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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:
379.2 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
12
Modified dose descriptor starting point:
NOAEC
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1 137.5 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
12
Modified dose descriptor starting point:
NOAEC

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:
54.2 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
12
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:
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

The DNELS for the following categories could not be derived:

-Acute local effects

-Longterm local effects

-Acute systemic dermal effects

An oral NOEL of 650 mg/kg bw/day was obtained in a subacute rat study. This NOEL is used to derive a DNEL long-term.

 

 

5.11.2.2 Modification of the dose descriptor to the correct starting point

 

NOEL(oral, rat) →NAEC (inhalative, worker); NAEC(inhalative, human)

A factor 2 is suggested in the ECHA Guidance for the oral to inhalation extrapolation without any further scientific or toxicological rationale. This extrapolation factor needs to be seriously questioned as documented experience has shown that in most cases a factor of 2 is disproportionate because systemic availability after oral intake often is very high.

This is confirmed by an evaluation of the published EU Risk Assessments (by April 2008):

  • All substances with the exception of metals and inorganic chemicals were evaluated (55 substances).
  • In 8 cases after inhalation exposure a higher absorption rate was considered than after oral intake (EDTA and Na4EDTA, musk ketone and musk xylene, DINP and DIDP, anthracene, Bis(pentabromophenyl)ether), but with DINP and DIDP the difference was less than 2.
  • In 3 cases the oral absorption was even higher compared to the inhalation absorption (tetrabromobisphenol A, 1,4-dichlorobenzene, 2-Methoxy-2-methylbutane TAME).
  • In the remaining 44 cases no difference was obvious.

Therefore, for the oral-to-inhalation extrapolation no correction was considered to be necessary. To cover interspecies differences between rats and humans the allometric scaling factor of 4 was applied. Thus the following NAEC worker (8h) and NAEC human (24h) values were derived as corrected starting points:

NAEC worker (8h) = (NOEL rat / 4) x (70 kg bw / 10 m3) = 1137.5 mg/m3

NAEC human (24h) = (NOEL rat / 4) x (70 kg bw / 20 m3) = 568.8 mg/m3

 

NOEL(oral, rat)NAEL (dermal, worker); NAEL (dermal, human)

To cover interspecies differences between rats and humans the allometric scaling factor of 4 was applied. Thus the follwing NAEL worker and NAEL human values were derived as corrected starting points:

NAEL worker = NOEL rat / 4 = 162.5 mg/kg bw/day

NAEL human = NOEL rat / 4 = 162.5 mg/kg bw/day

 

NOEL(oral, rat)NAEL (oral, human)

To cover interspecies differences between rats and humans the allometric scaling factor of 4 was applied. Thus the follwing NAEL human value was derived as corrected starting points:

NAEL human = NOEL rat / 4 = 162.5 mg/kg bw/day

 

 

5.11.2.3 calculation of the DNEL(s) by applying assessment factors to the

correct starting point

 

Allometric scaling to adjust for physiologically based species differences is widely accepted for systemic toxic substances (remark: this does not apply to direct local effects). However, as long as there is no evidence for differences in the general mode of action or kinetics there is no rationale for an additional factor of 2.5 for remaining differences. In this case this factor itself is arbitrary and has no scientific basis. Through the conservativeness of the factors and the multiplication of the different factors the assessment is already sufficiently conservative. This is also shown by the German AGW concept that does not apply this additional factor. Therefore, for remaining interspecies differences no further correction factor was applied.

 

NAEC (inhalative, worker); NAEC(inhalative, human)→DNEL(s)

 

To cover intraspecies differences in humans the assessment factor 3 and 5 were applied for worker and general population respectively as proposed by ECETOC. No assessment factor was applied for duration extrapolation. Thus the following DNEL values were derived:

 

Worker-DNELlongterm for inhalation route-systemic= NAEC (inhalative, worker) / 3 = 379.2 mg/m3

Human-DNELlongterm for inhalation route-systemic= NAEC (inhalative, human) / 5 = 113.8 mg/m3

 

NAEL (dermal, worker); NAEL (dermal, human)→DNEL(s)

 

To cover intraspecies differences in humans the assessment factor 3 and 5 were applied for worker and general population respectively. No assessment factor was applied for duration extrapolation. Thus the following DNEL values were derived:

 

Worker-DNELlongterm for dermal route-systemic= NAEL (dermal, worker) / 3 = 54.2 mg/kg bw/day

Human-DNELlongterm for dermal route-systemic= NAEL (dermal, human) / 5 = 32.5 mg/kg bw/day

 

NAEL (oral, human)→DNEL

To cover intraspecies differences in humans the assessment factor 5 was applied for general population. No assessment factor was applied for duration extrapolation. Thus the following DNEL value was derived:

 

Human-DNELlongterm for oral route-systemic= NAEL (oral, human) / 5 = 32.5 mg/kg bw/day

 

 

5.11.2.2 Derivation of DNEL acute

 

The acute toxicity studies available were studies with 2000 mg/kg bw. According to the guidance the DNEL for acute toxicity was set for a reference period of 15 minutes by multiplying the long-term DNELs with the default value of 3. Thus the following DNELacutevalues were derived:

 

Worker-DNELacute for inhalation route-systemic= Worker-DNELlongterm for inhalation route-systemicx 3 = 1137.5 mg/m3

 

Human-DNELacute for inhalation route-systemic= Human-DNELlongterm for inhalation route-systemicx 3 = 341.3 mg/m3

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
113 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
20
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
341 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
20
Modified dose descriptor starting point:
NOAEC

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:
32.5 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
20
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:
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:
32.5 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
20
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

The DNELS for the following categories could not be derived:

-Acute local effects

-Longterm local effects

-Acute systemic dermal effects

An oral NOEL of 650 mg/kg bw/day was obtained in a subacute rat study. This NOEL is used to derive a DNEL long-term.

