Methyl isothiocyanate

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.13 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

75

Modified dose descriptor starting point:

NOAEC

Value:

10 mg/m³

Explanation for the modification of the dose descriptor starting point:

Modification of starting point : NOAEC (rat) = 19.9 mg/m3. Correction of respiratory volume for relevant duration and, correction for exposure duration in study (6h/d, 5d/wk) to default worker exposure (8h/d, 5d/wk): NOAEC corrected = 19.9 x 6.7/10 x 6/8 x 5/5= 10 mg/m3

AF for dose response relationship:

1

Justification:

This factor is applied because the dose-descriptor starting point is a NOAEC.

AF for differences in duration of exposure:

6

Justification:

DNEL is based on a subacute study (28-day).

AF for interspecies differences (allometric scaling):

1

Justification:

AF not used for inhalation.

AF for other interspecies differences:

2.5

Justification:

A factor of 2.5 is applied for remaining difference.

AF for intraspecies differences:

5

Justification:

A factor of 5 is applied for worker DNELs.

AF for the quality of the whole database:

1

Justification:

The key study is considered as a reliable study.

AF for remaining uncertainties:

1

Justification:

No other assessment factor is applied.

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

51.6 mg/m³

Most sensitive endpoint:

acute toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

12.5

Modified dose descriptor starting point:

NOAEC

Value:

644.9 mg/m³

Explanation for the modification of the dose descriptor starting point:

Step 1: Selection of the relevant dose descriptor: NOAEC (rat, 1h) = 0.6 g/m3= 600 mg/m3 based on limited clinical signs and at this concentration and mortality at 1.5 g/m3 Step 2: Modification of the starting point: • Time extrapolation Time extrapolation to the reference period of 15 minutes for acute effects, using the modified Haber's law (Cn x t = k) with a n coefficient of 3 for extrapolation from a longer to a shorter exposure duration: NOAEC (15 minutes) = 952 mg/m3 • Modification for respiratory volume. Respiratory volume of human is 0.2 L/min/kg, for 15 minutes we have a respiratory volume of 3 L/kg, corresponding to 0.21 m3/person (70kg). Respiratory volume light activity for worker (8h) is 10 m3/person. For 15 minutes we have a respiratory volume of 0.31 m3/person. NOAEC = 952 x 0.21/0.31 = 644.9 mg/m3

AF for dose response relationship:

1

Justification:

This factor is applied because the dose-descriptor starting point is a NOAEC.

AF for interspecies differences (allometric scaling):

1

Justification:

DNEL is based on an acute study, no additional factor is required.

AF for other interspecies differences:

2.5

Justification:

A factor of 2.5 is applied for remaining difference.

AF for intraspecies differences:

5

Justification:

A factor of 5 is applied for worker DNELs.

AF for the quality of the whole database:

1

Justification:

The key study is considered as a reliable study.

AF for remaining uncertainties:

1

Justification:

No other assessment factor is applied.

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.65 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

1

Dose descriptor:

NOAEC

AF for dose response relationship:

1

Justification:

This factor is applied because the dose-descriptor starting point is a NOAEC.

AF for differences in duration of exposure:

1

Justification:

No cumulative effects are expected based on a rapid recovery upon cessation of the exposure.

AF for interspecies differences (allometric scaling):

1

Justification:

No factor is added because key study was made on humans.

AF for other interspecies differences:

1

Justification:

No factor is added because key study was made on humans.

AF for intraspecies differences:

1

Justification:

A large number of individuals were included in the study. A factor of 1 is sufficient.

AF for the quality of the whole database:

1

Justification:

The key study is considered as a reliable study.

AF for remaining uncertainties:

1

Justification:

No other assessment factor is applied.

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.8 mg/m³

Most sensitive endpoint:

skin irritation/corrosion

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

1

Dose descriptor starting point:

NOAEC

AF for dose response relationship:

1

Justification:

This factor is applied because the dose-descriptor starting point is a NOAEC.

AF for interspecies differences (allometric scaling):

1

Justification:

No factor is added because key study was made on humans.

AF for other interspecies differences:

1

Justification:

No factor is added because key study was made on humans.

AF for intraspecies differences:

1

Justification:

A large number of individuals were included in the study. A factor of 1 is sufficient.

AF for the quality of the whole database:

1

Justification:

The key study is considered as a reliable study.

AF for remaining uncertainties:

1

Justification:

No other assessment factor is applied.

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.027 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):

300

Modified dose descriptor starting point:

NOAEL

Value:

8 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

dermal Absorption = oral Absorption (worst case), Absorption in rat = Absorption in human

AF for dose response relationship:

1

Justification:

This factor is applied because the dose-descriptor starting point is a NOAEL

AF for differences in duration of exposure:

6

Justification:

DNEL is based on a subacute study (28-day).

AF for interspecies differences (allometric scaling):

4

Justification:

An allometric scaling factor of 4 must be applied because the key study was performed on rats.

AF for other interspecies differences:

2.5

Justification:

A factor of 2.5 is applied for remaining difference.

AF for intraspecies differences:

5

Justification:

A factor of 5 is applied for worker DNELs.

AF for the quality of the whole database:

1

Justification:

The key study is considered as a reliable study.

AF for remaining uncertainties:

1

Justification:

No other assessment factor is applied.

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.4 mg/kg bw/day

Most sensitive endpoint:

acute toxicity

Route of original study:

Dermal

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

150

Modified dose descriptor starting point:

LOAEL

Value:

60 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Step 1: Selection of the relevant dose descriptor: LOAEL (rat, 24h) = 60 mg/kg/d based on dyspnea observed at this dose, but no mortality. LOAEC (rabbit, 24h) = 50 mg/kg/d based on dyspnea observed at this dose, but no mortality. Step 2: Modification of the starting point: Time extrapolation: not required for dermal study. Absorption extrapolation rat/human: no difference of dermal absorption is expected between rat/rabbit and human.

AF for dose response relationship:

3

Justification:

This factor is applied because the dose-descriptor starting point is a LOAEL

AF for interspecies differences (allometric scaling):

4

Justification:

An allometric scaling factor of 4 must be applied because the key study was performed on rats.

AF for other interspecies differences:

2.5

Justification:

A factor of 2.5 is applied for remaining difference.

AF for intraspecies differences:

5

Justification:

A factor of 5 is applied for worker DNELs.

AF for the quality of the whole database:

1

Justification:

The key study is considered as a reliable study.

AF for remaining uncertainties:

1

Justification:

No other assessment factor is applied.

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:

skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - workers

DNEL Acute / short term exposure - local effects/ inhalation

The most relevant and supportable acute toxicity endpoint was eye irritation, identified in an experimental study conducted with 70 human volunteers (Russell and Rush, 1996). The air concentration NOEC was 0.6 ppm for a 14-min exposure, based on the occurrence of eye irritation at 1.9 ppm. The use of a NOEC based on eye irritation is considered a prudent step to protect the population not only from methyl isothiocyanate’s ocular effects, but also from potentially more serious impacts, notably to the respiratory system.

Step 1) Relevant dose-descriptor: NOEC, human = 1.8 mg/m³

Step 2) Modification of starting point:

Correction of respiratory volume for relevant duration: Correction for activity driven differences of respiratory volumes in workers compared to workers in rest (10 m³/6.7 m³) is not required (ECHA 2008) because it is a local, concentration-driven effect.

Step 3) Assessment factors:

* Interspecies: 1 - Justification: There are human data.

* Intraspecies: 1 – Justification: a large number of individuals have been enrolled in this study: seventy individuals (38 males, 32 females) with a mean age of 32 years (range, 18-67 years; median age, 28 years)

* Exposure duration: 1 (acute DNEL, 15-min exposure)

* Dose response: 1

* Quality of database: 1

Global assessment factor = 1

Step 4) DNEL calculation:

DNEL (acute inhalation, local effect) = 1.8 / 1 = 1.8 mg/m³

   

Long-term exposure - local effects/ Inhalation

a) The DNEL for long-term toxicity (local effects) is based on the definitive NOEC (8-hour exposure) of 0.22 ppm =0.65 mg/m³), based on the occurrence of eye irritation in humans at 0.8 ppm (Russell and Rush, 1996). 16 subjects were studied in this test.

Step 1) Relevant dose-descriptor: NOEC human = 0.65 mg/m³

Step 2) Modification of starting point:

Correction of respiratory volume for relevant duration: Correction for activity driven differences of respiratory volumes in workers compared to workers in rest (10 m³/6.7 m³) is not required (ECHA 2008) because it is a local, concentration-driven effect.

Step 3) Assessment factors:

* Interspecies: 1 (human data)

* Intraspecies: 1 – Justification: a large number of individuals have been enrolled in this study: seventy individuals (38 males, 32 females) with a mean age of 32 years (range, 18-67 years; median age, 28 years)

* Exp. duration: 1(No cumulative effects are expected based on a rapid recovery upon cessation of the exposure)

* Dose response: 1

* Quality of database: 1

Global assessment factor = 1

Step 4) DNEL calculation:

DNEL (long-term inhalation, local effect) = 0.65 mg/m³

b) The animal study selected for evaluation of potential local effects due to long-term exposure was the 4-week Wistar rat whole-body inhalation study of Klimisch et al. (1987). The endpoint used to establish the NOAEC was pathological changes of the respiratory tract, metaplasia of respiratory epithelium, atrophy of the olfactory epithelium, tracheal epithelial proliferation and single cell necrosis, bronchopneumonia and bronchial and bronchiolar epithelial proliferation at the concentration 34 ppm (100 mg/m³). The NOAEC was 6.8 ppm (19.9 mg/m³).

