Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.29 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):
12
Modified dose descriptor starting point:
LOAEC
DNEL value:
15.5 mg/m³
Explanation for the modification of the dose descriptor starting point:
No inhalation toxicity data are available. The LOAEL from the 26-week repeated-dose oral toxicity study is used for derivation of the DNEL-long-term for the inhalation route. For intestinal absorption a figure of 20% has been estimated (based on rat data). Inhalation absorption was estimated to be 100% (no data). Corrected inh NOAEL = oral NOAEL x [1/sRV(rat) ] x [absorption (oral-rat) / absorption (inh-human) ]. This will be: 43 x 1/0.38 m3(8h) x 20/100 = 23 mg/m3. Further correction for respiratory volume = x [sRV(human) / wRV]. This will be: 23 mg/m3x [6.7 m3(8h) / 10 m3(8h) = 15.5 mg/m3
AF for dose response relationship:
1
Justification:
no additional assessment factor is needed
AF for differences in duration of exposure:
2
Justification:
sub-chronic to chronic exposure
AF for interspecies differences (allometric scaling):
1
Justification:
not applicable as this has already been done at route to route extrapolation
AF for other interspecies differences:
1
Justification:
rats and dogs showed similar NOAELs following 26 weeks of exposure; mice showed a 2-times higher NOAEL at a 2-times shorter duration (13 weeks), indicating that interspecies effect concentrations are small if at all
AF for intraspecies differences:
3
Justification:
for workers a factor 3 is generally considered to be sufficient
AF for the quality of the whole database:
1
Justification:
no additional assessment factor is needed
AF for remaining uncertainties:
2
Justification:
LOAEL to NOAEL
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
6 940 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):
7.5
Modified dose descriptor starting point:
NOAEC
DNEL value:
1 627 mg/m³
Explanation for the modification of the dose descriptor starting point:
No inhalation toxicity data are available. The NOEL from the acute oral toxicity study is used for derivation of the DNEL-acute for the inhalation route. Based on the particle size distribution normally obtained after nebulizing, it is expected that 90% of the inhaled substance will be deposited in the upper respiratory tract, which will finally be taken up orally. Of this, only 20% will be absorbed in the gastrointestinal tract and become available systematically, i. e. 0.9 x 0.20 = 0.18. The other 10% may reach the alveoli and it is assumed that this will be absorbed completely (worst case). Therefore, the total inhalation absorption factor will be 0.18 + 0.10 = 0.28. Corrected inh NOAEL =oral NOAEL x [1/sRV(rat) ] x [absorption (oral-rat) / absorption (inh-human) ]. This will be: 1294 x 1/0.38 m3(8h) x 20/28 = 2432 mg/m3. Further correction for respiratory volume =x [sRV(human) / wRV]. This will be: 2432 mg/m3x [6.7 m3(8h) / 10 m3(8h) = 1627 mg/m3
AF for dose response relationship:
1
Justification:
no additional assessment factor is needed
AF for interspecies differences (allometric scaling):
1
Justification:
not applicable as this has already been done at route to route extrapolation
AF for other interspecies differences:
2.5
Justification:
systemic effects
AF for intraspecies differences:
3
Justification:
for workers a factor 3 is generally considered to be sufficient
AF for the quality of the whole database:
1
Justification:
no additional assessment factor is needed
AF for remaining uncertainties:
1
Justification:
no additional assessment factor is needed

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.74 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
87.5
Modified dose descriptor starting point:
NOAEL
Justification:
no additional assessment factor is needed
AF for differences in duration of exposure:
1.7
Justification:
lifetime study but exposure for 3 days a week rather than 5 days a week
AF for interspecies differences (allometric scaling):
7
Justification:
difference in bodyweight
AF for other interspecies differences:
2.5
Justification:
default assessment factor
AF for intraspecies differences:
3
Justification:
for workers a factor 3 is generally considered to be sufficient
Justification:
no additional assessment factor is needed
Justification:
no additional assessment factor is needed
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:
36 µg/cm²
Most sensitive endpoint:
skin irritation/corrosion
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
36
Dose descriptor:
other: LOAEL
Justification:
no additional assessment factor is needed
AF for differences in duration of exposure:
6
Justification:
sub-acute to chronic exposure
AF for interspecies differences (allometric scaling):
1
Justification:
no allometric scaling needed because of local effects
AF for other interspecies differences:
1
Justification:
local effects
AF for intraspecies differences:
3
Justification:
for workers a factor 3 is generally considered to be sufficient
Justification:
no additional assessment factor is needed
AF for remaining uncertainties:
2
Justification:
LOAEL to NOAEL
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)

Additional information - workers

Because a limited number of studies was available for TEPA and read across from TETA (Cas no 112 -24 -3) to TEPA was considered applicable, most DNELs are based on those of TETA. MW TETA = 146, MW TEPA = 189, therefore all values multiplied by 189/146

Repeated exposure (workers)

 

Inhalation (vapour)

A 26-week oral study in rats (1998) with TETA.2HCl showed a NOAEL of 50 mg/kg bw/day in females, and a LOAEL of 50 mg/kg bw in males. A 13 -week study in mice (1996) showed a NOAEL of 92 mg/kg bw. A 26-week study in dogs (1998) showed a NOAEL of 50 mg/kg bw. The rat study was chosen as POD because of a LOAEL of 50 mg/kg bw and the duration of 26 weeks. The LOAEL of 50 mg TETA.2HCL per kg bw per day corresponds to 33 mg TETA per kg bw per day and to 43 mg TEPA per kg bw per day. 

