Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.411 mg/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):
12.5
Modified dose descriptor starting point:
NOAEC
Value:
17.63 mg/m³
Explanation for the modification of the dose descriptor starting point:
Inhalation N(L)OAEC= oral N(L)OAEL*(1/0.38 m3/kg/d)*0.67*1
AF for dose response relationship:
1
AF for differences in duration of exposure:
1
Justification:
based on a 2-year study
AF for interspecies differences (allometric scaling):
1
Justification:
AF not used for inhalation route
AF for other interspecies differences:
2.5
AF for intraspecies differences:
5
Justification:
for workers
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3.333 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Dermal
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
300
Modified dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
No route-to-route extrapolation needed.
AF for dose response relationship:
1
AF for differences in duration of exposure:
6
Justification:
DNEL is based on 28-day study
AF for interspecies differences (allometric scaling):
4
Justification:
for rat
AF for other interspecies differences:
2.5
AF for intraspecies differences:
5
Justification:
for workers
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

Worker

No DNELs have been derived for systemic effects after short-term dermal and inhalation exposure of the test substance for workers, as it is assumed that the assessment of hazard is sufficiently covered by deriving the respective DNELs for long-term exposure. Even though a local NOAEL was observed in the dermal 28-day study it was not considered in the hazard assessment as the existing sensitising properties of the registered substance were not addressed in this study. No treshold can be derived for sensitisation.

Reliable studies with dietary administration of isoxadiphen-ethyl have been conducted in mice, rats and dogs on a subacute to chronic basis. For risk assessment the chronic oral studies are considered.

One of the two chronic studies was carried out in dogs. For 12 months 4 animals/sex/group received dose levels of 20, 100 and 700 ppm (corresponding to 0.7, 3.5 and 24 mg/kg bw/day for combined sexes). The kidney as target organ showed a tubular increase in the incidence and severity of vacuolation in the highest dose group. Hence, the NO(A)EL was set to 3.5mg/kg bw/day (Higgs, 1999a).

In the second chronic study 70 rats/sex/dose received 20, 200, 2000 and 4000 ppm (corresponding to 1.0, 10, 101 and 210 mg/kg bw/day for combined sexes) continuously for 104 weeks. This combined chronic/carcinogenicity study showed an increased incidence of ketones in the urine as well as decreased absolute and relative kidney and increased relative liver weights. Hence, the NO(A)EL was set at 10 mg/kg bw/day (Higgs, 1999b).

Dogs are the most sensitive species among all species tested, providing the lowest NOAELs in subacute, subchronic and chronic studies. Due to the fact that dog studies are less covered from a statistical point of view due to the amount of animals used, the second chronic study with rats is considered as well. Taken into account that the scaling factor for rat is 4 instead of 1.4 for the dog both NOAELs result in the same NAEL (3.5/1.4 = 2.5 mg/kg bw/day vs. 10/4 = 2.5 mg/kg bw/day).

Hence, for a conservative approach, the NOAEL of the chronic rat study (i.e. 10 mg/kg bw/day) was chosen for the risk assessment.

Regarding the dermal route one subacute study was conducted in rats. In a 28 day-study, isoxadiphen-ethyl was administered to 5 animals/sex/group at dose levels of 10, 100 and 1000 mg/kg bw/day for 5 days/week. The study was performed in accordance with OECD 410 and revealed a systemic NOAEL of 1000 mg/kg bw/day and a local NOAEL of 0.5 mg/cm²/day (calculated as follows 10 mg/kg bw*0.2 kg bw rat/4 cm²)(Weir, 1999).