 

 

5.11.2.2 Modification of the dose descriptor to the correct starting point

 

NOEL(oral, rat) →NAEC (inhalative, worker); NAEC(inhalative, human)

A factor 2 is suggested in the ECHA Guidance for the oral to inhalation extrapolation without any further scientific or toxicological rationale. This extrapolation factor needs to be seriously questioned as documented experience has shown that in most cases a factor of 2 is disproportionate because systemic availability after oral intake often is very high.

This is confirmed by an evaluation of the published EU Risk Assessments (by April 2008):

  • All substances with the exception of metals and inorganic chemicals were evaluated (55 substances).
  • In 8 cases after inhalation exposure a higher absorption rate was considered than after oral intake (EDTA and Na4EDTA, musk ketone and musk xylene, DINP and DIDP, anthracene, Bis(pentabromophenyl)ether), but with DINP and DIDP the difference was less than 2.
  • In 3 cases the oral absorption was even higher compared to the inhalation absorption (tetrabromobisphenol A, 1,4-dichlorobenzene, 2-Methoxy-2-methylbutane TAME).
  • In the remaining 44 cases no difference was obvious.

Therefore, for the oral-to-inhalation extrapolation no correction was considered to be necessary. To cover interspecies differences between rats and humans the allometric scaling factor of 4 was applied. Thus the following NAEC worker (8h) and NAEC human (24h) values were derived as corrected starting points:

NAEC worker (8h) = (NOEL rat / 4) x (70 kg bw / 10 m3) = 1137.5 mg/m3

NAEC human (24h) = (NOEL rat / 4) x (70 kg bw / 20 m3) = 568.8 mg/m3

 

NOEL(oral, rat)NAEL (dermal, worker); NAEL (dermal, human)

To cover interspecies differences between rats and humans the allometric scaling factor of 4 was applied. Thus the follwing NAEL worker and NAEL human values were derived as corrected starting points:

NAEL worker = NOEL rat / 4 = 162.5 mg/kg bw/day

NAEL human = NOEL rat / 4 = 162.5 mg/kg bw/day

 

NOEL(oral, rat)NAEL (oral, human)

To cover interspecies differences between rats and humans the allometric scaling factor of 4 was applied. Thus the follwing NAEL human value was derived as corrected starting points:

NAEL human = NOEL rat / 4 = 162.5 mg/kg bw/day

 

 

5.11.2.3 calculation of the DNEL(s) by applying assessment factors to the

correct starting point

 

Allometric scaling to adjust for physiologically based species differences is widely accepted for systemic toxic substances (remark: this does not apply to direct local effects). However, as long as there is no evidence for differences in the general mode of action or kinetics there is no rationale for an additional factor of 2.5 for remaining differences. In this case this factor itself is arbitrary and has no scientific basis. Through the conservativeness of the factors and the multiplication of the different factors the assessment is already sufficiently conservative. This is also shown by the German AGW concept that does not apply this additional factor. Therefore, for remaining interspecies differences no further correction factor was applied.

 

NAEC (inhalative, worker); NAEC(inhalative, human)→DNEL(s)

 

To cover intraspecies differences in humans the assessment factor 3 and 5 were applied for worker and general population respectively as proposed by ECETOC. No assessment factor was applied for duration extrapolation. Thus the following DNEL values were derived:

 

Worker-DNELlongterm for inhalation route-systemic= NAEC (inhalative, worker) / 3 = 379.2 mg/m3

Human-DNELlongterm for inhalation route-systemic= NAEC (inhalative, human) / 5 = 113.8 mg/m3

 

NAEL (dermal, worker); NAEL (dermal, human)→DNEL(s)

 

To cover intraspecies differences in humans the assessment factor 3 and 5 were applied for worker and general population respectively. No assessment factor was applied for duration extrapolation. Thus the following DNEL values were derived:

 

Worker-DNELlongterm for dermal route-systemic= NAEL (dermal, worker) / 3 = 54.2 mg/kg bw/day

Human-DNELlongterm for dermal route-systemic= NAEL (dermal, human) / 5 = 32.5 mg/kg bw/day

 

NAEL (oral, human)→DNEL

To cover intraspecies differences in humans the assessment factor 5 was applied for general population. No assessment factor was applied for duration extrapolation. Thus the following DNEL value was derived:

 

Human-DNELlongterm for oral route-systemic= NAEL (oral, human) / 5 = 32.5 mg/kg bw/day

 

 

5.11.2.2 Derivation of DNEL acute

 

The acute toxicity studies available were studies with 2000 mg/kg bw. According to the guidance the DNEL for acute toxicity was set for a reference period of 15 minutes by multiplying the long-term DNELs with the default value of 3. Thus the following DNELacutevalues were derived:

 

Worker-DNELacute for inhalation route-systemic= Worker-DNELlongterm for inhalation route-systemicx 3 = 1137.5 mg/m3

 

Human-DNELacute for inhalation route-systemic= Human-DNELlongterm for inhalation route-systemicx 3 = 341.3 mg/m3