 

No inhalation study is available; therefore there are no data on local effects. And no DNEL can be established for local effects.

 

Based on the MW of 146 and a vapour pressure of 0.0189 Pa at room temperature, the maximum vapour concentration in air that can be reached is 3 ppm which corresponds to 146/24.45 x 3 = 18 mg/m3.

 

For intestinal absorption a figure of 20% has been estimated (based on rat data). Inhalation absorption was estimated to be 100% (no data). 

 

Corrected inh NOAEC = oral NOAEL x [1/sRV(rat)] x [absorption (oral-rat) / absorption (inh-human)]

This will be: 33 x 1/0.38 m3(8h) x 20/100 = 17 mg/m3; sRV = respiratory volume rat in 8 h

 

Further correction for respiratory volume = x [sRV(human) / wRV]

This will be: 17 mg/m3x [6.7 m3(8h) / 10 m3(8h) = 12 mg/m3

sRV(human) = respiratory volume in 8 h (with a factor 4 for allometric scaling)

wRV = worker respiratory volume (light work)

 

Next the following assessment factors should be used

Interspecies:

- difference in BW (allometric scaling): in this case not applicable as this has already been done at the correction in sRV

- remaining differences: 1 instead of 2.5. Rats and dogs showed similar NOAELs following 26 weeks of exposure; mice showed a 2 -times higher NOAEL at a 2-times shorter duration (13 weeks), indicating that interspecies effect concentrations are small if at all.  

Intraspecies worker: 3. For workers, a factor 3 is generally considered to be sufficient (ECETOC).

Exposure duration: 2 (sub-chronic to chronic)

LOAEL to NOAEL: 2. Because 50 mg/kg bw TETA.2HCL was a NOAEL in females but a LOAEL in males.

 

This results in a total assessment factor of 1 x 3 x 2 x 2 = 12, or the DNEL will be: 12/12 = 1.0 mg/m3(TETA) or 1.29 mg/m3 (TEPA)

  

Inhalation (aerosol

A 26-week oral study in rats (1998) with TETA.2HCl showed a NOAEL of 50 mg/kg bw/day in females, and a LOAEL of 50 mg/kg bw in males. A 13-week study in mice (1996) showed a NOAEL of 92 mg/kg bw. A 26-week study in dogs (1998) showed a NOAEL of 50 mg/kg bw. The rat study was chosen as POD because of a LOAEL of 50 mg/kg bw and the duration of 26 weeks. The LOAEL of 50 mg TETA.2HCL per kg bw per day corresponds to 33 mg TETA per kg bw per day. 

 

For intestinal absorption a figure of 20% has been used (based on rat data).

 

For inhalation absorption the following is suggested: Based on the particle size distribution normally obtained after nebulizing, it is expected that 90% of the inhaled substance will be deposited in the upper respiratory tract, which will finally be taken up orally. Of this, only 20% will be absorbed in the gastrointestinal tract and become available systematically, i.e. 0.9 x 0.20 = 0.18. The other 10% may reach the alveoli and it is assumed that this will be absorbed completely (worst case). Therefore, the total inhalation absorption factor will be 0.18 + 0.10 = 0.28. 

 

Corrected inh NOAEC = oral NOAEL x [1/sRV(rat)] x [absorption (oral-rat) / absorption (inh-human)]

This will be: 33 x 1/0.38 m3(8h) x 20/28 = 62 mg/m3

sRV = respiratory volume rat in 8 h

 

Further correction for respiratory volume = x [sRV(human) / wRV]

This will be: 62 mg/m3x [6.7 m3(8h) / 10 m3(8h) = 42 mg/m3

sRV(human) = respiratory volume in 8 h (with a factor 4 for allometric scaling)

wRV = worker respiratory volume (light work)

 

Next the following assessment factors should be used

Interspecies:

- difference in BW (allometric scaling): in this case not applicable as this has already been done at the correction in sRV

- remaining differences: 1 instead of 2.5. Rats and dogs showed similar NOAELs following 26 weeks of exposure; mice showed a 2 -times higher NOAEL at a 2-times shorter duration (13 weeks), indicating that interspecies effect concentrations are small if at all.  

Intraspecies worker: 3. For workers, a factor 3 is generally considered to be sufficient (ECETOC).

Exposure duration: 2 (sub-chronic to chronic).

LOAEL to NOAEL: 2. Because 50 mg/kg bw TETA.2HCL was a NOAEL in females but a LOAEL in males.

 

This results in a total assessment factor of 1 x 3 x 2 x 2 = 12, indicating that the DNEL will be 42/12 = 3.5 mg/m3 (TETA) or 4.5 mg/m3 (TEPA)

Dermal

TEPA is corrosive and sensitizing; therefore a qualitative assessment rather than a quantitative assessment would be applicable for dermal exposure to the neat compound. Workers who would potentially be exposed should use PPE due to the corrosive and sensitizing nature of the substance.

A tentative systemic DNEL was however derived for comparison to DETA (DNEL DETA systemic dermal = 2.74 mg/kg bw)

However, for local dermal effects following exposure to solutions, DNELS have been calculated.

 

Systemic effects

In a 2-year study (Guzzie et al., 1982; DePass et al., 1987) 5.39 wt% inwas used 3 times per week; this corresponds to 25 µl x 0.0539 = ca. 1.25 mg mouse. Purity of TETA was stated to be ca. 79%. Systemic effects were absent and histopathological effects in the skin were also absent (so local effects were also absent). No tumours were found.

