organs or tissues were reported in the 90-day repeat dose oral toxicity study and no relevant effects were seen in the reproductive/developmental toxicity screening study. The findings from the 90-day repeated dose oral toxicity study and the reproductive/developmental toxicity screening test provide an adequate characterisation of the reproductive toxicity hazard of the substance.

DNEL derivation [Workers]

The relevant (lowest) NOAEL for general/systemic toxicity used for DNEL derivation is 116 mg/kg bw/day, obtained from a 90-day repeated dose oral (dietary) study in rats.

Local effects

DNEL values for local effects are not derived. The substance is not a skin or eye irritant or a skin sensitiser. DNELs for local effects are therefore not proposed as no hazard is identified.

Systemic effects

The substance is of low systemic toxicity and has a low vapour pressure. No acute toxicity hazard resulting in classification has been identified, therefore DNELs for acute systemic effects are not proposed as no hazard is identified. The relevant NOAEL for general/systemic toxicity is used for derivation of long-term systemic DNELs.

[Dermal – long-term systemic DNEL]

As a repeated dose dermal toxicity study is not available, the long-term systemic dermal DNEL is derived from the oral repeated dose NOAEL using the route-to-route extrapolation approach and default assumptions given in the ECHA REACH guidance. The NOAEL of 116 mg/kg bw/d is corrected for oral and dermal absorption. Oral absorption is 86%; no suitable dermal absorption data are available therefore dermal absorption is assumed to be the same as oral absorption according to the ECHA REACH guidance. Dermal absorption data are available for cloquintocet acid from a formulated plant protection product and in-use spray dilutions, indicating that dermal absorption is expected to be very low (<2%). However, in the absence of a study conducted with the substance as such, the default assumption (dermal absorption = oral absorption) is made as a conservative worst-case approach.

The corrected dermal NOAEL is derived as follows: oral NOAEL x (% oral absorption/% dermal absorption) = 116 mg/kg bw/day x (86%/86%) = 116 mg/kg bw/day.

The use of assessment factors according to ECHA REACH guidance is considered below:

Intraspecies: default factors of 4 (allometric scaling: rat) and 2.5 (remaining differences)

Interspecies: a default factor of 5 for workers.

Exposure duration: a default factor of 2 for extrapolation from a sub-chronic study to chronic exposure. This represents a conservative approach, as the data indicate low toxicity following single and repeated exposures.

Dose-response: a default factor of 1 as the substance is of low toxicity

Quality of the data base: default factor of 1

An overall assessment factor of 100 for long-term dermal effects is therefore calculated for workers.

Applying the assessment factor of 100 to the corrected dermal NOAEL of 116 mg/kg bw/d gives a dermal DNEL of 1.16 mg/kg bw/d for long-term systemic effects.

[Inhalation – long-term systemic DNEL]

As a repeated dose inhalation toxicity study is not available, the long-term systemic inhalation DNEL is derived from the oral repeated dose NOAEL using the route-to-route extrapolation approach and default assumptions given in the ECHA REACH guidance. A corrected inhalation starting point (NOAEC) is derived from the NOAEL of 116 mg/kg bw/d; the NOAEL is corrected for oral and inhalation absorption (86%/100%), the respiratory volume for the rat (0.38 m³/kg/d, 8 h exposure) and respiratory volume of the worker assuming light activity (6.7 m³/10 m³, 8 h exposure).

The corrected inhalation NOAEC is derived as follows: oral NOAEL * oral absorption / rat respiratory volume * worker respiratory volume = 116 mg/kg bw/d * 86% / 0.38 m³/kg/d * (6.7 m³/10 m³) = 175.9 mg/m³

The use of assessment factors according to ECHA REACH guidance is considered below:

Intraspecies: a default factor of 2.5 (remaining differences; the application of a factor for allometric scaling is not required when the starting point is a NOAEC)

Interspecies: a default factor of 5 for workers.

Exposure duration: a default factor of 2 for extrapolation from a sub-chronic study to chronic exposure. This represents a conservative approach, as the data indicate low toxicity following single and repeated exposures.

Dose-response: a default factor of 1as the substance is of low toxicity

Quality of the data base: a default factor of 1

An overall assessment factor of 25 for long-term inhalational effects is therefore calculated for workers.

Applying the assessment factor of 25 to the corrected inhalation NOAEC of 175.9 mg/m³ gives an inhalation DNEL of 7.0 mg/m³ for long-term systemic effects.

