Tetramethylammonium hydroxide

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.164 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:

5 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

12.3 mg/m³

Explanation for the modification of the dose descriptor starting point:

Kinetics (metabolism, distribution and excretion) are considered to be similar for oral and inhalation intake in the absence of evidence of the opposite.

Starting point:

NOAEL of 5 mg/kg bw/day in a 28-day repeated dose toxicity study in rat.

An additional factor of 1.4 was included in the modification calculation to take into account correction for differences between human and experimental exposure conditions. When correcting an oral NOAEL to inhalation NOAEC the correction factor for worker population would be: 7 day/week (experimental animal exposure, check study) / 5 days/week (worker exposure conditions) = 1.4. This additional factor is also provided by the IUCLID DNEL calculator tool.

 

Conversion of an oral NOAEL into a corrected NOAEC:

For workers (8h exposure/day), the corrected inhalatory NOAEC = oral NOAEL * 1/sRVrat * ABSoral-rat /ABSinhal-human * sRVhuman/wRV

= 5 * 1/0.38 m³/kg/8h * ABSoral-rat /ABSinhal-human * 6.7 m³ (8h)/10 m³ (8h) *1.4 

= 5 * 1/0.38 m³/kg/8h * 1 * 6.7 m3 (8h)/10 m³ (8h) *1.4

= 5 /0.38 * 1* (6.7/10) * 1.4 = 12.3 mg/m³

 

With ABS: Absorption, sRV: Standard Respiratory Volume; wRV: Worker Respiratory Volume;

ABSoral-rat /ABSinhal-human= 100/100= 1, assuming no differences in inhalation absorption between rats and humans.

AF for dose response relationship:

1

Justification:

Based on NOAEL

AF for differences in duration of exposure:

6

Justification:

Extrapolation from subacute study to chronic exposure worker

AF for interspecies differences (allometric scaling):

1

Justification:

No correction for caloric demand for inhalation; is included in dose descriptor starting point

AF for other interspecies differences:

2.5

Justification:

Factor to correct for toxicokinetic differences not related to metabolic rate (small part) and toxicodynamic differences (larger part). No substance-specific information is available to address this aspect more specifically.

AF for intraspecies differences:

5

Justification:

Difference in sensitivity among workers

AF for the quality of the whole database:

1

Justification:

Reliable studies

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties

Acute/short term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

33.33 µg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Dermal

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

300

Dose descriptor starting point:

NOAEL

Value:

10 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No modification needed, repeated dose study via the dermal route is available

AF for dose response relationship:

1

Justification:

Value is NOAEL

AF for differences in duration of exposure:

6

Justification:

Extrapolation from subacute study to chronic exposure worker

AF for interspecies differences (allometric scaling):

4

Justification:

Correction for caloric demand from rat to human

AF for other interspecies differences:

2.5

Justification:

Factor to correct for toxicokinetic differences not related to metabolic rate (small part) and toxicodynamic differences (larger part). No substance-specific information is available to address this aspect more specifically.

AF for intraspecies differences:

5

Justification:

Difference in sensitivity among workers

AF for the quality of the whole database:

1

Justification:

Reliable studies used

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties

Acute/short term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3.75 µg/cm²

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

5

Dose descriptor:

other: NOAEL

AF for dose response relationship:

1

Justification:

Value is NOAEL

AF for differences in duration of exposure:

1

Justification:

Local effects are not dependent on exposure duration

AF for interspecies differences (allometric scaling):

1

Justification:

No correction for caloric demand needed for local effects

AF for other interspecies differences:

1

Justification:

For effects on the skin, eye or GI tract, where the mechanism of effect is direct chemical/pH reactivity, no further kinetic considerations apply and no safety factor needs to be included. Where tissue metabolism is a factor, the same kinetic and dynamic considerations (i.e. a chemical specific remaining uncertainties factor or the default factor of 2.5) should apply

AF for intraspecies differences:

5

Justification:

Difference in sensitivity among workers

AF for the quality of the whole database:

1

Justification:

Reliable studies used

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties

Acute/short term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

high hazard (no threshold derived)

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.029 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):

150

Dose descriptor starting point:

NOAEL

Value:

5 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

4.35 mg/m³

Explanation for the modification of the dose descriptor starting point:

Kinetics (metabolism, distribution and excretion) are considered to be similar for oral and inhalation intake in the absence of evidence of the opposite.