In another 2-year dermal study (Young; 1986) 3 times/week for up to 104 weeks, 0, 0.2 and 2.0% in ethanol were tested. Ethanol was used because of better wettability of the skin. TETA was stated to be 95% pure. In a 3-week RF study, a solution of 4% showed ulcerative/necrotic, hyperkeratotic changes; systemic effects were absent. Systemic effects and histopathological effects in the skin were also absent at 2% (so local effects were also absent). No tumours were found. 25µl x 0.02 mg = 0.5 mg/mouse, taking into account BW of ~30 g, this corresponds to ≥ 16.5 mg/kg bw. 

In the developmental tox study in rabbits the NOEL (duration ~ subacute study), rabbits were dosed from day 6-18 (6 h/day). Rabbits died at 125 mg/kg and showed decreased BW gain. Severe, dose-related skin irritation was noted at 50 and 125 mg/kg bw, which was still present at the end of the study, and which may have caused animals to die. At 5 mg/kg bw skin irritation was slight and recovered during the remainder of the study. It can be concluded that also this study did not show systemic effects but only local effects were seen.

 

Dermal absorption of EDA was 12% in case of a 10% solution. Based on the above, because of lack of systemic effects at concentrations up to 5% inand up to 4% in ethanol, it can be assumed that dermal absorption is not sufficient at these concentrations to induce systemic effects. Therefore, no DNEL for systemic effects can be established.   

 

DNEL for systemic effects: taking the highest level tested in a 2-year mouse study not inducing systemic effects using a 5% solution in(we took thebecause this is more likely used than ethanol at the workplace), the NOEL was 1.25 mg/mouse or (using a BW of 25 g): 50 mg/kg bw.

 

The following assessment factors should be used:

Interspecies:

- difference in BW: 7 (allometric scaling)

- remaining differences: 2.5

Intraspecies worker: 3. For workers, a factor 3 is generally considered to be sufficient (ECETOC).

Exposure duration: 5/3 (lifetime study but exposure for 3 days a week rather than 5 days a week)

 

This results in a total assessment factor of 7 x 2.5 x 3 x 5/3 = 87.5, indicating that the DNEL will be 50/87.5 = 0.57 mg/kg bw (TETA) or 0.74 mg/kg bw (TEPA)

 

Local effects[1]

 

In acute studies:

- slight irritation was observed at an application of 5% at 0.5 ml onto 6 cm2, which corresponds to ca. 25 mg/ 5 cm2, or 5 mg/cm2

- necrosis was seen at an application of 25 and 50% (0.5 ml) onto 6 cm2, which corresponds to ca. 125 and 250 mg / 5 cm2, or 25 mg/cm2and 50 mg/cm2.

- corrosion was seen at an application of undiluted material (0.5 ml) onto 6 cm2(ca. 100 µl/cm2), which corresponds to ca. 500 mg/5 cm2or100 mg/cm2

 

No local effects were seen in a 2-year dermal study (application 3 times/week) in mice using a 5% solution in(1.25 mg/mouse), applied at 25 µl/0.25 cm2which corresponds to 1.25 mg/0.25 cm2, or 5 mg/cm2.

No local effects were seen in another 2-year dermal study in mice (application 3 times/week) using a 2% solution in ethanol (0.5 mg/mouse), applied at 25 µl/0.25 cm2which corresponds to 0.5 mg/0.25 cm2, or 2 mg/cm2.

Minimal skin irritation was seen in a developmental study in rabbits at 5 mg/kg (application 6 h/day daily from day 6 to day 18 during pregnancy). For a rabbit of 4 kg this would mean 20 mg, applied as a solution of 10 mg/mL (or 1%) to ca. 20 cm2 (i.e.1 mg/cm2). The next higher levels of 50 mg/kg bw (applied as 100 mg/mL (or 10%); i.e.10 mg/cm2) and 125 mg/kg bw (applied as 250 mg/mL, or 25%; i.e.25 mg/cm2) were severely irritating.

 

The following can be concluded:

-        Solutions up to 5% are at most slightly irritating upon a single or repeated application (e.g. as can be assumed during accidental spilling).

-        TETA in ethanol seems to be slightly more irritating than TETA in water

-        Occluded application of a solution of 1% TETA infor 6 h/day for 12 consecutive days resulted in slight irritation that was reversible at the end of the study. The latter study seems to be in line with worst case conditions for workers and was taken as starting point for DNEL setting; starting point is thus 1 mg/cm2

 

Local effects

If we take the ‘worst case’ occluded study as starting point for DNEL setting; starting point is 1 mg/cm2.

 

The following assessment factors should be used:

Interspecies:

- difference in BW: 1 (no allometric scaling needed because of local effects

- remaining differences: 1 (in case of local effects)

Intraspecies worker: 3 (local effects)

Exposure duration: 6 (subacute to chronic)

Extrapolation from MOAEL to NOAEL: 2

 

This results in a total assessment factor of 3 x 6 x 2 = 36, indicating that the DNEL will be 1/36 = 0.028 mg/cm2 (TETA) or 0.036 mg/cm2 (TEPA)

 

Under non-occluded conditions, the chronic dermal application study had a NOEL of 5 mg/cm2(see above):

The following assessment factors should be used:

Interspecies:

- difference in BW: 1 (no allometric scaling needed because of local effects

- remaining differences: 1 (in case of local effects)

Intraspecies worker: 3 (local effects)

Exposure duration: 5/3 (3 times a week rather than 5 times a week)

 

This results in a total assessment factor of 3 x 5/3 = 5, indicating that the DNEL will be 5/5 = 1 mg/cm2 (TETA) or 1.29 mg/cm2 (TEPA) 

 

Reproduction/developmental

 

Developmental inhalation (vapour)

The NOAEL in the Keen (1983) developmental study rat (oral) = 52 mg TETA /kg bw.

