Nicotine

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

31.3 µg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

other:

Overall assessment factor (AF):

225

Dose descriptor starting point:

LOAEC

Value:

10 mg/m³

Modified dose descriptor starting point:

LOAEC

Value:

7.04 mg/m³

Explanation for the modification of the dose descriptor starting point:

Correction factors for the modified starting point are as follows:

-Correction for differences between human and experimental exposure:

Worker exposure duration is considered to be 8 hours per day, 5 days/week. The animals in the experimental study were exposed 6 hours per day, 7 days/week:

1.05= 6/8 (hours/day)(animal/human) x 7/5 (days/week)

- Correction for differences in respiratory volume = 1

- Correction for differences in bioavailability = 1

- Correction for light activity at work = 0.67

The LOAECcorr is calculated as follows: LOAECcorr= 10 mg/m³ * ((6 h/d)/(8 h/d))*(7 d/w)/(5 d/w))* 0.67 (light activity) = 7.04 mg/m³

AF for dose response relationship:

3

Justification:

Default (DNEL calculator)

AF for differences in duration of exposure:

6

Justification:

Default (DNEL calculator)

AF for interspecies differences (allometric scaling):

1

Justification:

Default (DNEL calculator)

AF for other interspecies differences:

2.5

Justification:

Default (DNEL calculator)

AF for intraspecies differences:

5

Justification:

Default (DNEL calculator)

AF for the quality of the whole database:

1

Justification:

Default (DNEL calculator): Study was performed under GLP and the quality is considered to be very high (Klimisch 1).

AF for remaining uncertainties:

1

Justification:

The approach of the DNEL derivation is conservative. No further assessment factors are required.

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

8.6 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

Dose descriptor starting point:

NOAEC

Value:

10 mg/m³

Modified dose descriptor starting point:

NOAEC

Value:

107.2 mg/m³

Explanation for the modification of the dose descriptor starting point:

Correction factors for the modified starting point are as follows:

- Correction for differences in respiratory volume = 1

- Correction for differences in bioavailability = 1

- Correction for light activity at work = 0.67

- Correction for differences between human and experimental = 16 (240/15=16; default short-term exposure for workers is 15 min (ECHA guidance), 240 min is the standard exposure duration of acute inhalation toxicity tests and the convulsion in the 25µg/L dose group was observed after 4 hours of exposure.)

Corrected starting point:

NOAECcorr= 10 mg/m³ (NOAEC) x 0.67 (light activity at work) x 16 (differences in exposure duration) = 107.2 mg/m³

AF for dose response relationship:

1

Justification:

Default AF, ECHA guidance R.8

AF for interspecies differences (allometric scaling):

1

Justification:

Default (ECHA guidance)

AF for other interspecies differences:

2.5

Justification:

Default (ECHA guidance)

AF for intraspecies differences:

5

Justification:

Default (ECHA guidance)

AF for the quality of the whole database:

1

Justification:

Default (ECHA guidance)

AF for remaining uncertainties:

1

Justification:

The approach of the DNEL derivation is conservative. No further assessment factors are required.

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:

4.43 µg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

other:

Overall assessment factor (AF):

900

Dose descriptor starting point:

LOAEC

Value:

10 000 µg/m³

Modified dose descriptor starting point:

LOAEL

Value:

3.99 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Correction factors for the modified starting point are as follows:

- Correction for differences between human and experimental conditions:

Worker exposure duration is considered to be 8 hours per day, 5 days/week. The animals in the experimental study were exposed 6 hours per day, 7 days/week:

1.05= 6/8 (hours/day)(animal/human) x 7/5 (days/week)

-Correction for respiratory volume= 0.38

-Correction for light activity at work= 1

Corrected starting point:

LOAECcorr= 10000 µg/m³ (LOAEC) x 1 (light activity at work) x 0.38 (resp. volume) x 1.05 (differences in exposure duration) = 3.99 mg/kg bw/day

AF for dose response relationship:

3

Justification:

Default (DNEL calculator)

AF for differences in duration of exposure:

6

Justification:

Default (DNEL calculator)

AF for interspecies differences (allometric scaling):

4

Justification:

Default (DNEL calculator)

AF for other interspecies differences:

2.5

Justification:

Default (DNEL calculator)

AF for intraspecies differences:

5

Justification:

Default (DNEL calculator)

AF for the quality of the whole database:

1

Justification:

Default (DNEL calculator): Study was performed under GLP and the quality is considered to be very high (Klimisch 1).

AF for remaining uncertainties:

1

Justification:

The approach of the DNEL derivation is conservative. No further assessment factors are required.

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.84 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):

90

Dose descriptor starting point:

LOAEC

Value:

50 mg/kg bw/day

Modified dose descriptor starting point:

LOAEL

Value:

76 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Correction factors for the modified starting point are as follows:

- Correction for differences in respiratory volume = 0.38

- Correction for differences in bioavailability = 1

- Correction for light activity at work = 1

- Correction for differences between human and experimental conditions= 4 (60/15=4; default short-term exposure for workers is 15 min, signs of CNS depression were observed in the 50 mg/kg bw dose group after 1 hour of exposure.)

Corrected starting point:

LOAECcorr= 50 mg/kg bw (LOAEC) x 0.38 (resp. volume) x 1 (light activity at work) x 4 (differences in exposure duration) = 76 mg/kg bw

AF for dose response relationship:

3

Justification:

Default (ECHA guidance): Extrapolation from LOAEC to NOAEC

AF for interspecies differences (allometric scaling):

2.4

Justification:

Default (ECHA guidance): Allometric scaling rabbit - human.

AF for other interspecies differences:

2.5

Justification:

Default (ECHA guidance)

AF for intraspecies differences:

5

Justification:

Default (ECHA guidance)

AF for the quality of the whole database:

1

Justification:

Study was performed under GLP and the quality is considered to be very high (Klimisch 1).

AF for remaining uncertainties:

1

Justification:

The approach of the DNEL derivation is conservative. No further assessment factors are required.

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.2 mg/cm²

Most sensitive endpoint:

skin irritation/corrosion

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

15

Dose descriptor starting point:

LOAEC

Value:

3 mg/m³

AF for dose response relationship:

3

Justification:

Default (ECHA guidance): Extrapolation of the LOAEC to the NAEC.

AF for interspecies differences (allometric scaling):

1

Justification:

According to ECHA guidance R.8 allometric scaling should not be applied if the effects are not dependent on metabolic rate or systemic absorption, e.g. in the case of local effects.

AF for other interspecies differences:

1

Justification:

Since the mechanism (direct chemical reactivity with cell membranes) of skin irritation/corrosion is
considered to be the same in experimental animals and in human, no inter-species AF is to be applied (ECHA guidance R.8)

AF for intraspecies differences:

5

Justification:

Default (ECHA guidance)

AF for the quality of the whole database:

1

Justification:

Study was performed under GLP and the quality is considered to be very high (Klimisch 1).

AF for remaining uncertainties:

1

Justification:

The approach of the DNEL derivation is conservative. No further assessment factors are required.

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

5.56 µg/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):

450

Dose descriptor starting point:

LOAEC

Value:

10 mg/m³

Modified dose descriptor starting point:

LOAEC

Value:

2.5 mg/m³

Explanation for the modification of the dose descriptor starting point:

Correction factors for the modified starting point are as follows:

- Correction for differences in respiratory volume = 1

- Correction for differences in bioavailability = 1

- Correction for differences between human and experimental conditions=

Consumer exposure duration is considered to be 24 hours per day, 7 days/week. The animals in the experimental study were exposed 6 hours per day, 7 days/week:

0.25 = 6/24 (hours/day)(animal/human) x 7/7 (days/week)

Corrected starting point:

LOAECcorr= 10 mg/m³ (LOAEC) x 1 (resp. volume) x 1 (bioavailability) x 0.25 (differences in exposure duration) = 2.5 mg/m³

AF for dose response relationship:

3

Justification:

Default (DNEL calculator)

AF for differences in duration of exposure:

6

Justification:

Default (DNEL calculator)

AF for interspecies differences (allometric scaling):

1

Justification:

Default (DNEL calculator)2,5

AF for other interspecies differences:

2.5

Justification:

Default (DNEL calculator)

AF for intraspecies differences:

10

Justification:

Default (DNEL calculator)

AF for the quality of the whole database:

1

Justification:

Default (DNEL calculator)

AF for remaining uncertainties:

1

Justification:

No further uncertainties expected.