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.7 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

50

Modified dose descriptor starting point:

NOAEC

Value:

86.7 mg/m³

Explanation for the modification of the dose descriptor starting point:

In the absence of a repeated dose inhalation study, a corrected inhalation starting point (NOAEC) is derived from the oral repeated dose (90 -day) dietary study in the rat. Inhalation absorption is assumed to be 100%. The NOAEL of 116 mg/kg bw/d obtained in the oral rat study is corrected for oral and inhalation absorption (86%/100%) and standard respiratory volume for the rat (1.15 m³/kg/d, 24 h exposure):

Corrected inhalation NOAEC = oral NOAEL * oral absorption / rat respiratory volume

= 116 mg/kg bw/d * (86%/100%) / 1.15 m³/kg/d

= 86.7 mg/m³

AF for dose response relationship:

1

Justification:

Starting point is NOAEL/NOAEC

AF for differences in duration of exposure:

2

Justification:

Extrapolation from sub-chronic study to chronic exposure

AF for interspecies differences (allometric scaling):

1

Justification:

The application of a factor for allometric scaling is not required when the starting point is a NOAEC (allometric scaling is already taken into account when deriving the corrected starting point from the NOAEL).

AF for other interspecies differences:

2.5

Justification:

Default factor

AF for intraspecies differences:

10

Justification:

Default factor (general population)

AF for the quality of the whole database:

1

Justification:

Default factor

AF for remaining uncertainties:

1

Justification:

Default factor

Hazard assessment conclusion:

no hazard identified

Explanation for the modification of the dose descriptor starting point:

The substance is of low systemic toxicity and has a low vapour pressure. No acute toxicity hazard resulting in classification has been identified, therefore a DNEL for acute systemic effects is not proposed. The long term DNEL is considered to be protective of any short term effects.

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.58 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

200

Modified dose descriptor starting point:

NOAEL

Value:

116 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

In the absence of a repeated dose dermal toxicity study, a corrected dermal starting point is derived from the oral repeated dose (90 -day) dietary study in the rat. The NOAEL of 116 mg/kg bw/d is corrected for oral and dermal absorption. Oral absorption is 86%; no suitable dermal absorption data are available therefore dermal absorption is assumed to be the same as oral absorption according to the ECHA REACH guidance.

Corrected dermal NOAEL = oral NOAEL * (oral absorption %/dermal absorption %)

= 116 mg/kg bw/d * (86%/86%)

= 116 mg/kg bw/d

AF for dose response relationship:

1

Justification:

Starting point is NOAEL

AF for differences in duration of exposure:

2

Justification:

Extrapolation from sub-chronic study to chronic exposure

AF for interspecies differences (allometric scaling):

4

Justification:

Starting point is derived from a study in the rat

AF for other interspecies differences:

2.5

Justification:

Default factor

AF for intraspecies differences:

10

Justification:

Default factor (general population)

AF for the quality of the whole database:

1

Justification:

Default factor

AF for remaining uncertainties:

1

Justification:

Default factor

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.58 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

200

Dose descriptor starting point:

NOAEL

Value:

116 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The starting point is a NOAEL from a repeated dose oral toxicity study, therefore modification is not required.

AF for dose response relationship:

1

Justification:

Starting point is NOAEL

AF for differences in duration of exposure:

2

Justification:

Extrapolation from sub-chronic study to chronic exposure

AF for interspecies differences (allometric scaling):

4

Justification:

Starting point is derived from a study in the rat

AF for other interspecies differences:

2.5

Justification:

Default factor

AF for intraspecies differences:

10

Justification:

Default factor (general population)

AF for the quality of the whole database:

1

Justification:

Default factor

AF for remaining uncertainties:

1

Justification:

Default factor

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

DNEL derivation [General Population]

The relevant (lowest) NOAEL for general/systemic toxicity used for DNEL derivation is 116 mg/kg bw/day, obtained from a 90-day repeated dose oral (dietary) study in rats.

Local effects

DNEL values for local effects are not derived. The substance is not a skin or eye irritant or a skin sensitiser. DNELs for local effects are therefore not proposed as no hazard is identified.

Systemic effects

The substance is of low systemic toxicity and has a low vapour pressure. No acute toxicity hazard resulting in classification has been identified, therefore DNELs for acute systemic effects are not proposed as no hazard is identified. The relevant NOAEL for general/systemic toxicity is used for derivation of long-term systemic DNELs.

