Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
50.07 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
Dose descriptor starting point:
NOAEL
Value:
710 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
625.92 mg/m³
AF for dose response relationship:
1
Justification:
ECHA default guidance
AF for differences in duration of exposure:
1
Justification:
ECHA default guidance
AF for interspecies differences (allometric scaling):
1
Justification:
ECHA default guidance
AF for other interspecies differences:
2.5
Justification:
ECHA default guidance
AF for intraspecies differences:
5
Justification:
ECHA default guidance
AF for the quality of the whole database:
1
Justification:
ECHA default guidance
AF for remaining uncertainties:
1
Justification:
ECHA default guidance
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
50.07 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
Dose descriptor starting point:
NOAEL
Value:
710 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
625.92 mg/m³
AF for dose response relationship:
1
Justification:
ECHA default guidance
AF for interspecies differences (allometric scaling):
1
Justification:
ECHA default guidance
AF for other interspecies differences:
2.5
Justification:
ECHA default guidance
AF for intraspecies differences:
5
Justification:
ECHA default guidance
AF for the quality of the whole database:
1
Justification:
ECHA default guidance
AF for remaining uncertainties:
1
Justification:
ECHA default guidance

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
125.18 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
5
Dose descriptor:
NOAEC
Value:
625.92 mg/m³
AF for dose response relationship:
1
Justification:
ECHA default guidance
AF for differences in duration of exposure:
1
Justification:
ECHA default guidance
AF for interspecies differences (allometric scaling):
1
Justification:
ECHA default guidance
AF for other interspecies differences:
1
Justification:
ECHA default guidance
AF for intraspecies differences:
5
Justification:
ECHA default guidance
AF for the quality of the whole database:
1
Justification:
ECHA default guidance
AF for remaining uncertainties:
1
Justification:
ECHA default guidance
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
125.18 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
125.18
Dose descriptor starting point:
NOAEC
Value:
625.92 mg/m³
AF for dose response relationship:
1
Justification:
ECHA default guidance
AF for interspecies differences (allometric scaling):
1
Justification:
ECHA default guidance
AF for other interspecies differences:
1
Justification:
ECHA default guidance
AF for intraspecies differences:
5
Justification:
ECHA default guidance
AF for the quality of the whole database:
1
Justification:
ECHA default guidance
AF for remaining uncertainties:
1
Justification:
ECHA default guidance

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
14.2 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):
50
Dose descriptor starting point:
NOAEL
Value:
710 mg/kg bw/day
AF for dose response relationship:
1
Justification:
ECHA default guidance
AF for differences in duration of exposure:
1
Justification:
ECHA default guidance
AF for interspecies differences (allometric scaling):
4
Justification:
ECHA default guidance
AF for other interspecies differences:
2.5
Justification:
ECHA default guidance
AF for intraspecies differences:
5
Justification:
ECHA default guidance
AF for the quality of the whole database:
1
Justification:
ECHA default guidance
AF for remaining uncertainties:
1
Justification:
ECHA default guidance
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
14.2 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):
14.2
Dose descriptor starting point:
NOAEL
Value:
710 mg/kg bw/day
AF for dose response relationship:
1
Justification:
ECHA default guidance
AF for interspecies differences (allometric scaling):
4
Justification:
ECHA default guidance
AF for other interspecies differences:
2.5
Justification:
ECHA default guidance
AF for intraspecies differences:
5
Justification:
ECHA default guidance
AF for the quality of the whole database:
1
Justification:
ECHA default guidance
AF for remaining uncertainties:
1
Justification:
ECHA default guidance

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
35.5 mg/cm²
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
20
Dose descriptor:
NOAEC
Value:
625.92 mg/m³
AF for dose response relationship:
1
Justification:
ECHA default guidance
AF for differences in duration of exposure:
1
Justification:
ECHA default guidance
AF for interspecies differences (allometric scaling):
4
Justification:
ECHA default guidance
AF for other interspecies differences:
1
Justification:
ECHA default guidance
AF for intraspecies differences:
5
Justification:
ECHA default guidance
AF for the quality of the whole database:
1
Justification:
ECHA default guidance
AF for remaining uncertainties:
1
Justification:
ECHA default guidance
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
35.5 mg/cm²
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
20
Dose descriptor starting point:
NOAEC
Value:
625.92 mg/m³
AF for dose response relationship:
1
Justification:
ECHA default guidance
AF for interspecies differences (allometric scaling):
4
Justification:
ECHA default guidance
AF for other interspecies differences:
1
Justification:
ECHA default guidance
AF for intraspecies differences:
5
Justification:
ECHA default guidance
AF for the quality of the whole database:
1
Justification:
ECHA default guidance
AF for remaining uncertainties:
1
Justification:
ECHA default guidance

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

Based on the results of this combined 28-day repeated dose toxicity study with the reproduction/developmental toxicity screening test an parental, reproduction and developmental no-observed-adverse-effect level (NOAEL) of at least 10000 ppm for Aurantiol Pure was established, corresponding to an overall mean test item intake of 710 mg/kg bw/day for males.

No reproduction toxicity was observed up to the highest dose level tested (10000 ppm).

No treatment-related toxicologically significant changes were noted in any of the reproductive parameters investigated in this study (i.e. mating and fertility indices, precoital time, number of implantations, estrous cycle, spermatogenic profiling, and histopathological examination of reproductive organs).

No developmental toxicity was observed up to the highest dose level tested (10000 ppm).

No treatment-related changes were noted in any of the developmental parameters investigated in this study (i.e. gestation, viability and lactation indices, duration of gestation, parturition, sex ratio, maternal care and early postnatal pup development consisting of mortality, clinical signs, body weight, anogenital distance, areola/nipple retention, T4 thyroid hormone levels and macroscopic examination).

For the exposure scenarios assessment and DNELs, the male NOAEL has been chosen as the worse case parameter.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
12.35 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
Dose descriptor starting point:
NOAEL
Value:
710 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
308.7 mg/m³
AF for dose response relationship:
1
Justification:
ECHA default guidance
AF for differences in duration of exposure:
1
Justification:
ECHA default guidance
AF for interspecies differences (allometric scaling):
1
Justification:
ECHA default guidance
AF for other interspecies differences:
2.5
Justification:
ECHA default guidance
AF for intraspecies differences:
10
Justification:
ECHA default guidance
AF for the quality of the whole database:
1
Justification:
ECHA default guidance
AF for remaining uncertainties:
1
Justification:
ECHA default guidance
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
12.35 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
Dose descriptor starting point:
NOAEL
Value:
710 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
308.7 mg/m³
AF for dose response relationship:
1
Justification:
ECHA default guidance
AF for interspecies differences (allometric scaling):
1
Justification:
ECHA default guidance
AF for other interspecies differences:
2.5
Justification:
ECHA default guidance
AF for intraspecies differences:
10
Justification:
ECHA default guidance
AF for the quality of the whole database:
1
Justification:
ECHA default guidance
AF for remaining uncertainties:
1
Justification:
ECHA default guidance

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
30.87 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
10
Dose descriptor:
NOAEC
Value:
308.7 mg/m³
AF for dose response relationship:
1
Justification:
ECHA default guidance
AF for differences in duration of exposure:
1
Justification:
ECHA default guidance
AF for interspecies differences (allometric scaling):
1
Justification:
ECHA default guidance
AF for other interspecies differences:
1
Justification:
ECHA default guidance
AF for intraspecies differences:
10
Justification:
ECHA default guidance
AF for the quality of the whole database:
1
Justification:
ECHA default guidance
AF for remaining uncertainties:
1
Justification:
ECHA default guidance
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
30.87 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
10
Dose descriptor starting point:
NOAEC
Value:
308.7 mg/m³
AF for dose response relationship:
1
Justification:
ECHA default guidance
AF for interspecies differences (allometric scaling):
1
Justification:
ECHA default guidance
AF for other interspecies differences:
1
Justification:
ECHA default guidance
AF for intraspecies differences:
10
Justification:
ECHA default guidance
AF for the quality of the whole database:
1
Justification:
ECHA default guidance
AF for remaining uncertainties:
1
Justification:
ECHA default guidance