 

For intestinal absorption a figure of 20% has been estimated (based on rat data). Inhalation absorption was estimated to be 100% (no data). 

 

Corrected inh NOAEL = oral NOAEL x [1/sRV(rat)] x [absorption (oral-rat) / absorption (inh-human)]

This will be: 52 x 1/0.38 m3(8h) x 20/100 = 27 mg/m3

sRV = respiratory volume rat in 8 h

 

Further correction for respiratory volume = x [sRV(human) / wRV]

This will be: 27 mg/m3x [6.7 m3(8h) / 10 m3(8h) = 18 mg/m3

sRV(human) = respiratory volume in 8 h (with a factor 4 for allometric scaling)

wRV = worker respiratory volume (light work)

 

Next the following assessment factors should be used:

Interspecies:

- difference in BW (allometric scaling): in this case not applicable as this has already been done at the correction in sRV

- remaining differences: 2.5

Intraspecies worker: 5 (because of developmental effects).

Exposure duration: 1 (developmental study)

 

This results in a total assessment factor of 2.5 x 5 = 12.5, or the DNEL will be: 18/12.5 = 1.5 mg/m3 (TETA) or 1.9 mg/m3 (TEPA)

Developmental inhalation (aerosol)

The NOAEL in the Keen (1983) developmental study rat (oral) = 52 mg TETA /kg bw.

 

For intestinal absorption a figure of 20% has been estimated (based on rat data).

For inhalation absorption the following is suggested: Based on the particle size distribution normally obtained after nebulizing, it is expected that 90% of the inhaled substance will be deposited in the upper respiratory tract, which will finally be taken up orally. Of this, only 20% will be absorbed in the gastrointestinal tract and become available systematically, i.e. 0.9 x 0.20 = 0.18. The other 10% may reach the alveoli and it is assumed that this will be absorbed completely (worst case). Therefore, the total inhalation absorption factor will be 0.18 + 0.10 = 0.28. 

 

Corrected inh NOAEL = oral NOAEL x [1/sRV(rat)] x [absorption (oral-rat) / absorption (inh-human)]

This will be: 52 x 1/0.38 m3(8h) x 20/28 = 98 mg/m3

sRV = respiratory volume rat in 8 h (see Table 8.2, page 26)

 

Further correction for respiratory volume = x [sRV(human) / wRV]

This will be: 98 mg/m3x [6.7 m3(8h) / 10 m3(8h) = 65 mg/m3

sRV(human) = respiratory volume in 8 h (with a factor 4 for allometric scaling)

wRV = worker respiratiory volume (light work)

 

Next the following assessment factors should be used:

Interspecies:

- difference in BW (allometric scaling): in this case not applicable as this has already been done at the correction in sRV

- remaining differences: 2.5

Intraspecies worker: 5 (because of developmental effects).

Exposure duration: 1 (developmental study)

 

This results in a total assessment factor of 2.5 x 5 = 12.5, or the DNEL will be: 65/12.5 = 5.2 mg/m3 (TETA) or 6.7 mg/m3 (TEPA)

   

 

Developmental dermal

NOAEL developmental study rabbit (dermal) ≥ 125 mg/kg bw. At the highest level tested there was no developmental toxicity; so a DNEL for dermal developmental toxicity is not warranted. See also arguments for limited absorption above.

 

There are no studies available on reproduction toxicity.

 

 


Acute exposure (workers)

 

Inhalation (aerosol) (in case of peak exposure)

NOEL = 1000 mg/kg bw (acute oral rat study)

 

Based on a theoretically maximum vapour concentration of 18 mg/m3, acute inhalation exposure to high concentrations is limited to aerosol exposure.

 

For intestinal absorption (rat) a figure of 20% has been used.

For inhalation absorption the following is suggested: Based on the particle size distribution normally obtained after nebulizing, it is expected that 90% of the inhaled substance will be deposited in the upper respiratory tract, which will finally be taken up orally. Of this, only 20% will be absorbed in the gastrointestinal tract and become available systematically, i.e. 0.9 x 0.20 = 0.18. The other 10% may reach the alveoli and it is assumed that this will be absorbed completely (worst case). Therefore, the total inhalation absorption factor will be 0.18 + 0.10 = 0.28. 

 

Corrected inh NOAEL = oral NOAEL x [1/sRV(rat)] x [absorption (oral-rat) / absorption (inh-human)]

This will be: 1000 x 1/0.38 m3(8h) x 20/28 = 1880 mg/m3

sRV = respiratory volume rat in 8 h

 

Further correction for respiratory volume = x [sRV(human) / wRV]

This will be:

1880 mg/m3x [6.7 m3(8h) / 10 m3(8h) = 1259 mg/m3

sRV(human) = respiratory volume in 8 h (with a factor 4 for allometric scaling)

wRV = worker respiratory volume (light work)

 

Next the following assessment factors should be used:

Interspecies:

- difference in BW (allometric scaling): not in this case as this already has been done at correction of sRV

- remaining differences: 2.5 (in case of systemic effects)

Intraspecies worker: 3. For workers, a factor 3 is generally considered to be sufficient (ECETOC).