Determination of corrected starting point for DNEL derivation

Repeated dose toxicity – systemic effects – inhalation route – worker:

The DNEL for systemic effects via the inhalation route for worker is determined on the basis of route-to-route extrapolation from the OECD 453 oral study on isoxadiphen-ethyl, which established a NOAEL of 10 mg/kg bw day. In contrast to the recommendations of the ECHA Guidance, a factor of 1 (equal absorption of 100% assumed for the oral and the inhalative route for animals and humans) was included for the extrapolation from oral to inhalation absorption, as there is no valid data suggesting that inhalation leads to higher absorption than oral ingestion (recommendation of the VCI Working group "Toxicology", 2008). Molecules with a molecular weight <500 and a log Kow between 0 and 4 can be assumed to be well absorbed equivalently by the oral and inhalation route. Oral absorption may be reduced for acids and bases depending on their pKa value and their electric charge in the GI tract. More lipophilic substances may be better absorbed in the GI tract due to solubilisation with bile acids, and thus oral absorption may be higher than inhalation absorption (VCI Working group "Toxicology", 2008). Unless valid data suggest that inhalation leads to higher absorption than oral ingestion, equal absorption will be assumed when extrapolating from oral to inhalation route. The following corrections were made:

No correction for relative absorption oral vs. inhalation: 1
Correction for respiratory volume (standard breathing volume for the rat, 8 h): 0.38 m³/kg
Correction for respiratory volume (worker, light physical activity): 6.7 m³/day /10 m³/day

Therefore the corrected NOAEC for repeated dose systemic effects via the inhalation route is:

10 mg/kg bw/day / 0.38 m³/kg bw × 6.7 m³ /10 m³ × 1= 17.63 mg/m³

Repeated dose toxicity – systemic effects – dermal route – worker:

The DNEL for systemic effects via the dermal route for worker is determined from the OECD 410 dermal study on isoxadiphen-ethyl, which established a NOAEL of 1000 mg/kg bw day. No corrections were made to the NOAEL.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.348 mg/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
Modified dose descriptor starting point:
NOAEC
Value:
8.7 mg/m³
Explanation for the modification of the dose descriptor starting point:
Inhalation NOAEC= oral NOAEL*(1/1.15 m3/kg/d)*1
AF for dose response relationship:
1
AF for differences in duration of exposure:
1
Justification:
DNEL based on 2-year study
AF for interspecies differences (allometric scaling):
1
Justification:
AF not used for inhalation route
AF for other interspecies differences:
2.5
AF for intraspecies differences:
10
Justification:
for general population
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.67 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Dermal
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
600
Modified dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
No route-to-route extrapolation needed.
AF for dose response relationship:
1
AF for differences in duration of exposure:
6
Justification:
DNEL based on 28-day study
AF for interspecies differences (allometric scaling):
4
Justification:
for rat
AF for other interspecies differences:
2.5
AF for intraspecies differences:
10
Justification:
for general population
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.1 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):
100
Modified dose descriptor starting point:
NOAEL
Value:
10 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
No route-to-route extrapolation needed.
AF for dose response relationship:
1
AF for differences in duration of exposure:
1
Justification:
DNEL based on 2-year study
AF for interspecies differences (allometric scaling):
4
Justification:
for rats
AF for other interspecies differences:
2.5
AF for intraspecies differences:
10
Justification:
for general population
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

General population

No DNELs have been derived for systemic effects after short-term dermal and inhalation exposure of the test substance for the general population, as it is assumed that the assessment of hazard is sufficiently covered by deriving the respective DNELs for long-term exposure. Even though a local NOAEL was observed in a dermal 28-day study it was not considered in the hazard assessment as the existing sensitising properties of the registered substance were not addressed in this study. No treshold can be derived for sensitisation.

Reliable studies with dietary administration of isoxadiphen-ethyl have been conducted in mice, rats and dogs on a subacute to chronic basis. For risk assessment the chronic oral studies are considered.

One of the two chronic studies was carried out in dogs. For 12 months 4 animals/sex/group received dose levels of 20, 100 and 700 ppm (corresponding to 0.7, 3.5 and 24 mg/kg bw/day for combined sexes). The kidney as target organ showed a tubular increase in the incidence and severity of vacuolation in the highest dose group. Hence, the NO(A)EL was set to 3.5mg/kg bw/day (Higgs, 1999a).

