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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.5 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
1
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

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:
0.071 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
1
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - workers

Derivation of DNELs

For the derivation of the DNELs two different studies considering different endpoints can be used. Two studies were assigned relevant key studies reflecting repeated exposure. A 2-generation study in rats was qualified as subchronic study with a dose descriptor chosen to be the NOAEL of 70 mg/kg/day to address systemic toxicity.

The 2nd approach is used to consider the potential depigmentation effects (vitiligo) of ptBP. In a 6-month oral toxicity study in mice to address skin depigmentation, a LOAEL of 103 mg/kg/day was observed.

Modification of dose descriptor

In order to adjust the NOAEL for the other/relevant exposures, a modification has to be made for workers and the general public. Factors have to be applied to adjust for human respiratory conditions as well as duration of exposure.

All factors used in the calculation have been suggested in the technical guidance document for the derivation of DNELs (Chapter R8).

Two-generation reproduction toxicity in rats

Oral NOAEL = 70 mg/kg/d

Factor for standard respiratory volume rat: 1/0.38 m3/kg/d

Factor for standard respiratory volume man and 8-h exposure: 6.7 m3 (8h) / 10 m3 (8h)

Corrected NOAEC: 123 mg/ m3

Mouse depigmentation study

Oral LOAEL = 103 mg/kg/d

Factor for standard respiratory volume rat: 1/0.38 m3/kg/d

Factor for standard respiratory volume man and 8 -h exposure: 6.7 m3 (8h) / 10 m3 (8h)

Corrected NOAEC: 182 mg/ m3

Additional assessment factors to account for inter- and intraspecies differences, exposure duration, etc. have to be considered.

Starting point - rat multigeneration study:

-worker, dermal exposure: AF = 100 (10 for interspecies/allometric scaling and 5 for intraspecies differences, 2 for extrapolation from subchronic to chronic exposure)

-worker inhalation exposure: AF = 25 (2.5 for interspecies and 5 for intraspecies differences, 2 for extrapolation from subchronic to chronic exposure)

starting point - mouse depigmentation study:

-worker, dermal exposure: AF = 525 (17.5 for interspecies/allometric scaling and 5 for intraspecies differences, 2 for extrapolation from subchronic to chronic exposure, 3 since starting point is LOAEL)

-worker inhalation exposure: AF = 75 (2.5 for interspecies and 5 for intraspecies differences, 2 for extrapolation from subchronic to chronic exposure, 3 since starting point is LOAEL)

Summary DNELs

DNELs based on - two-generation reproduction toxicity in rats:

Oral route

oral NOAEL = 70 mg/kg/d

AF = 100

DNELoral = 0.7 mg/kg

Inhalation route / systemic exposure

Corrected NOAEC = 123 mg/m3

AF = 25

DNELinhal = 4.9 mg/m3

Dermal route/systemic exposure: No oral DNEL need to be derived for workers. However, in the absence of dermal data, the dermal route is covered by oral route information.

DNELs based on - mouse depigmentation study:

Oral Route

Oral LOAEL = 103 mg/kg/d

AF = 525

DNELoral = 0.2 mg/kg

Inhalation route / systemic exposure

Corrected LOAEC = 182 mg/m3

AF = 75

DNELinhal = 2.4 mg/m3

DNEL derivation starting from available OEL value

Dermal route/systemic exposure

ptBP is absorbed via the respiratory tract and through intact skin in workers exposed occupationally. Several human studies are available. However, these studies are of low quality and are therefore not suitable in risk characterization.

In a Japanese plant no new cases of skin depigmentation arose after improvement of the working conditions yielding an average excretion of ptBP in urine of about 2 mg ptBP/l urine in the highest exposed workers who were exposed both by inhalation and through skin contact. The German biological limit value (BAT-value) in urine is based on this study. This value corresponds to a working place exposure of 0.5 mg/m3, which was in consequence proposed as preliminary MAK-value by the German MAK Commission [4].

For worker exposure via the dermal and inhalative route, the MAK-value can be used as the base for the respective DNELs. In comparison to the DNEL calculations based on the selected mouse study, the MAK value represents the more stringent course of risk assessment. The MAK value considers both significant dermal and systemic exposure.

Since no data on absorption for the different routes of exposure are available, the assumption has to be made that no difference in exposure exists. Consequently, the DNELs for long-term exposure via the dermal and oral route are the same.

Acute DNELs: Worker: according to the REACh "Guidance on information requirements and chemical safety assessment, Part B: Hazard Assessment", above 10 t/y, the establishment of acute toxicity DNEL is unnecessary in most cases, as the DNEL based on repeated dose toxicity is normally sufficient to ensure that adverse effects do not occur. DNEL for acute/short-term exposure-local effects was not quantifiable; however, ptBP is reported to be highly irritating to skin, eyes and respiratory tract; therefore, effect must be assessed qualitatively. Thus, as long term DNELs are available for ptBP, separate acute DNELs were not derived.

Long-term DNELs: German MAK value: 0.5 mg/m3, based on occupational exposure of 8 hours/day, 5 days/week; (Reference: Deutsche Forschungsgemeinschaft List of MAK and BAT Values 2007 Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area Report No. 43)

Modified concentration for DNEL Calculation

Worker/Inhalation = 0.5 mg/m3 (no adjustment required)

Worker/Dermal =0.5 mg/m3 x 10 m3/d/70 kg = 0.071 mg/kg/d (no adjustment for absorption)

Assessment Factors: no adjustments required for interspecies, exposure duration, dose response or quality of whole database as DNEL is based on an occupational limit for workers.