 

This results in a total assessment factor of 2.5 x 3 = 7.5, indicating that the DNEL will be 1259/7.5= 168 mg/m3

Taking Haber’s rule into account: DNEL acute (15-min inhalation) would be 168 x 32 = 5.38 g/m3 (TETA) or 6.94 g/m3 (TEPA)

 

Notes:

[1]It was checked how much material is normally dosed in dermal studies (i.e. volume per unit area).

-         In a skin irritation test and a skin sensitization test, a solution of 0.5 ml is applied onto ca. 6 cm2, which corresponds to ca. 100 µl/cm2

-         In an acute dermal study (e.g rabbit); 2000 mg/kg bw is normally appliedundilutedon 10% skin area. For a rabbit of 2.5 kg, this would mean 5000 mg onto ca. 260 cm2(2600 cm2is body surface), or ca. 5000 µl onto 250 cm2, or 20 µl/cm2.

-         In the chronic dermal studies it was only indicated that 25 µl was applied without any indication of surface area. The size of a droplet generally is 40 µl, so 25 µl is at most a small droplet. 25 µl corresponds to 25 mm3, and if we assume that the ‘height’ of the application would be 1 mm, then a surface area of 25 mm2would be applicable (i.e. 5 x 5 mm; which seems to be in agreement with application of a small droplet). This also corresponds to 25 µl/0.25 cm2or 100 µl/cm2which would be in line with the skin irritation and skin sensitization test requirements.

-         In the developmental study, the MOAEL of 5 mg/kg bw was applied as 0.5 ml/kg bw and 2 ml per animal (solutions in; taking into account a rabbit of 4 kg bw). The 2-ml aliquot was drawn up in a 3 cc syringe and applied to the skin of a rabbit under a 4x4 inch gauze pad (1 inch = 2.54 cm; i.e. pad surface area was 103 cm2). If we again assume that the ‘height’ of the application of 2 ml (2000 mm3) would be 1 mm, then a surface area of 2000 mm2 would be applicable (= 20 cm2or ca. 4.5 x 4.5 cm). This corresponds to 2000 µl/ 20 cm2or 100 µl/cm2 which would be in line with the skin irritation and skin sensitization test requirements.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.38 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):
20
Modified dose descriptor starting point:
LOAEC
DNEL value:
7.4 mg/m³
Explanation for the modification of the dose descriptor starting point:
No inhalation toxicity data are available. The LOAEL from the 26-week repeated-dose oral toxicity study is used for derivation of the DNEL-long-term for the inhalation route. For intestinal absorption a figure of 20% has been estimated (based on rat data). Inhalation absorption was estimated to be 100% (no data). Corrected inh NOAEL = oral NOAEL x [1/sRV(rat) ] x [absorption (oral-rat) / absorption (inh-human) ]. This will be: 43 x 1/1.15 m3(24h) x 20/100 = 7.4 mg/m3.
Justification:
no additional assessment factor is needed
AF for differences in duration of exposure:
2
Justification:
sub-chronic to chronic exposure
AF for interspecies differences (allometric scaling):
1
Justification:
not applicable as this has already been done at route to route extrapolation
AF for other interspecies differences:
1
Justification:
rats and dogs showed similar NOAELs following 26 weeks of exposure; mice showed a 2-times higher NOAEL at a 2-times shorter duration (13 weeks), indicating that interspecies effect concentrations are small if at all
AF for intraspecies differences:
5
Justification:
for the general public a factor 5 is generally considered sufficient
Justification:
no additional assessment factor is needed
AF for remaining uncertainties:
2
Justification:
LOAEL to NOAEL
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2 071 mg/m³
Most sensitive endpoint:
acute toxicity
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
12.5
Modified dose descriptor starting point:
NOAEC
DNEL value:
804 mg/m³
Explanation for the modification of the dose descriptor starting point:
No inhalation toxicity data are available. The NOEL from the acute oral toxicity study is used for derivation of the DNEL-acute for the inhalation route. Based on the particle size distribution normally obtained after nebulizing, it is expected that 90% of the inhaled substance will be deposited in the upper respiratory tract, which will finally be taken up orally. Of this, only 20% will be absorbed in the gastrointestinal tract and become available systematically, i. e. 0.9 x 0.20 = 0.18. The other 10% may reach the alveoli and it is assumed that this will be absorbed completely (worst case). Therefore, the total inhalation absorption factor will be 0.18 + 0.10 = 0.28. Corrected inh NOAEL =oral NOAEL x [1/sRV(rat) ] x [absorption (oral-rat) / absorption (inh-human) ]. This will be: 1294 x 1/1.15 m3(24h) x 20/28 = 804 mg/m3.
AF for dose response relationship:
1
Justification:
no additional assessment factor is needed
AF for interspecies differences (allometric scaling):
1
Justification:
not applicable as this has already been done at route to route extrapolation
AF for other interspecies differences:
2.5
Justification:
systemic effects
AF for intraspecies differences:
5
Justification:
for the general public a factor 5 is generally considered sufficient
AF for the quality of the whole database:
1
Justification:
no additional assessment factor is needed
AF for remaining uncertainties:
1
Justification:
no additional assessment factor is needed

