Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
6.5 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Explanation for the modification of the dose descriptor starting point:

see 'Additional information - workers'

Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
84.8 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
DNEL extrapolated from long term DNEL

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:
0.93 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):
50
Dose descriptor starting point:
NOAEL
DNEL value:
46.86 mg/kg bw/day
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
52.75 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):
20
Dose descriptor starting point:
NOAEL
DNEL value:
1 055 mg/kg bw/day

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
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

Calculated DNELs for worker:  

 SHORT TERM EXPOSURE

 Inhalation:  84.8 mg/m³/day

   Dermal:  52.75 mg/kg bw/day

LONG TERM EXPOSURE

 Oral/Dermal:  1.5 mg/kg bw/day

  Inhalation:  10.6 mg/m³/day

REPRODUCTION

 Oral/Dermal:  0.93 mg/kg bw/day  

 Inhalation:  6.5 mg/m³/day

Derivation of DNELs

End point acute toxicity:

Short-term for inhalation route-systemic (workers):

No acute inhalation studies are available.

In several other acute studies Mesamoll showed no toxic characteristics, even in high doses.

In an acute oral toxicity study no deaths, but clinical signs were observed (apathy, ruffled fur and diarrhea) in the highest dose tested 5275 mg/kg (Bayer AG; Löser E./ Kimmerle G., 1975). In an acute dermal study no effects were seen at the highest dose tested (1055 mg/kg) (Bayer AG; Löser E. / Kimmerle G., 1975).

Due to the lack of acute inhalation data and low acute toxicity, short term exposure to workers should be based on the long-term exposure limit multiplied by an appropriate assessment factor. According to the German TRGS-900 a factor of 8 applied to the long-term exposure limit seems to be appropriate. If there is an eight-time exceedance of the occupational exposure limit for four-times in a working shift for more than 15 minutes no further exposition is tolerated. The product would otherwise exceed the occupational exposure limit (TRGS-900; 2006; modified and supplemented in 2008).

Therefore the acute DNEL for inhalation for worker based on the TRGS-900 is proposed to be 8 x 10.64 mg/m³/day = 84.8 mg/m³.

Mesamoll has no irritation capacity; consequently no local DNEL was established.

Short-term for dermal route-systemic (workers):

NOAEL (rat, dermal): 1055 mg/kg bw/day

For interspecies differences rat vs. human: 4

For remaining interspecies differences: 1 (not needed for acute toxicity based on the information available up to the 13 week study)

For intraspecies differences in worker: 5

For reliability of dose response: 1

For quality of whole database: 1

Overall factor 20

Worker DNEL acute toxicity dermal = 52.75 mg/kg bw/day

This DNEL is very conservative because not any effect was shown in an acute toxicity study at the highest dose tested (1055 mg/kg) and there is no information on the effect threshold. It is expected that the real DNEL acute dermal is at least in the area of the systemic NOAEL after 13 week oral intake in rats of ca. 220 mg/kg bw/day.

Repeated dose toxicity

Long-term for oral route-systemic (workers):

Starting point:

- Subchronic toxicity study; NOAEL 3000 ppm; LOAEL 12000; Effects seen at 12000 ppm: decrease of bw gain, liver and kidney weight changes; no histopathologic correlates.

- One-generation study was not used because: 1) no toxicity to males observed up to 15000 ppm (13 weeks exposure); 2) in females (20 weeks exposure) reduced bw. at 3000 ppm during gestation and lactation only; very slight kidney and liver weight increase with no histopathologic correlates.

Overall starting point: NOAEL 3000 ppm.

According to the study report the food intake in the 3000 ppm dose group is

76 g feed/kg bw. in male rats and 94 g feed/kg bw. in female rats (Ramm/Eiben, Bayer AG, 1987).

NOAEL (rat, male):

3000 ppm = 228 mg/kg bw/d

[3000 ppm= 3g Mesamoll/kg feed. = 3 mg Mesamoll/g feed

3 mg Mesamoll feed x 76 g feed/kg bw. = 228 mg Mesamoll /kg bw/d]

NOAEL (rat, female):

3000 ppm = 282 mg/kg bw/d

[3000 ppm= 3g Mesamoll/kg feed. = 3 mg Mesamoll/g feed

3 mg Mesamoll feed x 94 g feed/kg bw. = 282 mg Mesamoll /kg bw/d]

The lowest value 228 mg/kg bw/d was taken for further calculation of DNEL.

For interspecies differences rat vs. human: 4

For remaining interspecies differences: 2.5

For intraspecies differences in worker: 5

For extrapolation of exposure duration subchronic to chronic: 3* (Higher factor for time-extrapolation because of accumulation in fat tissue)

For reliability of dose response: 1

For quality of whole database: 1

Overall factor: 150

Worker DNEL long-term for oral route-systemic: 1.52 mg/kg bw/d

= 1.5 mg/kg bw/d

DNELs for long-term oral exposure are equal to the DNELs of long-term dermal exposure, if default assumption absorption oral= absorption dermal was considered.

