Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
13.22 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
DNEL value:
750 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
DNEL value:
661.18 mg/m³
Explanation for the modification of the dose descriptor starting point:

No available data on inhalatory study; therefore DNEL is derived from oral study route.

Inhalatory N(L)OAEC = oral N(L)OAEL*(1/0.38 m3/kg/d)*0.67*(ABSoral/ABSinh)

ABSoral/ABSinh = 0.5

AF for dose response relationship:
1
Justification:
Starting point NOAEL
AF for differences in duration of exposure:
2
Justification:
Subchronic to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
Default
AF for other interspecies differences:
2.5
Justification:
Default
AF for intraspecies differences:
5
Justification:
Workers
AF for the quality of the whole database:
1
Justification:
Default
AF for remaining uncertainties:
2
Justification:
Read-across from analogue substance.
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:
no hazard identified
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3.75 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
DNEL value:
750 mg/kg bw/day
DNEL value:
750 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

No available data on dermal study; therefore DNEL is derived from oral study route.

Dermal N(L)OAEC = oral (N(L)OAEL*(ABSoral/ABSdermal)

ABSoral/ABSdermal = 1

AF for dose response relationship:
1
Justification:
Starting point NOAEL
AF for differences in duration of exposure:
2
Justification:
Subchronic to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
Rat
AF for other interspecies differences:
2.5
Justification:
Default
AF for intraspecies differences:
5
Justification:
Worker
AF for the quality of the whole database:
1
Justification:
Default
AF for remaining uncertainties:
2
Justification:
Read-across from analogue substance.
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:
no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

As basis for DNEL derivation, the result from a sub-chronic feeding study (Wilson et al.) performed on rats was used. In this study hesperidin, as a structural surrogate for test item, was dosed up to 1% in food over 200 days, producing no evidence of cumulative injury, effects on blood sugar levels, weights of important viscera or macroscopic and microscopic tissues. Hence, this study is chosen as basis for DNEL derivation, applying the highest applied dose as NOAEL value (750 mg/kg bw/d), in line with a worst case approach. A sub-chronic 90-day oral toxicity test was conducted by Lina et al. in rats with neohesperidin dihydrochalcone as structural surrogates for test item, finding a NOAEL of 750 mg/kg bw/day, which supports this approach. According to the results of the toxicokinetic assessment, as there is no quantitative data available for dermal adsorption of test material, a worst case scenario is assumed in which the absorption rate from dermal route is considered to be same as oral route, and for both routes assumed to be 100%, thus rendering the NOAELcorr for the dermal route to be 750 mg/kg.bw/day. As for the inhalation route, it is not considered further, as exposure scenarios for this substance do not indicate inhalation to be the likely route of exposure for humans. According to the ECHA guidance document, the oral NOAEL is converted to an inhalative NOAECWorker by dividing through 0.38 m3/kg resulting in a NOAEC of 1974 mg/m3.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3.26 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):
50
Dose descriptor starting point:
NOAEL
DNEL value:
750 mg/kg bw/day
DNEL value:
326.087 mg/m³
Explanation for the modification of the dose descriptor starting point:

No available data on inhalatory study; therefore DNEL is derived from oral study route.

Inhalation N(L)OAEC = oral N(L)OAEL*(1/1.15 m3/kg/d)*(ABSoral/ABSinh)

ABSoral/ABSinh = 0.5

AF for dose response relationship:
1
Justification:
Starting point NOAEL
AF for differences in duration of exposure:
2
Justification:
Subchronic to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
Default
AF for other interspecies differences:
2.5
Justification:
Default
AF for intraspecies differences:
10
Justification:
General population
AF for the quality of the whole database:
1
Justification:
Default (DNEL calculator)
AF for remaining uncertainties:
2
Justification:
Read-across from analogue substance.
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:
no hazard identified
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.88 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):
200
Dose descriptor starting point:
NOAEL
DNEL value:
750 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
DNEL value:
750 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

No available data on dermal study; therefore DNEL is derived from oral study route.

Dermal N(L)OAEC = oral (N(L)OAEL*(ABSoral/ABSdermal).

ABSoral/ABSdermal = 1

AF for dose response relationship:
1
Justification:
Starting point NOAEL
AF for differences in duration of exposure:
2
Justification:
Subchronic to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
Rat
AF for other interspecies differences:
2.5
Justification:
Default
AF for intraspecies differences:
10
Justification:
General population
AF for the quality of the whole database:
1
Justification:
Default
AF for remaining uncertainties:
2
Justification:
Read-across from analogue substance.
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:
no hazard identified

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.88 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):
200
Dose descriptor starting point:
NOAEL
DNEL value:
750 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
DNEL value:
750 mg/kg bw/day
AF for dose response relationship:
1
Justification:
Starting point NOAEL
AF for differences in duration of exposure:
2
Justification:
Subchronic to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
Rat
AF for other interspecies differences:
2.5
Justification:
Default
AF for intraspecies differences:
10
Justification:
General population
AF for the quality of the whole database:
1
Justification:
Default
AF for remaining uncertainties:
2
Justification:
Read-across from analogue substance.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

As a basis for DNEL derivation, the result from a sub-chronic feeding study with rats was used (Wilson, 1940), applying the highest applied dose as the NOAEL (750mg/kg bw/d), in line with a worst case approach. In this study, the analogue hesperidin was dosed up to 1% in food for over 200 days, and no evidence of cumulative injury, blood sugar levels, weights of important viscera or macroscopic and microscopic tissues has been observed. In another 90d oral toxicity study (Lina et al., 1990), the same NOAEL was obtained, supporting this approach. According to the results of the toxicokinetic assessment, as there is no quantitative data available for dermal adsorption of test material, a worst case scenario is assumed in which the absorption rate from dermal route is considered to be same as oral route (100%). Hence, the NOAELcorr for the dermal route is considered to be 750mg/kg bw/d. According to ECHA guidance document the oral NOAEL is converted to an inhalative NOAECWorkerby dividing through 0.38 m3/kg resulting in a NOAEC of 1974 mg/m3.The inhalation route is not considered further, as exposure scenarios for test item do not indicate inhalative exposure to be the likely route of exposure to humans in regular use.