Final DNELs

Worker/Inhalation DNEL = 0.5 mg/m3

Worker/dermal DNEL =0.071 mg/kg/d

Absorption Data

Based on the physicochemical properties of ptBP alone [i.e., low molecular weight (150.22 g/mol), low Kow value (3.29), and high water solubility (610 mg/L)], the absorption of ptBP from various routes of exposure is expected to be 100%.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.09 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
2
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

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:
0.026 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
2
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.026 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
2
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Most sensitive endpoint:
acute toxicity
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - General Population

Derivation of DNELs For the derivation of the DNELs two different studies considering different endpoints can be used. Two studies were assigned relevant key studies reflecting repeated exposure. A 2-generation study in rats was qualified as subchronic study with a dose descriptor chosen to be the NOAEL of 70 mg/kg/day to address systemic toxicity. The 2nd approach is used to consider the potential depigmentation effects (vitiligo) of ptBP. In a 6-month oral toxicity study in mice to address skin depigmentation, a LOAEL of 103 mg/kg/day was observed. Modification of dose descriptor In order to adjust the NOAEL for the other/relevant exposures, a modification has to be made for workers and the general public. Factors have to be applied to adjust for human respiratory conditions as well as duration of exposure. All factors used in the calculation have been suggested in the technical guidance document for the derivation of DNELs (Chapter R8). Two-generation reproduction toxicity in rats Oral NOAEL = 70 mg/kg/d Factor for standard respiratory volume rat: 1/1.15 m3/kg/d Corrected NOAEC: 61 mg/ m3 Mouse depigmentation study Oral LOAEL = 103 mg/kg/d Factor for standard respiratory volume rat: 1/1.15 m3/kg/d Corrected NOAEC: 90 mg/ m3 Additional assessment factors to account for inter- and intraspecies differences, exposure duration, etc. have to be considered. Starting point: rat multigeneration study - General population/dermal exposure: AF = 200 (10 for interspecies/allometric scaling and 10 for intraspecies differences, 2 for extrapolation from subchronic to chronic exposure) - General population/inhalation exposure: AF = 50 (2.5 for interspecies and 10 for intraspecies differences, 2 for extrapolation from subchronic to chronic exposure) starting point: mouse depigmentation study - General population/dermal exposure: AF = 1050 (17.5 for interspecies/allometric scaling and 10 for intraspecies differences, 2 for extrapolation from subchronic to chronic exposure, 3 since starting point is LOAEL) - General population/inhalation exposure: AF = 150 (2.5 for interspecies and 10 for intraspecies differences, 2 for extrapolation from subchronic to chronic exposure, 3 since starting point is LOAEL) Summary DNELs DNELs based on two-generation reproduction toxicity in rats. Oral route oral NOAEL = 70 mg/kg/d AF = 200 DNELoral = 0.35 mg/kg Inhalation route / systemic exposure Corrected NOAEC = 61 mg/m3 AF = 50 DNELinhal = 1.2 mg/m3 DNELs based on mouse depigmentation study. Oral Route Oral LOAEL = 103 mg/kg/d AF = 1050 DNELoral = 0.1 mg/kg Inhalation route / systemic exposure Corrected LOAEC = 90 mg/m3 AF = 150 DNELinhal = 0.6 mg/m3 DNEL derivation starting from available OEL value Dermal route/systemic exposure ptBP is absorbed via the respiratory tract and through intact skin in workers exposed occupationally. Several human studies are available. However, these studies are of low quality and are therefore not suitable in risk characterization. In a Japanese plant no new cases of skin depigmentation arose after improvement of the working conditions yielding an average excretion of ptBP in urine of about 2 mg ptBP/l urine in the highest exposed workers who were exposed both by inhalation and through skin contact. The German biological limit value (BAT-value) in urine is based on this study. This value corresponds to a working place exposure of 0.5 mg/m3, which was in consequence proposed as preliminary MAK-value by the German MAK Commission [4]. Since no data on absorption for the different routes of exposure are available, the assumption has to be made that no difference in exposure exists. Consequently, the DNELs for long-term exposure via the dermal and oral route are the same. Acute DNELs - General Population: Similar to above for worker, assessment of acute systemic effects should default to the long term systemic DNELs; ptBP is reported to be highly irritating to skin and eyes, however, effect must be assessed qualitatively. Long-term DNELs: The long-term DNEL for the general population was derived from the worker MAK. Starting Dose for DNEL calculation: 0.5 mg/m3 (based on occupational exposure of 8 hours/day, 5 days/week; need to be corrected to account for different respiratory volume and exposure frequency & duration Modified dose for DNEL Calculation General Population/Inhalation = 0.5 mg/m3x10/6.7 x 8/24 x 5/7 = 0.18 mg/m3 General Population/Oral = 0.18 mg/m3 x 20 m3/d/70 kg = 0.0514 mg/kg/d (no adjustment for absorption) General Population /Dermal = 0.18 mg/m3 x 20 m3/d/70 kg = 0.0514 mg/kg/d (no adjustment for absorption) Assessment Factors (AF): No adjustments required for interspecies, exposure duration, dose response or quality of whole database as DNEL is based on an occupational limit for workers. An AF of 2 is applied for differences between workers and general population (basis: when extrapolating from animal to human, the recommended AF is 10 for general population and 5 for worker. Since the starting dose is corrected for continuous exposure, an additional 2 fold AF for differences was considered sufficient) Final DNELs General population/dermal DNEL = 0.0514mg/kg/d/2 = 0.026 mg/kg/d; General population/Inhalation DNEL 0.18 mg/m3/2 = 0.09 mg/m3; General population/oral DNEL = 0.0514mg/kg/d/2 = 0.026 mg/kg/d Absorption Data Based on the physicochemical properties of ptBP alone [i.e., low molecular weight (150.22 g/mol), low Kow value (3.29), and high water solubility (610 mg/L)], the absorption of ptBP from various routes of exposure is expected to be 100%.