Step 1) Relevant dose-descriptor: NOAEC rat = 19.9 mg/m³

Step 2) Modification of starting point:

* Correction of respiratory volume for relevant duration:

Correction for activity driven differences of respiratory volumes in workers compared to workers in rest (10 m³/6.7 m³) is not required (ECHA 2008) because it is a local, concentration-driven effect

* Correction or exposure duration in study (6h/d, 5d/wk) to default worker exposure (8h/d, 5d/wk).

* No difference in inhalation absorption between rat and human.

NOAEC corrected = 19.9 x 6/8 x 5/5 = 14.9 mg/m³

Step 3) Assessment factors:

* Interspecies: 1Justification: AF for remaining differences is not justified for local irritation (ECETOC, 2009)

* Intraspecies: 5

* Exposure duration: 1Justification: The effect is considered concentration- rather than dose-dependent

* Dose response: 1

* Quality of database: 1

Global assessment factor = 5

Step 4) DNEL calculation:

DNEL (long-term inhalation, local effect) = 14.9 / 5 = 3 mg/m³

c) A conservative DNEL of 0.65 mg/m³is selected for long-term exposure, local effects by inhalation

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.024 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

150

Modified dose descriptor starting point:

NOAEC

Value:

3.55 mg/m³

Explanation for the modification of the dose descriptor starting point:

Step 1: Selection of the relevant dose descriptor: NOAEC = 19.9 mg/m3 (28j rat) Step 2: Modification of the starting point: Modification for respiratory volume: not required for general population. Modification for exposure duration (general population vs study exposure): NOAEC = 19.9 x 6/24 x 5/7 = 3.55 mg/m3

AF for dose response relationship:

1

Justification:

This factor is applied because the dose-descriptor starting point is a NOAEC.

AF for differences in duration of exposure:

6

Justification:

DNEL is based on a subacute study (28-day).

AF for interspecies differences (allometric scaling):

1

Justification:

AF not used for inhalation.

AF for other interspecies differences:

2.5

Justification:

A factor of 2.5 is applied for remaining difference.

AF for intraspecies differences:

10

Justification:

A factor of 10 is applied for the general population DNELs.

AF for the quality of the whole database:

1

Justification:

The key study chosen for DNEL calculation is considered as a reliable study.

AF for remaining uncertainties:

1

Justification:

No other assessment factor is applied.

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

38.1 mg/m³

Most sensitive endpoint:

acute toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

25

Modified dose descriptor starting point:

NOAEC

Value:

952 mg/m³

Explanation for the modification of the dose descriptor starting point:

Step 1: Selection of the relevant dose descriptor: NOAEC (rat, 1h) = 0.6 g/m3= 600 mg/m3 based on limited clinical signs and at this concentration and mortality at 1.5 g/m3 Step 2: Modification of the starting point: • Time extrapolation Time extrapolation to the reference period of 15 minutes for acute effects, using the modified Haber's law (Cn x t = k) with a n coefficient of 3 for extrapolation from a longer to a shorter exposure duration: NOAEC (15 minutes) = 952 mg/m3 • Modification for respiratory volume. Not required for general population

AF for dose response relationship:

1

Justification:

This factor is applied because the dose-descriptor starting point is a NOAEC.

AF for interspecies differences (allometric scaling):

1

Justification:

DNEL is based on an acute study, no additional factor is required.

AF for other interspecies differences:

2.5

Justification:

A factor of 2.5 is applied for remaining difference.

AF for intraspecies differences:

10

Justification:

A factor of 10 is applied for the general population DNELs.

AF for the quality of the whole database:

1

Justification:

The key study chosen for DNEL calculation is considered as a reliable study.

AF for remaining uncertainties:

1

Justification:

No other assessment factor is applied.

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.355 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

AF for dose response relationship:

1

Justification:

This factor is applied because the dose-descriptor starting point is a NOAEC.

AF for differences in duration of exposure:

1

Justification:

The effects are not considered to be dose-dependent.

AF for interspecies differences (allometric scaling):

1

Justification:

AF not used for inhalation.

AF for other interspecies differences:

1

Justification:

Assessment factor for remaining difference is not justified for local irritation.

AF for intraspecies differences:

10

Justification:

A factor of 10 is applied for the general population DNELs.

AF for the quality of the whole database:

1

Justification:

The key study chosen for DNEL calculation is considered as a reliable study.

AF for remaining uncertainties:

1

Justification:

No other assessment factor is applied.

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.8 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

1

Dose descriptor starting point:

NOAEC

AF for dose response relationship:

1

Justification:

This factor is applied because the dose-descriptor starting point is a NOAEC.

AF for interspecies differences (allometric scaling):

1

Justification:

There is a human data.

AF for other interspecies differences:

1

Justification:

There is a human data.

AF for intraspecies differences:

1

Justification:

A large if number of individuals have been enrolled in this study: 70 individuals (38 males and 32 females) with a mean age of 32 years (range 18/67 years; median age 28 years).

AF for the quality of the whole database:

1

Justification:

A factor of 10 is applied for the general population DNELs.

AF for remaining uncertainties:

1

Justification:

No other assessment factor is applied.

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.013 mg/kg bw/day

Most sensitive endpoint:

acute toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

600

Modified dose descriptor starting point:

NOAEL

Value:

8 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

NOAEL (oral) = 8 mg/kg/d (28 jours, rat) Modification of the starting point: Dermal Absorption = oral Absorption (worst case) Absorption in rat = Absorption in human

AF for dose response relationship:

1

Justification:

This factor is applied because the dose-descriptor starting point is a NOAEL

AF for differences in duration of exposure:

6

Justification:

DNEL is based on a subacute study (28-day).

AF for interspecies differences (allometric scaling):

4

Justification:

An allometric scaling factor of 4 must be applied because the key study was performed on rats.

AF for other interspecies differences:

2.5

Justification:

A factor of 2.5 is applied for remaining difference.

AF for intraspecies differences:

10

Justification:

A factor of 10 is applied for the general population DNELs.

AF for the quality of the whole database:

1

Justification:

The key study chosen for DNEL calculation is considered as a reliable study.

AF for remaining uncertainties:

1

Justification:

No other assessment factor is applied.

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.2 mg/kg bw/day

Most sensitive endpoint:

acute 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:

LOAEL

Value:

60 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Step 1: Selection of the relevant dose descriptor: LOAEL (rat, 24h) = 60 mg/kg/d based on dyspnea observed at this dose, but no mortality. Step 2: Modification of the starting point: • Time extrapolation: not required for dermal study. • Absorption extrapolation rat/human: no difference of dermal absorption is expected between rat and human.

AF for dose response relationship:

3

Justification:

This factor is applied because the dose-descriptor starting point is a LOAEL.

AF for interspecies differences (allometric scaling):

4

Justification:

An allometric scaling factor of 4 must be applied because the key study was performed on rats.

AF for other interspecies differences:

2.5

Justification:

A factor of 2.5 is applied for remaining difference.

AF for intraspecies differences:

10

Justification:

A factor of 10 is applied for the general population DNELs.

AF for the quality of the whole database:

1

Justification:

The key study chosen for DNEL calculation is considered as a reliable study.

AF for remaining uncertainties:

1

Justification:

No other assessment factor is applied.

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:

skin irritation/corrosion

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.013 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):

600

Modified dose descriptor starting point:

NOAEL

Value:

8 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No Modification of the starting point: Absorption in rat = Absorption in human

AF for dose response relationship:

1

Justification:

This factor is applied because the dose-descriptor starting point is a NOAEL

AF for differences in duration of exposure:

6

Justification:

DNEL is based on a subacute study (28-day).

AF for interspecies differences (allometric scaling):

4

Justification:

An allometric scaling factor of 4 must be applied because the key study was performed on rats.

AF for other interspecies differences:

2.5

Justification:

A factor of 2.5 is applied for remaining difference.

AF for intraspecies differences:

10

Justification:

A factor of 10 is applied for the general population DNELs.

AF for the quality of the whole database:

1

Justification:

The key study chosen for DNEL calculation is considered as a reliable study.

AF for remaining uncertainties:

1

Justification:

No other assessment factor is applied.

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.08 mg/kg bw/day

Most sensitive endpoint:

acute toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

300

Modified dose descriptor starting point:

LOAEL

Value:

25 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Time extrapolation: not required for oral study. Absorption extrapolation rat/human: no difference of oral absorption is expected between rat and human.

AF for dose response relationship:

3

Justification:

This factor is applied because the dose-descriptor starting point is a LOAEL

AF for interspecies differences (allometric scaling):

4

Justification:

An allometric scaling factor of 4 must be applied because the key study was performed on rats.