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.32 mg/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):
204
Modified dose descriptor starting point:
NOAEL
Justification:
no additional assessment factor is needed
AF for differences in duration of exposure:
2.3
Justification:
lifetime study but exposure for 3 days a week rather than 7 days a week
AF for interspecies differences (allometric scaling):
7
Justification:
difference in bodyweight
AF for other interspecies differences:
2.5
Justification:
default assessment factor
AF for intraspecies differences:
5
Justification:
for the general public a factor 5 is generally considered sufficient
Justification:
no additional assessment factor is needed
Justification:
no additional assessment factor is needed
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
10 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):
50
Modified dose descriptor starting point:
NOAEL
AF for dose response relationship:
1
Justification:
no additional assessment factor is needed
AF for interspecies differences (allometric scaling):
4
Justification:
difference in bodyweight
AF for other interspecies differences:
2.5
Justification:
default assessment factor
AF for intraspecies differences:
5
Justification:
for the general public a factor 5 is generally considered sufficient
AF for the quality of the whole database:
1
Justification:
no additional assessment factor is needed
AF for remaining uncertainties:
1
Justification:
no additional assessment factor is needed

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.56 mg/cm²
Most sensitive endpoint:
skin irritation/corrosion
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
11.7
Dose descriptor:
other: NOAEL
Justification:
no additional assessment factor is needed
AF for differences in duration of exposure:
2.3
Justification:
lifetime study but exposure for 3 days a week rather than 7 days a week
AF for interspecies differences (allometric scaling):
1
Justification:
no allometric scaling needed because of local effects
AF for other interspecies differences:
1
Justification:
local effects
AF for intraspecies differences:
5
Justification:
for the general public a factor 5 is generally considered sufficient
Justification:
no additional assessment factor is needed
Justification:
no additional assessment factor is needed
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.29 mg/cm²
Most sensitive endpoint:
skin irritation/corrosion
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
5
Dose descriptor starting point:
other: NOAEL
AF for dose response relationship:
1
Justification:
no additional assessment factor is needed
AF for interspecies differences (allometric scaling):
1
Justification:
no allometric scaling needed because of local effects
AF for other interspecies differences:
1
Justification:
local effects
AF for intraspecies differences:
5
Justification:
for the general public a factor 5 is generally considered sufficient
AF for the quality of the whole database:
1
Justification:
no additional assessment factor is needed
AF for remaining uncertainties:
1
Justification:
no additional assessment factor is needed

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.53 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):
80
Modified dose descriptor starting point:
LOAEL
AF for dose response relationship:
1
Justification:
no additional assessment factor is needed
AF for differences in duration of exposure:
2
Justification:
sub-chronic to chronic exposure
AF for interspecies differences (allometric scaling):
4
Justification:
difference in bodyweight
AF for other interspecies differences:
1
Justification:
rats and dogs showed similar NOAELs following 26 weeks of exposure; mice showed a 2-times higher NOAEL at a 2-times shorter duration (13 weeks), indicating that interspecies effect concentrations are small if at all
AF for intraspecies differences:
5
Justification:
for the general public a factor 5 is generally considered sufficient
AF for the quality of the whole database:
1
Justification:
no additional assessment factor is needed
AF for remaining uncertainties:
2
Justification:
LOAEL to NOAEL
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
26 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):
50
Modified dose descriptor starting point:
NOAEL
AF for dose response relationship:
1
Justification:
no additional assessment factor is needed
AF for interspecies differences (allometric scaling):
4
Justification:
difference in bodyweight
AF for other interspecies differences:
2.5
Justification:
default assessment factor
AF for intraspecies differences:
5
Justification:
for the general public a factor 5 is generally considered sufficient
AF for the quality of the whole database:
1
Justification:
no additional assessment factor is needed
AF for remaining uncertainties:
1
Justification:
no additional assessment factor is needed

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
high hazard (no threshold derived)

Additional information - General Population

Because a limited number of studies was available for TEPA and read across from TETA (Cas no 112 -24 -3) to TEPA was considered applicable, most DNELs are based on those of TETA. MW TETA = 146, MW TEPA = 189, therefore all values multiplied by 189/146

General population

Long term systemic

 

Oral (long term)

Assuming that absorption is similar for rats, mice and humans: LOAEL = 33 mg/kg bw (26-week study rats)

 

Next the following assessment factors should be used:

Interspecies:

- difference in BW (allometric scaling): 4

- remaining differences: 1 instead of 2.5. Rats and dogs showed similar NOAELs following 26 weeks of exposure; mice showed a 2 -times higher NOAEL at a 2-times shorter duration (13 weeks), indicating that interspecies effect concentrations are small if at all.  

Intraspecies general population: 5. For the general public, a factor 5 is generally considered to be sufficient (ECETOC).

Exposure duration: 2 (sub-chronic to chronic)

LOAEL to MOAEL: 2

 

This results in a total assessment factor of 4 x 1 x 5 x 2 x 2 = 80, indicating that the DNEL oral will be 33 / 80 = 0.41 mg/kg

Thus: DNEL oral repeated (systemic) =         0.41 mg/kg (TETA) or 0.53 mg/kg (TEPA)

 

Inhalation (vapour; long term)

A 26-week oral study in rats (1998) with TETA.2HCl showed a NOAEL of 50 mg/kg bw/day in females, and a LOAEL of 50 mg/kg bw in males. A 13 -week study in mice (1996) showed a NOAEL of 92 mg/kg bw. A 26-week study in dogs (1998) showed a NOAEL of 50 mg/kg bw. The rat study was chosen as POD because of a LOAEL of 50 mg/kg bw and the duration of 26 weeks. The LOAEL of 50 mg TETA.2HCL per kg bw per day corresponds to 33 mg TETA per kg bw per day. 