For the general population (24h exposure/day), the corrected inhalatory NOAEC = oral NOAEL * 1/sRVrat * ABSoral-rat /ABSinhal-human

= 5 * 1/1.15 m³/kg * ABSoral-rat /ABSinhal-human

= 5 * 1/1.15 m³/kg  * 1 =  4.35 mg/m³

 

With ABS: Absorption, sRV: Standard Respiratory Volume;

ABSoral-rat /ABSinhal-human= 100/100= 1, assuming no differences in inhalation absorption between rats and humans.

AF for dose response relationship:

1

Justification:

Value is NOAEL

AF for differences in duration of exposure:

6

Justification:

Extrapolation from subacute study to chronic exposure

AF for interspecies differences (allometric scaling):

1

Justification:

No correction for caloric demand for inhalation; is included in dose descriptor starting point

AF for other interspecies differences:

2.5

Justification:

Factor to correct for toxicokinetic differences not related to metabolic
rate (small part) and toxicodynamic differences (larger part). No substance-specific information is available to address this aspect more specifically. In case substance-specific information shows specific susceptibility differences between species, which are not related to differences in basal metabolic rate, the additional factor of 2.5 for ‘remaining differences’ should be modified accordingly.

AF for intraspecies differences:

10

Justification:

Difference in sensitivity within general population

AF for the quality of the whole database:

1

Justification:

Reliable studies used

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties

Acute/short term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

16.67 µg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Dermal

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

600

Dose descriptor starting point:

NOAEL

Value:

10 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No modification needed, repeated dose study via the dermal route is available

AF for dose response relationship:

1

Justification:

Value is NOAEL

AF for differences in duration of exposure:

6

Justification:

Extrapolation from subacute study to chronic exposure

AF for interspecies differences (allometric scaling):

4

Justification:

Correction for caloric demand from rat to human

AF for other interspecies differences:

2.5

Justification:

Factor to correct for toxicokinetic differences not related to metabolic
rate (small part) and toxicodynamic differences (larger part). No substance-specific information is available to address this aspect more specifically.

AF for intraspecies differences:

10

Justification:

Difference in sensitivity within general population

AF for the quality of the whole database:

1

Justification:

Reliable studies used

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties

Acute/short term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.875 µg/cm²

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

10

Dose descriptor:

other: NOAEL

AF for dose response relationship:

1

Justification:

Value is NOAEL

AF for differences in duration of exposure:

1

Justification:

Local effects are not dependent on exposure duration

AF for interspecies differences (allometric scaling):

1

Justification:

No correction for caloric demand needed for local effects

AF for other interspecies differences:

1

Justification:

For effects on the skin, eye or GI tract, where the mechanism of effect is direct chemical/pH reactivity, no further kinetic considerations apply and no safety factor needs to be included. Where tissue metabolism is a factor, the same kinetic and dynamic considerations (i.e. a chemical specific remaining uncertainties factor or the default factor of 2.5) should apply

AF for intraspecies differences:

10

Justification:

Difference in sensitivity within general population

AF for the quality of the whole database:

1

Justification:

Reliable studies used

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties

Acute/short term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

8.33 µg/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

Dose descriptor starting point:

NOAEL

Value:

5 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No modification needed, repeated dose study via the oral route is available

AF for dose response relationship:

1

Justification:

Value is NOAEL

AF for differences in duration of exposure:

6

Justification:

Extrapolation from subacute study to chronic exposure

AF for interspecies differences (allometric scaling):

4

Justification:

Correction for caloric demand from rat to human

AF for other interspecies differences:

2.5

Justification:

Factor to correct for toxicokinetic differences not related to metabolic rate (small part) and toxicodynamic differences (larger part). No substance-specific information is available to address this aspect more specifically.

AF for intraspecies differences:

10

Justification:

Difference in sensitivity among general population

AF for the quality of the whole database:

1

Justification:

Reliable studies used

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties

Acute/short term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

high hazard (no threshold derived)