[Dermal – long-term systemic DNEL]

As a repeated dose dermal toxicity study is not available, the long-term systemic dermal DNEL is derived from the oral repeated dose NOAEL using the route-to-route extrapolation approach and default assumptions given in the ECHA REACH guidance. The NOAEL of 116 mg/kg bw/d is corrected for oral and dermal absorption. Oral absorption is 86%; no suitable dermal absorption data are available therefore dermal absorption is assumed to be the same as oral absorption according to the ECHA REACH guidance. Dermal absorption data are available for cloquintocet acid from a formulated plant protection product and in-use spray dilutions, indicating that dermal absorption is expected to be very low (<2%). However, in the absence of a study conducted with the substance as such, the default assumption (dermal absorption = oral absorption) is made as a conservative worst-case approach.

The corrected dermal NOAEL is derived as follows: oral NOAEL x (% oral absorption/% dermal absorption) = 116 mg/kg bw/day x (86%/86%) = 116 mg/kg bw/day.

The use of assessment factors according to ECHA REACH guidance is considered below:

Intraspecies: default factors of 4 (allometric scaling: rat) and 2.5 (remaining differences).

Interspecies: a default factor of 10 for the general population.

Exposure duration: a default factor of 2 for extrapolation from a sub-chronic study to chronic exposure. This represents a conservative approach, as the data indicate low toxicity following single and repeated exposures

Dose-response: a default factor of 1 is proposed as the substance is of low toxicity

Quality of the data base: default factor of 1

An overall assessment factor of 200 for long-term dermal effects is therefore calculated for the general population

Applying the assessment factor of 200 to the corrected dermal NOAEL of 116 mg/kg bw/d gives a dermal DNEL of 0.58 mg/kg bw/d for long-term systemic effects.

[Inhalation – long-term systemic DNEL]

As a repeated dose inhalation toxicity study is not available, the long-term systemic inhalation DNEL is derived from the oral repeated dose NOAEL using the route-to-route extrapolation approach and default assumptions given in the ECHA REACH guidance. A corrected inhalation starting point (NOAEC) is derived from the NOAEL of 116 mg/kg bw/d; the NOAEL is corrected for oral and inhalation absorption (86%/100%) and the standard respiratory volume for the rat (1.15 m³/kg/d, 24 h exposure).

The corrected inhalation NOAEC is derived as follows: oral NOAEL * oral absorption / rat respiratory volume = 116 mg/kg bw/d * 86% / 1.15 m³/kg/d = 86.7 mg/m³

The use of assessment factors according to ECHA REACH guidance is considered below:

Intraspecies: a default factor of 2.5 (remaining differences; the application of a factor for allometric scaling is not required when the starting point is a NOAEC)

Interspecies: a default factor of 10 for the general population

Exposure duration: a default factor of 2 for extrapolation from a sub-chronic study to chronic exposure. This represents a conservative approach, as the data indicate low toxicity following single and repeated exposures

Dose-response: a default value of 1 as the substance is of low toxicity

Quality of the data base: default factor of 1

An overall assessment factor of 50 for long-term inhalational effects is therefore calculated for the general population.

Applying the assessment factor of 50 to the corrected inhalation NOAEC of 86.7 mg/m³ gives an inhalation DNEL of 1.7 mg/m³ for long-term systemic effects.

[Oral – long-term systemic DNEL]

The NOAEL of 116 mg/kg bw/d obtained in the repeated dose oral toxicity study is used as the starting point; route-to-route extrapolation is not required.

The use of assessment factors according to ECHA REACH guidance is considered below:

Intraspecies: default factors of 4 (allometric scaling: rat) and 2.5 (remaining differences).

Interspecies: a default factor of 10 for the general population.

Exposure duration: a default factor of 2 for extrapolation from a sub-chronic study to chronic exposure. This represents a conservative approach, as the data indicate low toxicity following single and repeated exposures

Dose-response: a default factor of 1 is proposed as the substance is of low toxicity

Quality of the data base: default factor of 1

An overall assessment factor of 200 for long-term oral effects is therefore calculated for the general population

Applying the assessment factor of 200 to the oral NOAEL of 116 mg/kg bw/d gives an oral DNEL of 0.58 mg/kg bw/d for long-term systemic effects.