3,4-dihydro-2H-1,4-benzoxazin-6-ol

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.12 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):

75

Dose descriptor starting point:

NOAEL

Value:

10 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

8.82 mg/m³

Explanation for the modification of the dose descriptor starting point:

Data used for the calculation:
The Relevant dose descriptor: NOAEL: 10 mg/kg/bw based on microscopic findings in the kidneys observed with a dose-related incidence and severity at 100 and 1000 mg/kg/day in 28 days repeated dose toxicity study on rat Sprague Dawley OFA, receiving the substance in suspended 2 % Polysorbate 80 sterile water hydrogel (containing dimethicone) at doses: 0, 10, 100 and 1000 mg/kg bw/day in a volume of 10 mg/kg bw.

Route to route extrapolation: NOAEC = NOAEL x (1/sRV(rat)) x (sRVhuman/wRV) x (ABSoral/ABSinhal.)
NOAEC = 10 mg/kg/day x (1/0.38 m3/kg/bw) x (6.7 m3/10 m3) x (50%*/100%) = 8.82 mg/m3

*oral bioavailability as determined in toxicokinetic study, by default, inhalation bioavailability is supposed to be 100%.

In absence of toxicokinetic data, 50% (instead of 100%) absorption is assumed for oral absorption, and 100% for inhalation. (Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health)

The Assessment factor = 1 x 2.5 x 5 x 6 x 1 x 1 = 75
Worker-DNEL long term inhalation systemic= 8.82 mg/m3 / 75
Worker-DNEL long term inhalation systemic= 0.12 mg/m3

 

AF for dose response relationship:

1

Justification:

default value

AF for differences in duration of exposure:

6

Justification:

default value for extrapolation subacute to chronic

AF for interspecies differences (allometric scaling):

1

Justification:

Extrapolation from oral to inhalation route (example B3 of guidance R8))

AF for other interspecies differences:

2.5

Justification:

R8 ECHA guidance

AF for intraspecies differences:

5

Justification:

default value for workers

AF for the quality of the whole database:

1

AF for remaining uncertainties:

1

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

353 mg/m³

Most sensitive endpoint:

acute 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:

500 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

4.41 mg/m³

Explanation for the modification of the dose descriptor starting point:

The NOAEL = 500 mg/kg bw.
Calculation: according to ECHA guidance document R8, the rat respiratory volume is 0.2L/min/rat that mean for 4h: 0.2x 60x 4 = 48 L. The maximum achievable exposure regarding required 5 mg/L for 4 hours (OECD 403: 48 L x 5 mg/L = 240 mg/rat). 240 mg/0.250 kg bw = 960 mg/kg bw maximum achievable exposure
Oral Bioavailability = 50% (default value) Inhalation Bioavailability: Assumed to be 100% Determination of the correction factor oral vs. inhalation route: 50% oral vs. 100% inhalation = 0.50
NOAEC calc inhal.: 500 mg/kg bw x 0.250 kg bw x 0.5/48 L = 1.30 mg/L for 4h supposed exposure.
For the DNEL derivation the first step is to modify the starting point Rat NOAEC (4h) into NOAEC worker (4h), according to ECHA guidance on information requirements and chemical safety assessment R8. Rat NOAEC (4h) = 1.30 mg/L --> inhalation NOAEC worker (4h) = 1.30 mg/L x (sRVhuman/wRV) sRVhuman: standard respiratory volume for human: 6.7 m3 wRV: worker respiratory volume for 4 hours: 5 m3 --> NOAEC worker (4h) = 1.30 x (6.7/5) = 1.75 mg/L
NOAEC free base worker (4h) = 1.75 mg/L Conversion of the NOAEC for 4 hours to NOAEC for 15 minutes using Haber low: Haber law Cn x t = k with n=3 for extrapolation from longer to shorter duration: (1.75)3 x 4 x 60 = k = 1286.25 NOAEC (15 min) = 3√(1286.25/15) = 4.41 mg/L, NOAEC free base worker (15 min). Overall assessment factors (AS): 125 DNEL (4h) = NOAEC / AS = 4.41 / 12.5 = 0.353 mg/L = 353 mg/m3 Worker-DNEL acute for inhalation route-systemic (15 min) = 353 mg/m3.
This value is indicative and qualitative evaluation should also be considered.

AF for dose response relationship:

1

AF for interspecies differences (allometric scaling):

1

Justification:

Extrapolation from oral to inhalation route (example B3 of guidance R8)

AF for other interspecies differences:

2.5

Justification:

default value

AF for intraspecies differences:

5

Justification:

default value for workers

AF for the quality of the whole database:

1

AF for remaining uncertainties:

1

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.894 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):

120

Dose descriptor starting point:

NOAEL

Value:

10 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

227.27 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Further explanation on hazard conclusions:
In absence of toxicokinetic data, 50% (instead of 100%) absorption is assumed for oral absorption, and 2.2% for dermal exposure.
NOAEL: 10 mg/kg/bw based on microscopic findings in the kidneys observed with a dose-related incidence and severity at 100 and 1000 mg/kg/day in 28 days repeated dose toxicity study on rat Sprague Dawley OFA, receiving the substance in suspended 2 % Polysorbate 80 sterile water hydrogel (containing dimethicone) at doses: 0, 10, 100 and 1000 mg/kg bw/day in a volume of 10 mg/kg bw.
Determination of the correction factor oral vs. dermal route 50 % oral vs. 2.2 % dermal = 10 * (50/2.2) = 227.27 mg/kg bw /d NOAEL dermal
Assessment factor = 1x6x1x4x5x1x1 = 120
Worker DNEL for long term dermal route = 227.27 mg/kg /120
Worker DNEL for long term dermal route: 1.894 mg/kg bw

AF for dose response relationship:

1

Justification:

default value

AF for differences in duration of exposure:

6

Justification:

default value for extrapolation subacute to chronic

AF for interspecies differences (allometric scaling):

1

Justification:

default value

AF for other interspecies differences:

4

Justification:

default value

AF for intraspecies differences:

5

Justification:

default value for worker

AF for the quality of the whole database:

1

Justification:

default value

AF for remaining uncertainties:

1

Justification:

default factor

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

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

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified