Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DMEL (Derived Minimum Effect Level)
Value:
0.001 mg/m³
Most sensitive endpoint:
carcinogenicity
DNEL related information
Overall assessment factor (AF):
10 000
Modified dose descriptor starting point:
BMCL10
Acute/short term exposure
DNEL related information

Local effects

Acute/short term exposure
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DMEL (Derived Minimum Effect Level)
Value:
0.004 mg/kg bw/day
Most sensitive endpoint:
carcinogenicity
DNEL related information
Overall assessment factor (AF):
40 000
Modified dose descriptor starting point:
BMDL10
Acute/short term exposure
DNEL related information

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

The DNELs for human exposure are derived according to the ECETOC guidance (final draft March 17, 2010) and DMELs for human exposure are derived according to the ECHA guidance (2008).

In the absence of classification for systemic and local effects after acute dermal and inhalation exposure to MOCA, no acute DNELs are considered applicable.

In the absence of local effects after repeated exposure to MOCA, no long-term DNELs for local effects are considered applicable.

For long-term exposures DMELs will be derived as a genotoxic carcinogen has by default no threshold, unless data prove otherwise. DNELs for systemic effects other than carcinogenic effects after long-term exposure are considered to be covered by the DMELs.

 

The following DMELs were derived:

Systemic:

Long-term oral general population (from 2-year diet study in rats)

Long-term inhalation workers (from 2-year diet study in rats)

Long-term inhalation general population (from 2-year diet study in rats)

Long-term dermal workers (from 2-year diet study in rats)

Long-term dermal general population (from 2-year diet study in rats)

Route-to-route extrapolation

Necessary for the long-term systemic dermal and inhalation DMEL for the general population and workers.

 

Based on available toxicokinetic studies (see IUCLID), the following absorption values are used:

Oral: 100%

Dermal: 2.5%

Inhalation: 100%

 

Human body weight is considered to be 70 kg.

Long-term DMEL

 

For long-term exposure a DMEL is derived as MOCA is a genotoxic carcinogen without a threshold. A 2-year study in rats with 18 -month exposure and quantitative data for control group and three dose levels is available. Therefore, dose descriptors, T25 and BMD10 can be derived. According to ECHA, “in case of a linear response a BMD10 will produce the same value as the T25 method, however, with clearly sublinear or supralinear dose response curves it will do more justice to the available dose-response relationship from the bioassay than the T25 method.” (ECHA, 2008)

As BMD10 values (and BMDL10) have been calculated by US EPA for the tumours found in lung, mammary gland, zymbal gland and liver in the Kommineni study (Kommineni et al. 1979 in US EPA, 2006), the lowest of these BMD10 values is used to derive DMELs for this substance. (see Table 1)

 

Table 1.BMD10 values based on lung, mammary, zymbal gland and liver tumour incidences in male rats (Kommineni et al. 1979 as cited in US EPA, 2006)

 

Tumor

Average Daily Dose (mg/kg-day) 

rat BMD10

 

0

 

9.4

 

18.8

37.5

 

Lung (adenoma, epidermoid carcinoma, adenocarcinoma)

1/100

23/100

28/75

35/50

4.45

Lung (adenocarcinoma)

0/100

14/100

20/75

31/50

7.45

Mammary (adenocarcinoma)

1/100

5/100

8/75

14/50

18.70

Zymbal gland (adenocarcinoma)

1/100

8/100

5/75

11/50

19.66

Liver (hepatocellular carcinoma)

0/100

3/100

3/75

18/50

20.03

 

The lowest BMD10 value of 4.45 mg/kg-day is found for combined tumours in the lung and as the dose-response relationship for these tumours is slightly supralinear (US EPA,2006), the linearised approach for derivation of the DMEL is used.

Long-term inhalation, systemic effects

Worker

Starting point: BMD10 = 4.45 mg/kg bw/d

 

Corrected inhalatory BMD10 = 4.45 * 1/0.384a* 6.7/10b* 100/100c= 7.76 mg/m3.

 

a          1/standard resp. volume rat, 8 h (oral to inhalation rat)

b          8-h respiratory volume at rest/light activity (m3)

c          conversion rest to light activity

 

Safety factors:

-      Interspecies extrapolation:       1

-      Intraspecies extrapolation:       not applied

-      Nature of carcinogenic process:not applied

-      Point of comparison:                not applied

-      High to low dose:                     10,000 (risk of 1:100,000) and 100,000 (risk of 1:1000,000)

-      Quality of the data base:          1

Total safety factor: 10,000 and 100,000

 

Based on the above, the long-term DMEL for systemic effects after inhalation exposure of the worker is 7.76 x 10-4mg/m3(linearity, 1:100,000) or 7.76 x 10-5mg/kg bw/day (linearity, 1:1000,000).

 

Long-term dermal, systemic effects

 

Worker

Starting point: BMD10 = 4.45 mg/kg bw/d

 

Corrected dermal BMD10 = 4.45 x 100/2.5a= 178 mg/kg bw/day

 

a          oral/dermal absorption

 

Safety factors:

-      Interspecies extrapolation:       4 (rat to human metabolic rate)

-      Intraspecies extrapolation:       not applied

-      Nature of carcinogenic process:not applied

-      High to low dose extrapolation: 10,000 (risk of 1:100,000) and 100,000 (risk of 1:1000,000)

-      Quality of the data base:          1

Total safety factor: 40,000 and 400,000

 

Based on the above, the long-term DMEL for systemic effects after dermal exposure of the worker is 4.45 x 10-3mg/kg bw/day (0.31 mg/day; linearity, 1:100,000) or 4.45 x 10-4mg/kg bw/day (0.031 mg/day; linearity, 1:1000,000).

  References

 

  1. ECETOC, Guidance on assessment factors to derive DNELs, final draft, March 17, 2010.
  2. ECHA, Guidance on information requirements and chemical safety assessment: Chapter R8: Characterisation of dose[concentration]-response for human health. May 2008
  3. US EPA, Provisional peer reviewed toxicity values for 4,4’-methylenebis(2-chloroaniline), 12 April 2006 (downloaded fromhttp://www.epa.gov/oswer/riskassessment/sghandbook/pdfs/pprtv-moca.pdf August 19, 2010)

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DMEL (Derived Minimum Effect Level)
Value:
0 mg/m³
Most sensitive endpoint:
carcinogenicity
DNEL related information
Overall assessment factor (AF):
10 000
Modified dose descriptor starting point:
BMCL10
Acute/short term exposure
DNEL related information

Local effects

Acute/short term exposure
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DMEL (Derived Minimum Effect Level)
Value:
0.004 mg/kg bw/day
Most sensitive endpoint:
carcinogenicity
DNEL related information
Overall assessment factor (AF):
40 000
Modified dose descriptor starting point:
BMDL10
Acute/short term exposure
DNEL related information

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DMEL (Derived Minimum Effect Level)
Value:
0 mg/kg bw/day
Most sensitive endpoint:
carcinogenicity
DNEL related information
Overall assessment factor (AF):
40 000
Modified dose descriptor starting point:
BMDL10
Acute/short term exposure
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

The DNELs for human exposure are derived according to the ECETOC guidance (final draft March 17, 2010) and DMELs for human exposure are derived according to the ECHA guidance (2008).

In the absence of classification for systemic and local effects after acute dermal and inhalation exposure to MOCA, no acute DNELs are considered applicable.

In the absence of local effects after repeated exposure to MOCA, no long-term DNELs for local effects are considered applicable.

For long-term exposures DMELs will be derived as a genotoxic carcinogen has by default no threshold, unless data prove otherwise. DNELs for systemic effects other than carcinogenic effects after long-term exposure are considered to be covered by the DMELs.

 

The following DMELs were derived:

Systemic:

Long-term oral general population (from 2-year diet study in rats)

Long-term inhalation workers (from 2-year diet study in rats)

Long-term inhalation general population (from 2-year diet study in rats)

Long-term dermal workers (from 2-year diet study in rats)

Long-term dermal general population (from 2-year diet study in rats)

Route-to-route extrapolation

Necessary for the long-term systemic dermal and inhalation DMEL for the general population and workers.

 

Based on available toxicokinetic studies (see IUCLID), the following absorption values are used:

Oral: 100%

Dermal: 2.5%

Inhalation: 100%

 

Human body weight is considered to be 70 kg.

Long-term DMEL

 

For long-term exposure a DMEL is derived as MOCA is a genotoxic carcinogen without a threshold. A 2-year study in rats with 18-month exposure and quantitative data for control group and three dose levels is available. Therefore, dose descriptors, T25 and BMD10 can be derived. According to ECHA, “in case of a linear response a BMD10 will produce the same value as the T25 method, however, with clearly sublinear or supralinear dose response curves it will do more justice to the available dose-response relationship from the bioassay than the T25 method.” (ECHA, 2008)

As BMD10 values (and BMDL10) have been calculated by US EPA for the tumours found in lung, mammary gland, zymbal gland and liver in the Kommineni study (Kommineni et al. 1979 in US EPA, 2006), the lowest of these BMD10 values is used to derive DMELs for this substance. (see Table 1)

 

Table 1.BMD10 values based on lung, mammary, zymbal gland and liver tumour incidences in male rats (Kommineni et al. 1979 as cited in US EPA, 2006)

Tumor

Average Daily Dose (mg/kg-day) 

rat BMD10

 

0

 

9.4

 

18.8

37.5

 

Lung (adenoma, epidermoid carcinoma, adenocarcinoma)

1/100

23/100

28/75

35/50

4.45

Lung (adenocarcinoma)

0/100

14/100

20/75

31/50

7.45

Mammary (adenocarcinoma)

1/100

5/100

8/75

14/50

18.70

Zymbal gland (adenocarcinoma)

1/100

8/100

5/75

11/50

19.66

Liver (hepatocellular carcinoma)

0/100

3/100

3/75

18/50

20.03

The lowest BMD10 value of 4.45 mg/kg-day is found for combined tumours in the lung and as the dose-response relationship for these tumours is slightly supralinear (US EPA,2006), the linearised approach for derivation of the DMEL is used.

Long-term oral, systemic effects

 

General population

 

Starting point: BMD10 = 4.45 mg/kg bw/d

No data on a possible difference in bioavailability between experimental animals and humans after oral exposure are available.

 

Safety factors:

-      Interspecies extrapolation:       4 (rat to human metabolic rate)

-      Intraspecies extrapolation:       not applied

-      Nature of carcinogenic process:not applied

-      High to low dose extrapolation: 10,000 (risk of 1:100,000) and 100,000 (risk of 1:1000,000)

-      Quality of the data base:          1

Total safety factor: 40,000 and 400,000

 

Based on the above, the long-term DMEL for systemic effects after oral exposure of the general population is 1.11 x 10-4mg/kg bw/day (7.8 x 10-3mg/day; linearity, 1:100,000) or 1.11 x 10-5mg/kg bw/day (7.8 x 10-4mg/day; linearity, 1:1000,000).

 

Long-term inhalation, systemic effects

General population

Starting point: BMD10 = 4.45 mg/kg bw/d

 

Corrected inhalatory BMD10 = 4.45 * 1/1.15a* 100/100b= 3.07 mg/m3

 

a          1/standard respiratory volume rat, 24h (m3/kg/d)

b          absorption oral rat/absorption inhalation human

 

Safety factors:

-      Interspecies extrapolation:       1

-      Intraspecies extrapolation:       not applied

-      Nature of carcinogenic process:not applied

-      Point of comparison:                not applied

-      High to low dose:                     10,000 (risk of 1:100,000) and 100,000 (risk of 1:1000,000)

-      Quality of the data base:          1

Total safety factor: 10,000 and 100,000

 

Based on the above, the long-term DMEL for systemic effects after inhalation exposure of the general population is 3.07 x 10-4mg/m3(linearity, 1:100,000) or 3.07 x 10-5mg/kg bw/day (linearity, 1:1000,000).

 

Long-term dermal, systemic effects General population

Starting point: BMD10 = 4.45 mg/kg bw/d

 

Corrected dermal BMD10 = 4.45 x 100/2.5a= 178 mg/kg bw/day

 

a          oral/dermal absorption

 

Safety factors:

-      Interspecies extrapolation:       4 (rat to human metabolic rate)

-      Intraspecies extrapolation:       not applied

-      Nature of carcinogenic process:not applied

-      High to low dose extrapolation: 10,000 (risk of 1:100,000) and 100,000 (risk of 1:1000,000)

-      Quality of the data base:          1

Total safety factor: 40,000 and 400,000

 

Based on the above, the long-term DMEL for systemic effects after dermal exposure of the worker is 4.45 x 10-3mg/kg bw/day (0.31 mg/day; linearity, 1:100,000) or 4.45 x 10-4mg/kg bw/day (0.031 mg/day; linearity, 1:1000,000).

 

 

References

 

  1. ECETOC, Guidance on assessment factors to derive DNELs, final draft, March 17, 2010.
  2. ECHA, Guidance on information requirements and chemical safety assessment: Chapter R8: Characterisation of dose[concentration]-response for human health. May 2008
  3. US EPA, Provisional peer reviewed toxicity values for 4,4’-methylenebis(2-chloroaniline), 12 April 2006 (downloaded fromhttp://www.epa.gov/oswer/riskassessment/sghandbook/pdfs/pprtv-moca.pdf August 19, 2010)