In the second chronic study 70 rats/sex/dose received 20, 200, 2000 and 4000 ppm (corresponding to 1.0, 10, 101 and 210 mg/kg bw/day for combined sexes) continuously for 104 weeks. This combined chronic/carcinogenicity study showed an increased incidence of ketones in the urine as well as decreased absolute and relative kidney and increased relative liver weights. Hence, the NO(A)EL was set at 10 mg/kg bw/day (Higgs, 1999b).

Dogs are the most sensitive species among all species tested, providing the lowest NOAELs in subacute, subchronic and chronic studies. Due to the fact that dog studies are less covered from a statistical point of view due to the amount of animals used, the second chronic study with rats is considered as well. Taken into account that the scaling factor for rat is 4 instead of 1.4 for the dog both NOAELs result in the same NAEL (3.5/1.4 = 2.5 mg/kg bw/day vs. 10/4 = 2.5 mg/kg bw/day).

Hence, for a conservative approach, the NOAEL of the chronic rat study (i.e. 10 mg/kg bw/day)was chosen for the risk assessment.

Regarding the dermal route one subacute study was conducted in rats. In a 28 day-study, isoxadiphen-ethyl was administered to 5 animals/sex/group at dose levels of 10, 100 and 1000 mg/kg bw/day for 5 days/week. The study was performed in accordance with OECD 410 and revealed a systemic NOAEL of 1000 mg/kg bw/day and a local NOAEL of 0.5 mg/cm²/day (calculated as follows 10 mg/kg bw*0.2 kg bw rat/4 cm²)(Weir, 1999).

Determination of corrected starting point for DNEL derivation

Repeated dose toxicity – systemic effects – inhalation route – general population:

The DNEL for systemic effects via the inhalation route for the general population is determined on the basis of route-to-route extrapolation from the OECD 453 oral study on isoxadiphen-ethyl, which established a NOAEL of 10 mg/kg bw day. In contrast to the recommendations of the ECHA Guidance, a factor of 1 (equal absorption of 100% assumed for the oral and the inhalative route for animals and humans) was included for the extrapolation from oral to inhalation absorption, as there is no valid data suggesting that inhalation leads to higher absorption than oral ingestion (recommendation of the VCI Working group "Toxicology", 2008). Molecules with a molecular weight <500 and a log Kow between 0 and 4 can be assumed to be well absorbed equivalently by the oral and inhalation route. Oral absorption may be reduced for acids and bases depending on their pKa value and their electric charge in the GI tract. More lipophilic substances may be better absorbed in the GI tract due to solubilisation with bile acids, and thus oral absorption may be higher than inhalation absorption (VCI Working group "Toxicology", 2008). Unless valid data suggest that inhalation leads to higher absorption than oral ingestion, equal absorption will be assumed when extrapolating from oral to inhalation route. The following corrections were made:

No correction for relative absorption oral vs. inhalation: 1
Correction for respiratory volume (standard breathing volume for the rat, 24 h): 1.15m³/kg

Therefore the corrected NOAEC for repeated dose systemic effects via the inhalation route is:

10 mg/kg bw/day / 1.15 m³/kg bw = 8.70 mg/m³

Repeated dose toxicity – systemic effects – dermal route – general population:

The DNEL for systemic effects via the dermal route for worker is determined from the OECD 410 dermal study on isoxadiphen-ethyl, which established a NOAEL of 1000 mg/kg bw day. No corrections were made to the NOAEL.

Repeated dose toxicity – systemic effects – oral route – general population:

The DNEL for systemic effects via the oral route for the general population is determined from the OECD 453 oral study on isoxadiphen-ethyl, which established a NOAEL of 10 mg/kg bw day. No corrections were made to the NOAEL.