Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Acute/short term exposure
DNEL related information

Local effects

Acute/short term exposure
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
697.29 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
24
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
DNEL related information

Workers - Hazard for the eyes

Additional information - workers

Worker-DNEL long-term dermal route

The substance is considered as a non-hazardous substance which has no local toxicity and CMR concern. Therefore, the long term systemic toxicity is regarded as the leading health effect.

For isosorbide, a valid study addressing repeated dose toxicity is available:

In an oral (feed) 90-day subchronic toxicity study in rats according to OECD TG 408 (Repeated Dose 90-Day Oral Toxicity in Rodents), the No Observed Effect Level (NOEL) was established at 12500 ppm (corresponding to 748 mg/kg/day in males and 937 mg/kg/day in females) and the No Observed Adverse Effect Level (NOAEL) was set at 50,000 ppm (corresponding to 3,347 mg /kg/day in malesand 3,970 mg/kg/day in females).

Data from this study was considered a suitable dose descriptor for derivation of respective DNELs, and the defined NOAEL was chosen as the point of departure for derivation of the dermal long term systemic DNEL by route to route extrapolation. Based on the physical state of isosorbide, which has low vapour pressure (between 0.0057 and 0.0079 Pa) and is used in a granular form, dermal exposure is considered to be the relevant route, whereas inhalation route is considered as insignificant exposure.

NOAEL= 3,347 mg /kg/day was selected to derive DNELs.

There is no toxicokinetics study availe for isosorbide and only limited pharmacokinetic data were provided from the production of LAB 3822 (a mixture) by read-across approach. Hence there is no absorption data by either route.

Isosorbide is highly bioavaile and high levelof the systemic exposure was clearly demonstrated in a reproductive toxicity study and suggests no barriers to oral absorption but information from acute dermal toxicity (LD50>2,000 mg/kg, no effects) indicates low dermal absorption and no irritant effects on the skin.

Due to the lack on further specific route information, it is assumed that the bioavaiility across the skin is no greater than the oral bioavaiility. Therefore, an oral absorption of 50 % and dermal absorption of 10 % were assumed for isosorbide (CR12, IGHRC 2006).

To derive the long-term systemic dermal DNEL, the oral NOAEL of 3,347 mg /kg/day was converted into a corrected dermal NOAEL of 16,735 mg/kg bw/day according to the procedure recommended in the guidance document (R8, ECHA 2010).

Oral NOAEL =3,347 mg /kg/day; Absorption-oral =50 %Absorption-dermal =10 %.

Corrected dermal NOAEL=oral NOAEL * (Absorption-oral/ Absorption-dermal)

=3,347* (50/10) = 16,735 mg /kg/day

General Population - Hazard via inhalation route

Systemic effects

Acute/short term exposure
DNEL related information

Local effects

Acute/short term exposure
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
418.38 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
40
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
DNEL related information

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
83.68 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
40
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
DNEL related information

General Population - Hazard for the eyes

Additional information - General Population

General Population-DNEL long-term oral and dermal routes

The substance is considered as a non-hazardous substance which has no local toxicity and CMR concern. Therefore, the long term systemic toxicity is regarded as the leading health effect.

For isosorbide, a valid study addressing repeated dose toxicity is available:

In an oral (feed) 90-day subchronic toxicity study in rats according to OECD TG 408 (Repeated Dose 90-Day Oral Toxicity in Rodents), the No Observed Effect Level (NOEL) was established at 12,500 ppm (corresponding to 748 mg/kg/day in males and 937 mg/kg/day in females) and the No Observed Adverse Effect Level (NOAEL) was set at 50,000 ppm (corresponding to 3347 mg /kg/day in malesand 3,970 mg/kg/day in females).

Data from this study was considered a suitable dose descriptor for derivation of respective DNELs, and the defined NOAEL was chosen as the point of departure for derivation of the dermal long term systemic DNEL by route to route extrapolation. Based on the physical state of isosorbide, which has low vapour pressure (between 0.0057 and 0.0079 Pa) and is used in a granular form, oral and dermal exposure are considered to be the relevant routes, whereas inhalation route is considered as insignificant exposure.

NOAEL= 3,347 mg /kg/day was selected to derive both oral and dermal DNELs

There is no toxicokinetics study availe for isosorbide and only limited pharmacokinetic data were provided from the production of LAB 3822 (a mixture) by read-across approach. Hence there is no absorption data by either route.

Isosorbide is highly bioavailable and high levelof the systemic exposure was clearly demonstrated in a reproductive toxicity study and suggests no barriers to oral absorption but information from acute dermal toxicity (LD50>2000 mg/kg, no effects) indicates low dermal absorption and no irritant effects on the skin.

Due to the lack on further specific route information, it is assumed that the bioavailability across the skin is no greater than the oral bioavailability. Therefore an oral absorption of 50 % and dermal absorption of 10 % were assumed for isosorbide (CR12, IGHRC 2006).

To derive the long-term systemic dermal DNEL, the oral NOAEL of 3347 mg /kg/day was converted into a corrected dermal NOAEL of 16,735 mg/kg bw/day according to the procedure recommended in the guidance document (R8, ECHA 2010).

Oral NOAEL =3,347 mg /kg/day; Absorption-oral =50 %Absorption-dermal =10 %.

Corrected dermal NOAEL=oral NOAEL * (Absorption-oral/ Absorption-dermal)

=3347* (50/10) = 16,735 mg /kg/day