Long-term for inhalation route-systemic (workers):

NOAEL (rat) oral: 3000 ppm= 228 mg/kg bw/d

The lowest value 228 mg/kg bw/d was taken for further calculation of DNEL

For interspecies differences rat vs. human: 4

228 mg/kg bw/d: 4= 57 mg/kg bw/d

Body weight worker: 70 kg bw/person

57 mg/kg bw/d x 70 kg be/person= 3990 mg/person/d

Respiratory vol. worker: 10 m³/person

3990 mg/person/d: 10 m³/person = 399 mg/m³/8h

NAEC worker (8h) = 399 mg/m³

For remaining interspecies differences: 2.5

For intraspecies differences in worker: 5

For extrapolation of exposure duration subchronic to chronic: 3 (Higher factor for time-extrapolation because of accumulation in fat tissue)

For reliability of dose response: 1

For quality of whole database: 1

Overall factor: 37.5

Worker DNEL long-term for inhalation route-systemic: 10.64 mg/m³/8h = 10.6 mg/m³/8h

Reproductive Toxicity:

Toxicity to reproduction for oral route-systemic (workers):

NOAEL: 600 ppm

According to the study report the food intake in the 600 mg/kg bw. dose group is 78.1 g feed/kg bw. in male rats and 113.1 g feed/kg bw. in female rats (Eiben/Rinke, Bayer AG, 2002).

NOAEL (rat, male):

600 ppm = 46.86 mg/kg bw/d

[600 ppm= 0.6g Mesamoll/kg feed. = 0.6 mg Mesamoll/g feed

0.6 mg Mesamoll /kg feed x 78.1 g feed/kg bw. = 46.86 mg Mesamoll /kg bw/d]

NOAEL (rat, female):

600 ppm = 67.86 mg/kg bw/d

[600 ppm= 0.6g Mesamoll/kg feed. = 0.6 mg Mesamoll/g feed

0.6 mg Mesamoll /kg feed x 113.1 g feed/kg bw. = 67.86 mg Mesamoll /kg bw/d]

The lowest value 46.86 mg/kg bw/d was taken for further calculation of DNEL.

For interspecies differences rat vs. human: 4

For intraspecies differences in worker: 5

For remaining interspecies differences: 2.5

For reliability of dose-response: 1

For quality of whole database: 1

Overall factor: 50

Worker-DNEL reproduction toxicity for oral route-systemic: 0.937 mg/kg bw/d

= 0.93 mg/kg bw/d

DNELs for reproduction toxicity for oral exposure are equal to the DNELs of reproduction toxicity dermal exposure, if default assumption "absorption oral= absorption dermal" is considered.

Toxicity to reproduction for inhalation route-systemic (workers):

NOAEL (rat) oral: 600 ppm

The lowest value 46.86 mg/kg bw/d was taken for further calculation of DNEL.

For interspecies differences rat vs. human: 4

46.86 mg/kg bw/d: 4= 11.71 mg/kg bw/d

Body weight worker: 70 kg bw/person

11.71 mg/kg bw/d x 70 kg be/person= 820.05 mg/person/d

Respiratory vol. worker: 10 m³/person

820.05 mg/person/d: 10 m³/person = 82.0 mg/m³/8h

NAEC worker (8h) = 82.0 mg/m³

For remaining interspecies differences: 2.5

For intraspecies differences in worker: 5

For reliability of dose response: 1

For quality of whole database: 1

Overall factor: 12.5

Worker DNEL long-term for inhalation route-systemic: 6.56 mg/m³/8h = 6.6 mg/m³/8h

The lowest repeated dose exposure DNEL value for workers is 0.93 mg/kg bw/day (oral or dermal exposure) or 6.5 mg/m3/day (inhalation exposure)

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.64 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Explanation for the modification of the dose descriptor starting point:

see 'Additional information - general population'

Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
21.28 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
DNEL extrapolated from long term DNEL

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:
0.47 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Explanation for the modification of the dose descriptor starting point:

see 'Additional information - general population'

Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
26.37 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):
40
Dose descriptor starting point:
NOAEL
DNEL value:
1 055 mg/kg bw/day

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
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:
0.47 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):
40
Dose descriptor starting point:
NOAEL
DNEL value:
1 055 mg/kg bw/day
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
26.37 mg/kg bw/day
DNEL related information
DNEL derivation method:
ECHA REACH Guidance

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

Calculated DNELs for general population:

LONG TERM

Oral/Dermal:   0.8 mg/kg bw/d

REPRODUCTION

Oral/Dermal:  0.47 mg/kg bw/d

Derivation of DNELs

End point acute toxicity:

Short-term for inhalation route-systemic (general population):

No acute inhalation studies are available.

In several other acute studies Mesamoll showed no toxic characteristics, even in high doses.