AF for other interspecies differences:

2.5

Justification:

A factor of 2.5 is applied for remaining difference.

AF for intraspecies differences:

10

Justification:

A factor of 10 is applied for the general population DNELs.

AF for the quality of the whole database:

1

Justification:

The key study chosen for DNEL calculation is considered as a reliable study.

AF for remaining uncertainties:

1

Justification:

No other assessment factor is applied.

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - General Population

Long-term exposure - local effects/ Inhalation

a) The DNEL for long-term toxicity (local effects) is based on the definitive NOEC (8-hour exposure) of 0.22 ppm =0.65 mg/m³), based on the occurrence of eye irritation in humans at 0.8 ppm (Russell and Rush, 1996). 16 subjects were studied in this test.

Step 1) Relevant dose-descriptor: NOEC human = 0.65 mg/m³

Step 2) Modification of starting point:

Correction of respiratory volume for relevant duration: Not required for general population

Step 3) Assessment factors:

* Interspecies: 1 (human data)

* Intraspecies: 1 – Justification: a large number of individuals have been enrolled in this study: seventy individuals (38 males, 32 females) with a mean age of 32 years (range, 18-67 years; median age, 28 years)

* Exp. duration: 1(No cumulative effects are expected based on a rapid recovery upon cessation of the exposure)

* Dose response: 1

* Quality of database: 1

Global assessment factor = 1

Step 4) DNEL calculation:

DNEL (long-term inhalation, local effect) = 0.65 mg/m³

 

b) The animal study selected for evaluation of potential local effects due to long-term exposure was the 4-week Wistar rat whole-body inhalation study of Klimisch et al. (1987). The endpoint used to establish the NOAEC was pathological changes of the respiratory tract, metaplasia of respiratory epithelium, atrophy of the olfactory epithelium, tracheal epithelial proliferation and single cell necrosis, bronchopneumonia and bronchial and bronchiolar epithelial proliferation at the concentration 34 ppm (100 mg/m³). The NOAEC was 6.8 ppm (19.9 mg/m³).

Step 1) Relevant dose-descriptor: NOAEC rat = 19.9 mg/m³

Step 2) Modification of starting point:

* Correction of respiratory volume for relevant duration: not required for general population

* Correction or exposure duration in study (6h/d, 5d/wk) to default general population (24h/d, 7d/wk).

* No difference in inhalation absorption between rat and human.

NOAEC corrected = 19.9 x 6/24 x 5/7 = 3.55 mg/m³

Step 3) Assessment factors:

* Interspecies: 1AF for remaining differences is not justified for local irritation (ECETOC, 2009)

* Intraspecies: 10

* Exposure duration: 1Justification: The effect is considered concentration- rather than dose-dependent

* Dose response: 1

* Quality of database: 1

Global assessment factor = 10

Step 4) DNEL calculation:

DNEL (long-term inhalation, local effect) = 3.55/10 = 0.355 mg/m³

 

c) A conservative DNEL of 0.355 mg/m³is selected for long-term exposure, local effects by inhalation

Acute / short term exposure - systemic effects/ Dermal

 

Step 1: Selection of the relevant dose descriptor:

LOAEL (rat, 24h) = 60 mg/kg/dbased on dyspnea observed at this dose, but no mortality.

LOAEL (rabbit, 24h) = 50 mg/kg/dbased on dyspnea observed at this dose, but no mortality.

 

Step 2: Modification of the starting point:

 

·                    Time extrapolation: not required for dermal study.

·                    Absorption extrapolation rat/human: no difference of dermal absorption is expected between rat/rabbit and human.

 

 

Step 3: Assessment factors:

- Interspecies differences: a factor of 4 is applied for rats, and a factor of 2.4 for rabbits. However, a factor of 2.5 to correct for differences other than differences in metabolic rate is applied.

- Intraspecies differences: the default assessment factor of 10 is applied (for general pop)

-Dose-response: a factor of 3 is applied because we have a LOAEC

-Quality of whole database: a factor of 1 is applied based on the good quality of the whole database.

-Exposure duration: no factor is necessary (acute study / acute DNEL)

 

Global assessment factor (rat study) = 4 x 2.5 x 10 x 3 = 300

Global assessment factor (rat study) = 2.4 x 2.5 x 10 x 3 = 180

 

Step 4: DNEL derivation:

Rat study: DNEL = 60 / 300 = 0.20 mg/kg/d

Rabbit study: DNEL = 50 / 180 = 0.28 mg/kg/d

 

DNEL (acute, systemic effects)/dermal = 0.20 mg/kg/d (worst case)