 

No inhalation study is available; therefore there are no data on local effects. And no DNEL can be established for local effects.

 

For intestinal absorption a figure of 20% has been estimated (based on rat data). Inhalation absorption was estimated to be 100% (no data). 

 

Corrected inh NOAEC = oral NOAEL x [1/sRV(rat)] x [absorption (oral-rat) / absorption (inh-human)]

This will be: 33 x 1/1.15 m3(24 h) x 20/100 = 5.7 mg/m3

sRV = respiratory volume rat in 24 h 

 

Next the following assessment factors should be used:

Interspecies:

- difference in BW (allometric scaling): in this case not applicable as this has already been done at the correction in sRV

- remaining differences: 1 instead of 2.5. Rats and dogs showed similar NOAELs following 26 weeks of exposure; mice showed a 2 -times higher NOAEL at a 2-times shorter duration (13 weeks), indicating that interspecies effect concentrations are small if at all.  

Intraspecies: 5. For the general public, a factor 5 is generally considered to be sufficient (ECETOC).

Exposure duration: 2 (sub-chronic to chronic)

LOAEL to NOAEL: 2. Because 50 mg/kg bw TETA.2HCL was a NOAEL in females but a LOAEL in males.

 

This results in a total assessment factor of 1 x 5 x 2 x 2 = 20, or the DNEL will be: 5.7/20 = 0.29 mg/m3

Thus DNEL repeated (inhalation, vapour, systemic effects) would be: 0.29 mg/m3 (TETA) or 0.38 mg/m3 (TEPA)

 

Inhalation (aerosol; long term)

A 26-week oral study in rats (1998) with TETA.2HCl showed a NOAEL of 50 mg/kg bw/day in females, and a LOAEL of 50 mg/kg bw in males. A 13 -week study in mice (1996) showed a NOAEL of 92 mg/kg bw. A 26-week study in dogs (1998) showed a NOAEL of 50 mg/kg bw. The rat study was chosen as POD because of a LOAEL of 50 mg/kg bw and the duration of 26 weeks. The LOAEL of 50 mg TETA.2HCL per kg bw per day corresponds to 33 mg TETA per kg bw per day. 

 

For intestinal absorption a figure of 20% has been used (based on rat data).

 

For inhalation absorption the following is suggested: Based on the particle size distribution normally obtained after nebulizing, it is expected that 90% of the inhaled substance will be deposited in the upper respiratory tract, which will finally be taken up orally. Of this, only 20% will be absorbed in the gastrointestinal tract and become available systematically, i.e. 0.9 x 0.20 = 0.18. The other 10% may reach the alveoli and it is assumed that this will be absorbed completely (worst case). Therefore, the total inhalation absorption factor will be 0.18 + 0.10 = 0.28. 

 

Corrected inh NOAEL = oral NOAEL x [1/sRV(rat)] x [absorption (oral-rat) / absorption (inh-human)]

This will be: 33 x 1/1.15 m3(24 h) x 20/28 = 20.5 mg/m3

sRV = respiratory volume rat in 24 h

 

Next the following assessment factors should be used:

Interspecies:

- difference in BW (allometric scaling): in this case not applicable as this has already been done at the correction in sRV

- remaining differences: 1 instead of 2.5. Rats and dogs showed similar NOAELs following 26 weeks of exposure; mice showed a 2 -times higher NOAEL at a 2-times shorter duration (13 weeks), indicating that interspecies effect concentrations are small if at all.  

Intraspecies: 5. For the general public, a factor 5 is generally considered to be sufficient (ECETOC).

Exposure duration: 2 (sub-chronic to chronic).

LOAEL to NOAEL: 2. Because 50 mg/kg bw TETA.2HCL was a NOAEL in females but a LOAEL in males.

 

This results in a total assessment factor of 1 x 5 x 2 x 2 = 20, indicating that the DNEL will be 20.5/20 = 1.0 mg/m3

Thus DNEL repeated (inhalation, aerosol, systemic effects) would be: 1.0 mg/m3 (TETA) or 1.29 mg/m3 (TEPA)

Dermal (long term)

Taking the highest level tested in a 2-year mouse study not inducing systemic effects using a 5% solution in water (we took the study with water because this is more likely used than ethanol at the workplace), the NOEL was 1.25 mg/mouse or (using a BW of 25 g): 50 mg/kg bw.

 

The following assessment factors should be used:

Interspecies:

- difference in BW: 7 (allometric scaling)

- remaining differences: 2.5

Intraspecies human: 5. For the general public, a factor 5 is generally considered to be sufficient (ECETOC).