In an acute oral toxicity study no deaths, but clinical signs were observed (apathy, ruffled fur and diarrhea) in the highest dose tested 5275 mg/kg (Bayer AG; Löser E./ Kimmerle G., 1975). In an acute dermal study no effects were seen at the highest dose tested (1055 mg/kg) (Bayer AG; Löser E. / Kimmerle G., 1975).

Due to the lack of acute inhalation data and low acute toxicity, short term exposure to the general population should be based on the long-term exposure limit multiplied by an appropriate assessment factor. A factor of 8 applied to the long-term exposure limit seems to be appropriate.

Therefore the acute DNEL for inhalation is proposed to be 8 x 2.66 mg/m³/day = 21.28 mg/m³.

Mesamoll has no irritation capacity; consequently no local DNEL was established.

Short-term for dermal route-systemic (general population):

NOAEL (rat, dermal): 1055 mg/kg bw/day

For interspecies differences rat vs. human: 4

For remaining interspecies differences: 1 (not needed for acute toxicity based on the information available up to the 13 week study)

For intraspecies differences in general population: 10

For reliability of dose response: 1

For quality of whole database: 1

Overall factor 40

Worker DNEL acute toxicity dermal = 26.375 mg/kg bw/day

The DNEL for acute dermal systemic toxicity is adopted for acute oral systemic toxicity.

This DNEL is very conservative because not any effect was shown in an acute toxicity study at the highest dose tested (1055 mg/kg) and there is no information on the effect threshold. It is expected that the real DNEL acute dermal is at least in the area of the systemic NOAEL after 13 week oral intake in rats of ca. 220 mg/kg bw/day.

Repeated dose toxicity

Long-term for oral route-systemic (general population):

According to the study report the food intake in the 3000ppm dose group is 76 g feed/kg bw in male rats and 94 g feed/kg bw. in female rats (Ramm/Eiben, Bayer AG, 1987).

The lowest value 228 mg/kg bw/d was taken for further calculation of DNEL.

For interspecies differences rat vs. human: 4

For remaining interspecies differences: 2.5

For intraspecies differences in general population: 10

For extrapolation of exposure duration subchronic to chronic: 3 (Higher factor for time-extrapolation because of accumulation in fat tissue)

For reliability of dose response: 1

For quality of whole database: 1

Overall factor: 300

General population DNEL long-term for oral route-systemic: 0.76 mg/kg bw/d

= 0.8 mg/kg bw/d

DNELs for long-term oral exposure are equal to the DNELs of long-term dermal exposure, if default assumption absorption oral= absorption dermal was considered.

Long-term for inhalation route-systemic (general population):

NOAEL (rat) oral: 3000 ppm= 228 mg/kg bw/d

The lowest value 228 mg/kg bw/d was taken for further calculation of DNEL

For interspecies differences rat vs. human: 4

228 mg/kg bw/d: 4= 57 mg/kg bw/d

Body weight general population: 70 kg bw/person

57 mg/kg bw/d x 70 kg bw/person= 3990 mg/person/d

Respiratory vol. general population: 20 m³/person

3990 mg/person/d: 20 m³/person = 199.5 mg/m³/24h

NAEC general population (24h) = 199.5 mg/m³

For remaining interspecies differences: 2.5

For intraspecies differences in general population: 10

For extrapolation of exposure duration subchronic to chronic: 3 (Higher factor for time-extrapolation because of accumulation in fat tissue)

For reliability of dose response: 1

For quality of whole database: 1

Overall factor: 75

Worker DNEL long-term for inhalation route-systemic: 2.66 mg/m³/24h

Reproductive Toxicity:

Toxicity to reproduction for oral route-systemic (general population):

NOAEL: 600 ppm

The lowest value 46.86 mg/kg bw/d was taken for further calculation of DNEL.

For interspecies differences rat vs. human: 4

For intraspecies differences in general population: 10

For remaining interspecies differences: 2.5

For reliability of dose-response: 1

For quality of whole database: 1

Overall factor: 100

General population DNEL reproductive toxicity for oral route-systemic: 0.468 mg/kg bw/d

=0.47 mg/kg bw/d

Toxicity to reproduction for inhalation route-systemic (general population):

NOAEL (rat) oral: 600 ppm

The lowest value 46.86 mg/kg bw/d was taken for further calculation of DNEL.

For interspecies differences rat vs. human: 4

46.86 mg/kg bw/d: 4= 11.71 mg/kg bw/d

Body weight general population: 70 kg bw/person

11.71 mg/kg bw/d x 70 kg bw/person= 820.05 mg/person/d

Respiratory vol. general population: 20 m³/person

820.05 mg/person/d: 20 m³/person = 41.0 mg/m³/24h

NAEC  general population (24h) = 41.0 mg/m³

For remaining interspecies differences: 2.5

For intraspecies differences in general population: 10

For reliability of dose response: 1

For quality of whole database: 1

Overall factor: 25

General population DNEL long-term for inhalation route-systemic: 1.64 mg/m³/24h

Conclusion:

The lowest repeated dose exposure DNEL value for the general population  0.47 mg/kg bw/day (oral or dermal exposure)