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

6.4 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

Dose descriptor starting point:

NOAEC

Value:

10 mg/m³

Modified dose descriptor starting point:

NOAEC

Value:

160 mg/m³

Explanation for the modification of the dose descriptor starting point:

Correction factors for the modified starting point are as follows:

- Correction for differences in respiratory volume = 1

- Correction for differences in bioavailability = 1

- Correction for differences between human and experimental conditions= 16 (240/15=12; default short-term exposure is 15 min (ECHA guidance), 240 min is the standard exposure duration of acute inhalation toxicity tests and the convulsion in the 25µg/L dose group was observed after 4 hours of exposure.)

Corrected starting point:*NOAECcorr= 10 mg/m³ (NOAEC) x 16 (differences in exposure duration) = 160 mg/m³

AF for dose response relationship:

1

Justification:

Default (ECHA guidance)

AF for interspecies differences (allometric scaling):

1

Justification:

Default (ECHA guidance)

AF for other interspecies differences:

2.5

Justification:

Default (ECHA guidance)

AF for intraspecies differences:

10

Justification:

Default (ECHA guidance)

AF for the quality of the whole database:

1

Justification:

Study was performed under GLP and the quality is considered to be very high (Klimisch 1).

AF for remaining uncertainties:

1

Justification:

The approach of the DNEL derivation is conservative. No further assessment factors are required.

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:

1.597 µg/kg bw/day

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):

1 800

Dose descriptor starting point:

LOAEC

Value:

10 mg/m³

Modified dose descriptor starting point:

LOAEL

Value:

2.875 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Correction factors for the modified starting point are as follows:

- Correction for differences in respiratory volume = 1.15

- Correction for differences in bioavailability = 1

- Correction for differences between human and experimental exposure duration=

Consumer exposure duration is considered to be 24 hours per day, 7 days/week. The animals in the experimental study were exposed 6 hours per day, 7 days/week:

0.25 = 6/24 (hours/day)(animal/human) x 7/7 (days/week)

Corrected starting point:

LOAECcorr= 10 mg/m³ (LOAEC) x 1.15 m³/kg bw (resp.volume) x 0.25 (differences in exposure duration) = 2.875 mg/kg bw/day

AF for dose response relationship:

3

Justification:

Default (DNEL calculator)

AF for differences in duration of exposure:

6

Justification:

Default (DNEL calculator)

AF for interspecies differences (allometric scaling):

4

Justification:

Default (DNEL calculator)

AF for other interspecies differences:

2.5

Justification:

Default (DNEL calculator)

AF for intraspecies differences:

10

Justification:

Default (DNEL calculator)

AF for the quality of the whole database:

1

Justification:

Default (DNEL calculator): Study was performed under GLP and the quality is considered to be very high (Klimisch 1).

AF for remaining uncertainties:

1

Justification:

The approach of the DNEL derivation is conservative. No further assessment factors are required.

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.1 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):

180

Dose descriptor starting point:

LOAEC

Value:

50 mg/kg bw/day

Modified dose descriptor starting point:

LOAEL

Value:

200 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Correction factors for the modified starting point are as follows:

- Correction for differences in respiratory volume = 1

- Correction for differences in bioavailability = 1

- Correction for differences between human and experimental exposure duration= 4 (60/15=4; default short-term dermal exposure for consumers is 15 min, signs of CNS depression were observed in the 50 mg/kg bw dose group after 1 hour of exposure.)

Corrected starting point:

LOAECcorr= 50 mg/kg bw (LOAEC) x 4 (differences in exposure duration) = 200 mg/kg bw

AF for dose response relationship:

3

Justification:

Default (ECHA guidance): Extrapolation from LOAEC to NOAEC

AF for interspecies differences (allometric scaling):

2.4

Justification:

Default (ECHA guidance): Allometric scaling rabbit - human.

AF for other interspecies differences:

2.5

Justification:

Default (ECHA guidance)

AF for intraspecies differences:

10

Justification:

Default (ECHA guidance)

AF for the quality of the whole database:

1

Justification:

Study was performed under GLP and the quality is considered to be very high (Klimisch 1).

