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Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.297 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
22
Modified dose descriptor starting point:
NOAEC
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information
Explanation for the modification of the dose descriptor starting point:

It is described in ECHA's guidance document on information requirements and chemical safety assessment, part R8 that a DNEL for acute toxicity should only be derived if an acute toxicity hazard (leading to C&L) has been identified and there is potential for high peak exposures. Since the determined LC50 of the substance is above 2000 mg/kg, no acute toxicity hazard was established. Therefore, there is no need to define a DNEL for acute toxicity, the long-term DNELs are considered to be sufficient.

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
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:
0.307 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
50
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information
Explanation for the modification of the dose descriptor starting point:

It is described in ECHA's guidance document on information requirements and chemical safety assessment, part R8 that a DNEL for acute toxicity should only be derived if an acute toxicity hazard (leading to C&L) has been identified and there is potential for high peak exposures. Since the determined LC50 of the substance is above 2000 mg/kg, no acute toxicity hazard was established. Therefore, there is no need to define a DNEL for acute toxicity, the long-term DNELs are considered to be sufficient.

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.027 mg/cm²
Most sensitive endpoint:
skin irritation/corrosion
DNEL related information
Overall assessment factor (AF):
3 000
Dose descriptor:
other: NOAEL
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

Long-term exposure – systemic effects

Dermal DNEL:

The NOAEL derived from the 52 week chronic feeding study in rats (Iatropoulos, 1996) was used as the starting point for derivation of the worker-DNEL long-term for dermal route-systemic via route-to-route extrapolation.

NOAEL = 310 mg/kg diet.

The actual ingested dose corresponding to this dietary concentration was calculated from food consumption data present in the study:

NOAEL = 16.00 mg/kg bw/day

Subsequently, the NOAEL is corrected for difference in absorption between dermal and oral route in the rat, and for difference in dermal absorption in rat versus dermal absorption in human, according to example B5 of Chapter R8 of the Guidance on information requirements and chemical safety assessment.

a) corrected dermal rat NOAEL = oral rat NOAEL * (ABS oral-rat / ABS derm-rat).

According to the available study on percutaneous absorption of one of the main constituents of 1,4 -benzenediamine, N,N'-mixed Ph and tolyl derivs. (Hui, 1997), 60% of the dermally-applied test chemical was absorbed during the 7 -day study.

According to two available studies on metabolism and excretion of two different main constituents of 1,4 -benzenediamine, N,N'-mixed Ph and tolyl derivs (Jeffcoat, 1998 and Jeffcoat, 1998), the mean value for absorption of the by the rats ingested test substances is 57.5%.

Due to the clear structural similarities between the main constituents of 1,4 -benzenediamine, N,N'-mixed Ph and tolyl derivs. it can be assumed that the absorption values resulting from the above mentioned studies can be used as reasonable estimates for absorption behaviour of the multi-constituent substance as such. As a consequence, ABS derm-rat = 0.60, and ABS oral-rat is 0.575.

Corrected dermal rat NOAEL = 15.33 mg/kg bw/day.

b) corrected dermal human NOAEL = corrected dermal rat NOAEL * (ABS derm-rat / ABS derm-human).

No test data are available regarding absorption of 1,4 -benzenediamine, N,N'-mixed Ph and tolyl derivs. nor its main constituents. Nevertheless, as penetration through rodent skin is generally considered to be faster than penetration through human skin (textbook reference: Casarett & Doul, 2001, p.656), a worst-case ABS derm-human value of 60% can be assumed.

Corrected dermal human NOAEL = 15.33 mg/kg bw/day.

Assessment factors applied:

Allometric scaling factors: 4 (for rat vs. human) * 2.5 (for differences not related to calorimetric differences)

AF for oral-to-dermal extrapolation: 1 (default value according to R.8.4.2 of the guidance document)

AF for intra-species differences: 5 (default value for workers according to R.8.4.3.2 of the guidance document) AF for duration of exposure: 1 (default value as the NOAEL is derived from a chronic toxicity study)

Overall AF: 50

worker-DNEL long-term for dermal route-systemic: 0.307 mg/kg bw/day.

Inhalation DNEL:

Again, the NOAEL derived from the 52 week chronic feeding study in rats (Iatropoulos, 1996) was used as the starting point for derivation of the worker-DNEL long-term for inhalation route-systemic via route-to-route extrapolation.

NOAEL = 310 mg/kg diet.

NOAEL = 16.00 mg/kg bw/day

Subsequently, the NOAEL is corrected according to the default physiological parameters under the allometric scaling prinicple, as described in table R.8 -2 in section R.8.4.2 of the guidance document.

Corrected NOAEL for workers via inhalation = (NOAEL oral rat / 0.38 m3/kg bw) * (6.7 m3 / 10 m3)

Corrected NOAEL for workers via inhalation = 28.21 mg/m3

Assessment factors applied:

Allometric scaling factors: 2.5 (for differences not related to calorimetric differences)

AF for oral-to-inhalation extrapolation: 1.74 (value derived from the oral absorption study (see above): ABS oral rat = 57.5% -> AF = 100/57.5 = 1.74)

AF for intra-species differences: 5 (default value for workers according to R.8.4.3.2 of the guidance document)

AF for duration of exposure: 1 (default value as the NOAEL is derived from a chronic toxicity study)

Overall AF: 21.75

worker-DNEL long-term for inhalation route-systemic: 1.297 mg/m3

Long-term exposure – local effects:

Dermal DNEL:

There are two studies available that assess the skin irritation of 1,4-benzenediamine, N,N’-mixed Ph and tolyl derivs. (Merriman, 1995 and Bomhard and Martins, 1990). Both studies are of good quality (Klimisch 1 score). However, in neither of both a dose descriptor is derived that can be used as a starting point for the DNEL derivation.

However, the study by Merriman uses a higer concentration of the test substance (as expressed both in dose per cm2 and dose per kg bw) than the concentration used by Bomhard and Martins. Moreover, slight signs of irritation are observed at the higher dose exposure conditions. As a consequence a NOAEL for skin irriation in rabbits can be derived by combining the results of both studies. When a DNEL is derived starting from this NOAEL, an additional assessment factor will be taken into account in order to compensate for the uncertainty in the dose-response relationship.

Derivation of the NOAEL for skin irritation:

Information from study reports:

  Merriman   Bomhard and Martins
 Rabbit average weight  2.3 kg  3.6 kg
 Sex  Female  Not specified
 Dose  500 mg  500 mg
 Exposure area  1 inch square = 2.54 cm2 6 cm2 
Exposure time   4h  4h
# Test animals used  6
 # Animals affected by erythema  5
 # Animals affected by oedema  0
Dose per kg bw   217.4 mg/kg bw  138.9 mg/kg bw
 Dose per cm2 196.9 mg/cm2  83.34 mg/cm2 
 % Animals affected by erythema  83.30% 0% 

NOAEL for skin irriation = 83.30 mg/cm2

NOAEL for skin irriation = 138.9 mg/kg bw

Assessment factors:

AF for intra-species differences: 5 (default value according to R.8.4.2 of the guidance document)

AF for duration of exposure: 120 (see below)

AF for inter-species differences other than calorimetric differences: 2.5

AF for uncertainty in the dose-response relationship: 2

Overall AF: 3000

Although for local effects mostly no assessment factor is needed for exposure duration extrapolation (cfr. R.8.4.3.1, section “differences in duration of exposure”), it seems appropriate to apply an assessment factor of a factor 20 higher than the default value in this specific case, due to the fact that the NOAEL is based on an experimental exposure duration of 4 hours.

Worker-DNEL long-term for dermal route-local: 0.027 mg/cm2

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.32 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
44
Modified dose descriptor starting point:
NOAEC
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
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:
0.153 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
100
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.014 mg/cm²
Most sensitive endpoint:
skin irritation/corrosion
DNEL related information
Overall assessment factor (AF):
6 000
Dose descriptor:
other: NOAEL
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.16 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
100
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

Long-term exposure – systemic effects

Dermal DNEL:

The NOAEL derived from the 52 week chronic feeding study in rats (Iatropoulos, 1996) was used as the starting point for derivation of the general population-DNEL long-term for dermal route-systemic via route-to-route extrapolation.

NOAEL = 310 mg/kg diet.

The actual ingested dose corresponding to this dietary concentration was calculated from food consumption data present in the study:

NOAEL = 16.00 mg/kg bw/day.

Subsequently, the NOAEL is corrected for difference in absorption between dermal and oral route in the rat, and for difference in dermal absorption in rat versus dermal absorption in human, according to example B5 of Chapter R8 of the Guidance on information requirements and chemical safety assessment.

a) corrected dermal rat NOAEL = oral rat NOAEL * (ABS oral-rat / ABS derm-rat).

According to the available study on percutaneous absorption of one of the main constituents of 1,4 -benzenediamine, N,N'-mixed Ph and tolyl derivs. (Hui, 1997), 60% of the dermally-applied test chemical was absorbed during the 7 -day study.

According to two available studies on metabolism and excretion of two different main constituents of 1,4 -benzenediamine, N,N'-mixed Ph and tolyl derivs (Jeffcoat, 1998 and Jeffcoat, 1998), the mean value for absobtion of the by the rats ingested test substances is 57.5%.

Due to the clear structural similarities between the main constituents of 1,4 -benzenediamine, N,N'-mixed Ph and tolyl derivs. it can be assumed that the absoption values resulting from the above mentioned studies can be used as reasonable estimates for absorption behaviour of the multi-constituent substance as such. As a consequence, ABS derm-rat = 0.60, and ABS oral-rat is 0.575.

Corrected dermal rat NOAEL = 15.33 mg/kg bw/day.

b) corrected dermal human NOAEL = corrected dermal rat NOAEL * (ABS derm-rat / ABS derm-human).

No test data are available regarding absorption of 1,4 -benzenediamine, N,N'-mixed Ph and tolyl derivs. nor its main constituents. Nevertheless, as penetration through rodent skin is usually believed to be faster than penetration through human skin (textbook reference: Casarett & Doul, 2001, p.656), a worst-case ABS derm-human value of 60% can be assumed.

Corrected dermal human NOAEL = 15.33 mg/kg bw/day.

Assessment factors applied:

Allometric scaling factors: 4 (for rat vs. human) * 2.5 (for differences not related to calorimetric differences)

AF for oral-to-dermal extrapolation: 1 (default value according to R.8.4.2 of the guidance document)

AF for intra-species differences: 10 (default value for general population according to R.8.4.3.2 of the guidance document)

AF for duration of exposure: 1 (default value as the NOAEL is derived from a chronic toxicity study)

Overall AF: 100

general population-DNEL long-term for dermal route-systemic: 0.153 mg/kg bw/day.

Inhalation DNEL:

Again, the NOAEL derived from the 52 week chronic feeding study in rats (Iatropoulos, 1996) was used as the starting point for derivation of the general population-DNEL long-term for inhalation route-systemic via route-to-route extrapolation.

NOAEL = 310 mg/kg diet.

NOAEL = 16.00 mg/kg bw/day.

Subsequently, the NOAEL is corrected according to the default physiological parameters under the allometric scaling prinicple, as described in table R.8 -2 in section R.8.4.2 of the guidance document.

Corrected NOAEL for the general population via inhalation = (NOAEL oral rat / 1.15 m3/kg bw)

Corrected NOAEL for the general population via inhalation = 13.9 mg/m3

Assessment factors applied:

Allometric scaling factors: 2.5 (for differences not related to calorimetric differences)

AF for oral-to-inhalation extrapolation: 1.74 (value derived from the oral absorption study (see above): ABS oral rat = 57.5% -> AF = 100/57.5 = 1.74)

AF for intra-species differences: 10 (default value for the general population according to R.8.4.3.2 of the guidance document)

AF for duration of exposure: 1 (default value as the NOAEL is derived from a chronic toxicity study)

Overall AF: 43.5

general population-DNEL long-term for inhalation route-systemic: 0.320 mg/m3.

Oral DNEL:

Again, the NOAEL derived from the 52 week chronic feeding study in rats (Iatropoulos, 1996) was used as the starting point for derivation of the general population-DNEL long-term for inhalation route-systemic via route-to-route extrapolation.

NOAEL = 310 mg/kg diet.

NOAEL = 16.00 mg/kg bw/day.

As oral absorption by rat and human are assumed to be equal, no further corrections of the NOAEL value are required.

Assessment factors applied:

Allometric scaling factors: 4 (for rat vs. human) * 2.5 (for differences not related to calorimetric differences)

AF for intra-species differences: 10 (default value for the general population according to R.8.4.3.2 of the guidance document)

AF for duration of exposure: 1 (default value as the NOAEL is derived from a chronic toxicity study)

Overall AF: 100

general population-DNEL long-term for oral route-systemic: 0.160 mg/kg bw.

Long-term exposure – local effects:

Dermal DNEL:

The NOAEL is derived as described above in the section on workers.

NOAEL for skin irritation = 83.30 mg/cm2

NOAEL for skin irritation = 138.9 mg/kg bw

Assessment factors:

AF for intra-species differences: 10 (default value according to R.8.4.2 of the guidance document)

AF for duration of exposure: 120 (see below)

AF for inter-species differences other than calorimetric differences: 2.5

AF for uncertainty in the dose-response relationship: 2

Overall AF: 6000

Worker-DNEL long-term for dermal route-local: 0.014 mg/cm2