Exposure duration: 7/3 (lifetime study but exposure for 3 days a week rather than 7 days a week)

 

This results in a total assessment factor of 7 x 2.5 x 5 x 7/3 = 204, indicating that the DNEL will be 50/204 = 0.25 mg/kg bw

Thus DNEL repeated (dermal, systemic effects) would be: 0.25 mg/kg bw (TETA) or 0.32 mg/kg bw (TEPA)

Long term local effects

 

Inhalation:as there are no inhalation studies available, no data are known on local effects. Therefore it is not possible to derive a DNEL for local effects following inhalation exposure

 

Oral: not applicable to local effects

 

Dermal

The chronic dermal application study at a NOEL of 5 mg/cm2 was used (see above)

 

The following assessment factors should be used:

Interspecies:

- difference in BW: 1 (no allometric scaling needed because of local effects)

- remaining differences: 1 (in case of local effects)

Intraspecies general public: 5

Exposure duration: 7/3 (3 times a week rather than 7 times a week)

 

This results in a total assessment factor of 5 x 7/3 = 11.7, indicating that the DNEL will be 5/11.7 = 0.43 mg/cm2    

Thus DNEL repeated (dermal, local effects, non-occluded) would be: 0.43 mg/cm2 (TETA) or 0.56 mg/cm2 (TEPA)

Acute systemic

Inhalation (aerosol) (in case of peak exposure)

NOEL = 1000 mg/kg bw (acute oral rat study)

 

Based on a theoretically maximum vapour concentration of 18 mg/m3, acute inhalation exposure is limited to aerosol exposure.

 

For intestinal absorption (rat) a figure of 20% has been used.

For inhalation absorption the following is suggested: Based on the particle size distribution normally obtained after nebulizing, it is expected that 90% of the inhaled substance will be deposited in the upper respiratory tract, which will finally be taken up orally. Of this, only 20% will be absorbed in the gastrointestinal tract and become available systematically, i.e. 0.9 x 0.20 = 0.18. The other 10% may reach the alveoli and it is assumed that this will be absorbed completely (worst case). Therefore, the total inhalation absorption factor will be 0.18 + 0.10 = 0.28. 

 

Corrected inh NOAEC = oral NOAEL x [1/sRV(rat)] x [absorption (oral-rat) / absorption (inh-human)]

This will be: 1000 x 1/1.15 m3(24 h) x 20/28 = 621 mg/m3

sRV = respiratory volume rat in 24 h

 

Next the following assessment factors should be used:

Interspecies:

- difference in BW (allometric scaling): not in this case as this already has been done at correction of sRV

- remaining differences: 2.5 (in case of systemic effects)

Intraspecies general population: 5. For the general public, a factor 5 is generally considered to be sufficient (ECETOC).

 

This results in a total assessment factor of 2.5 x 5 = 12.5, indicating that the DNEL will be 621/12.5 = 50 mg/m3

Thus DNEL acute (8-h inhalation) would be: 50 mg/m3

Taking Haber’s rule: DNEL acute (15-min inhalation; systemic effects) would be 50 x 32 = 1600 mg/m3 (TETA) or 2071 mg/m3 (TEPA)

 

Oral

NOEL = 1000 mg/kg bw (acute oral rat study)

 

Next the following assessment factors should be used:

Interspecies:

- difference in BW (allometric scaling): 4

- remaining differences: 2.5.  

Intraspecies general population: 5. For the general public, a factor 5 is generally considered to be sufficient (ECETOC).

 

This results in a total assessment factor of 4 x 2.5 x 5 = 50, indicating that the DNEL oral will be 1000 / 50 = 20 mg/kg

Thus: DNEL oral acute (systemic effects) =   20 mg/kg bw (TETA) or 26 mg/kg bw (TEPA)

Dermal

In one study (1993) 2/10 rabbits died at 1000 mg/kg bw, whereas in a second study (1977) 0% of the rats died at that level (occluded conditions). Therefore, 400 mg/kg bw (same acute dermal study rats; 1977) was taken as NOAEL.

 

Next the following assessment factors should be used:

Interspecies:

- difference in BW (allometric scaling): 4

- remaining differences: 2.5.  

Intraspecies general population: 5. For the general public, a factor 5 is generally considered to be sufficient (ECETOC).

 

This results in a total assessment factor of 4 x 2.5 x 5 = 50, indicating that the DNEL dermal will be 400 / 50 = 8 mg/kg

Thus: DNEL dermal acute (systemic effects) =           8 mg/kg bw (TETA) or 10 mg/kg bw (TEPA)

Acute local

 

Inhalation:as there are no inhalation studies available, no data are known on local effects. Therefore it is not possible to derive a DNEL for local effects following inhalation exposure

 

Oral: not applicable to local effects

 

Dermal

In acute studies:

- slight irritation was observed at an application of 5% at 0.5 ml onto 6 cm2, which corresponds to ca. 25 mg/ 5 cm2, or 5 mg/cm2

- necrosis was seen at an application of 25 and 50% (0.5 ml) onto 6 cm2, which corresponds to ca. 125 and 250 mg / 5 cm2, or 25 mg/cm2and 50 mg/cm2.

- corrosion was seen at an application of undiluted material (0.5 ml) onto 6 cm2(ca. 100 µl/cm2), which corresponds to ca. 500 mg/5 cm2or100 mg/cm2

The slight irritation was observed using semi-occlusive conditions. The chronic dermal application study under non-occlusive conditions resulted in a NOEL of 5 mg/cm2. Therefore, 5 mg/cm2was chosen as LOAEL. 

The following assessment factors should be used:

Interspecies:

- difference in BW: 1 (no allometric scaling needed because of local effects)

- remaining differences: 1 (in case of local effects)

Intraspecies general public: 5

Exposure duration: not applicable; single exposure

 

This results in a total assessment factor of 5, indicating that the DNEL will be 5/5 = 1 mg/cm2    

Thus DNEL acute (dermal, local effects, non-occluded) would be: 1 mg/cm2 (TETA) or 1.29 mg/cm2 (TEPA)

Data was used predominantly from the linear fraction of the multi consituent because this has the biggest percentage within the MCS