AF for remaining uncertainties:

1

Justification:

The approach of the DNEL derivation is conservative. No further assessment factors are required.

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.1 mg/cm²

Most sensitive endpoint:

skin irritation/corrosion

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

30

Dose descriptor starting point:

LOAEC

AF for dose response relationship:

3

Justification:

Default (ECHA guidance): Extrapolation of the LOAEC to the NAEC.

AF for interspecies differences (allometric scaling):

1

Justification:

According to ECHA guidance R.8 allometric scaling should not be applied if the effects are not dependent on metabolic rate or systemic absorption, e.g. in the case of local effects.

AF for other interspecies differences:

1

Justification:

Since the mechanism (direct chemical reactivity with cell membranes) of skin irritation/corrosion is
considered to be the same in experimental animals and in human, no inter-species AF is to be applied (ECHA guidance R.8)

AF for intraspecies differences:

10

Justification:

Default (ECHA guidance)

AF for the quality of the whole database:

1

Justification:

Study was performed under GLP and the quality is considered to be very high (Klimisch 1).

AF for remaining uncertainties:

1

Justification:

The approach of the DNEL derivation is conservative. No further assessment factors are required.

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

6.4 µg/kg bw/day

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):

1 800

Dose descriptor starting point:

LOAEC

Value:

10 mg/kg bw/day

Modified dose descriptor starting point:

LOAEL

Value:

11.5 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Correction factors for the modified starting point are as follows:

-Correction for differences in exposure duration:

Consumer exposure duration is considered to be 7 days/week. The animals in the experimental study were exposed  7 days/week:

1.0 = n.a. (hours/day)(animal/human) x 7/7 (days/week)

-Correction for differences in bioavailability = 1

-Correction for differences in respiratory volume = 1.15

Corrected starting point:

LOAECcorr= 10 mg/m³ (LOAEC) x 1 (light activity at work) x 1 (differences in exposure duration) x 1 (bioavailability) x 1.15 m³/kg bw (resp. volume) = 11.5 mg/kg bw/day

AF for dose response relationship:

3

Justification:

Default (DNEL calculator)

AF for differences in duration of exposure:

6

Justification:

Default (DNEL calculator)

AF for interspecies differences (allometric scaling):

4

Justification:

Default (DNEL calculator)

AF for other interspecies differences:

2.5

Justification:

Default (DNEL calculator)

AF for intraspecies differences:

10

Justification:

Default (DNEL calculator)

AF for the quality of the whole database:

1

Justification:

Default (DNEL calculator)

AF for remaining uncertainties:

1

Justification:

The approach of the DNEL derivation is conservative. No further assessment factors are required.

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

76.7 µg/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):

525

Dose descriptor starting point:

LOAEC

Value:

17.5 mg/kg bw/day

Modified dose descriptor starting point:

LOAEL

Value:

40.25 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Correction factors for the modified starting point are as follows:

- Correction for differences in respiratory volume = 1.15

- Correction for differences in bioavailability = 1

- Correction for differences between human and experimental conditions= 2 (30/15=2; default short-term exposure is 15 min, signs of CNS depression were observed in the 17.5 mg/kg bw dose group 30 min after the treatment.)

Corrected starting point:

LOAECcorr= 17.5 mg/kg bw (LOAEC) x 1.15 (resp. volume) x 1 (bioavailability) x 2 (differences in exposure duration) = 40.25 mg/kg bw

AF for dose response relationship:

3

Justification:

Default (ECHA guidance): Extrapolation from LOAEC to NOAEC

AF for interspecies differences (allometric scaling):

7

Justification:

Default (ECHA guidance): Allometric scaling mouse - human.

AF for other interspecies differences:

2.5

Justification:

Default (ECHA guidance)

AF for intraspecies differences:

10

Justification:

Default (ECHA guidance)

AF for the quality of the whole database:

1

Justification:

Study was performed under GLP and the quality is considered to be very high (Klimisch 1).

AF for remaining uncertainties:

1

Justification:

The approach of the DNEL derivation is conservative. No further assessment factors are required.

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)