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
7.1 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
Dose descriptor starting point:
NOAEL
Value:
710 mg/kg bw/day
AF for dose response relationship:
1
Justification:
ECHA default guidance
AF for differences in duration of exposure:
1
Justification:
ECHA default guidance
AF for interspecies differences (allometric scaling):
4
Justification:
ECHA default guidance
AF for other interspecies differences:
2.5
Justification:
ECHA default guidance
AF for intraspecies differences:
10
Justification:
ECHA default guidance
AF for the quality of the whole database:
1
Justification:
ECHA default guidance
AF for remaining uncertainties:
1
Justification:
ECHA default guidance
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
7.1 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
Dose descriptor starting point:
NOAEL
Value:
710 mg/kg bw/day
AF for dose response relationship:
1
Justification:
ECHA default guidance
AF for interspecies differences (allometric scaling):
4
Justification:
ECHA default guidance
AF for other interspecies differences:
2.5
Justification:
ECHA default guidance
AF for intraspecies differences:
10
Justification:
ECHA default guidance
AF for the quality of the whole database:
1
Justification:
ECHA default guidance
AF for remaining uncertainties:
1
Justification:
ECHA default guidance

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
17.75 mg/cm²
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
40
Dose descriptor:
NOAEC
Value:
308.7 mg/m³
AF for dose response relationship:
1
Justification:
ECHA default guidance
AF for differences in duration of exposure:
1
Justification:
ECHA default guidance
AF for interspecies differences (allometric scaling):
4
Justification:
ECHA default guidance
AF for other interspecies differences:
1
Justification:
ECHA default guidance
AF for intraspecies differences:
10
Justification:
ECHA default guidance
AF for the quality of the whole database:
1
Justification:
ECHA default guidance
AF for remaining uncertainties:
1
Justification:
ECHA default guidance
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
17.75 mg/cm²
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
40
Dose descriptor starting point:
NOAEC
Value:
308.7 mg/m³
AF for dose response relationship:
1
Justification:
ECHA default guidance
AF for interspecies differences (allometric scaling):
4
Justification:
ECHA default guidance
AF for other interspecies differences:
1
Justification:
ECHA default guidance
AF for intraspecies differences:
10
Justification:
ECHA default guidance
AF for the quality of the whole database:
1
Justification:
ECHA default guidance
AF for remaining uncertainties:
1
Justification:
ECHA default guidance

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
7.1 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
Dose descriptor starting point:
NOAEL
Value:
710 mg/kg bw/day
AF for dose response relationship:
1
Justification:
ECHA default guidance
AF for differences in duration of exposure:
1
Justification:
ECHA default guidance
AF for interspecies differences (allometric scaling):
4
Justification:
ECHA default guidance
AF for other interspecies differences:
2.5
Justification:
ECHA default guidance
AF for intraspecies differences:
10
Justification:
ECHA default guidance
AF for the quality of the whole database:
1
Justification:
ECHA default guidance
AF for remaining uncertainties:
1
Justification:
ECHA default guidance
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
7.1 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
Dose descriptor starting point:
NOAEL
Value:
710 mg/kg bw/day
AF for dose response relationship:
1
Justification:
ECHA default guidance
AF for interspecies differences (allometric scaling):
4
Justification:
ECHA default guidance
AF for other interspecies differences:
2.5
Justification:
ECHA default guidance
AF for intraspecies differences:
10
Justification:
ECHA default guidance
AF for the quality of the whole database:
1
Justification:
ECHA default guidance
AF for remaining uncertainties:
1
Justification:
ECHA default guidance

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

Based on the results of this combined 28-day repeated dose toxicity study with the reproduction/developmental toxicity screening test an parental, reproduction and developmental no-observed-adverse-effect level (NOAEL) of at least 10000 ppm for Aurantiol Pure was established, corresponding to an overall mean test item intake of 710 mg/kg bw/day for males.

No reproduction toxicity was observed up to the highest dose level tested (10000 ppm).

No treatment-related toxicologically significant changes were noted in any of the reproductive parameters investigated in this study (i.e. mating and fertility indices, precoital time, number of implantations, estrous cycle, spermatogenic profiling, and histopathological examination of reproductive organs).

No developmental toxicity was observed up to the highest dose level tested (10000 ppm).

No treatment-related changes were noted in any of the developmental parameters investigated in this study (i.e. gestation, viability and lactation indices, duration of gestation, parturition, sex ratio, maternal care and early postnatal pup development consisting of mortality, clinical signs, body weight, anogenital distance, areola/nipple retention, T4 thyroid hormone levels and macroscopic examination).

For the exposure scenarios assessment and DNELs, the male NOAEL has been chosen as the worse case parameter.