Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3.5 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
5
Dose descriptor starting point:
NOAEL
Value:
7 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
17.3 mg/m³
Explanation for the modification of the dose descriptor starting point:

There are no adequate experimental data on the inhalation route available. Therefore, the worker-DNEL long-term for inhalation route - systemic is derived from the NOAEL of 7 mg/kg bw/day, obtained in the key chronic oral repeated dose study in Wistar rats. The NOAECcorr. is calculated as follows:

- standard respiratory volume rat = 0.38 m³/kg/8h

- standard respiratory volume human = 6.7 m³/8h

- worker respiratory volume = 10 m³/8h

- absorption (oral, rat) = 100 % (based on experimental data, a vitrually complete absorbtion is expected)

- absorption (inhalative, human) = 100 % (default)

- experimental exposure time = 7 days/week

- exposure time worker = 5 days/week

--> modified dose descriptor (corrected inhalatory NOAEC) = 7 mg/kg bw/day * (1/0.38 m³/kg/d) * (6.7 m³ (8h)/10 m³ (8h)) * (1/1) * (7 exposure days/week; rat/5 exposure days/week; worker) = 17.3 mg/m³

AF for dose response relationship:
1
Justification:
ECHA REACH Guidance: starting point for the DNEL calculation is a NOAEL
AF for differences in duration of exposure:
1
Justification:
ECHA REACH Guidance: chronic exposure
AF for interspecies differences (allometric scaling):
1
Justification:
ECHA REACH Guidance: no additional factor needed for extrapolation from oral to inhalation route
AF for other interspecies differences:
1
Justification:
There is no evidence for species differences in general mode of actions or kinetics
AF for intraspecies differences:
5
Justification:
ECHA REACH Guidance: default factor for worker
AF for the quality of the whole database:
1
Justification:
ECHA REACH Guidance: good quality of data base
AF for remaining uncertainties:
1
Justification:
ECHA REACH Guidance: default factor
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
10.5 mg/m³
DNEL related information
DNEL extrapolated from long term DNEL

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.5 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
5
Dose descriptor:
other: NOEC
Value:
38 mg/m³
AF for dose response relationship:
1
Justification:
The dose response relationship is considered unremakable, therefore no additional factor is used.
AF for differences in duration of exposure:
1
Justification:
Irritation is considered to be mainly conc. dependent. No assessment factor for differences in duration is required.
AF for interspecies differences (allometric scaling):
1
Justification:
Local effects, dose in experimental animal study is expressed as concentration.
AF for other interspecies differences:
1
Justification:
There is no evidence for species differences in general mode of actions or kinetics.
AF for intraspecies differences:
5
Justification:
ECHA REACH Guidance: default factor for worker
AF for the quality of the whole database:
1
Justification:
The quality of the whole data base is considered to be sufficient and uncritical.
AF for remaining uncertainties:
1
Justification:
The approach used for DNEL derivation is conservative. No further assessment factors are required.
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.5 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA REACH guidance and EFSA Guidance on Dermal Absorption (2012).
Overall assessment factor (AF):
20
Dose descriptor starting point:
NOAEL
Value:
7 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
39.2 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

There are no adequate experimental data on the dermal route available. Therefore, the worker-DNEL long-term for the dermal route - systemic is derived from the NOAEL of 7 mg/kg bw/day, obtained in the key chronic oral repeated dose study in Wistar rats. The NOAELcorr. is calculated as follows:

- absorption (oral, rat) = 100 % (default)

- absorption (dermal, human) = 25 % (ESFA Guidance on Dermal Absorption, 2012)

- experimental exposure time = 7 days/week

- exposure time worker = 5 days/week

--> modified dose descriptor (corrected dermalNOAEC) = 7 mg/kg bw/day * (1/0.25) * (7 exposure days/week; rat/5 exposure days/week; worker) = 39.2 mg/m³

AF for dose response relationship:
1
Justification:
ECHA REACH Guidance: starting point for the DNEL calculation is a NOAEL
AF for differences in duration of exposure:
1
Justification:
ECHA REACH Guidance: default for chronic exposure
AF for interspecies differences (allometric scaling):
4
Justification:
ECHA REACH Guidance: default for rat to human extrapolation
AF for other interspecies differences:
1
Justification:
There is no evidence for species differences in general mode of actions or kinetics
AF for intraspecies differences:
5
Justification:
ECHA REACH Guidance: default factor for worker
AF for the quality of the whole database:
1
Justification:
ECHA REACH Guidance: good quality of data base
AF for remaining uncertainties:
1
Justification:
ECHA REACH Guidance: default factor
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
6 mg/kg bw/day
DNEL related information
DNEL extrapolated from long term DNEL

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
8 µg/cm²
Most sensitive endpoint:
skin irritation/corrosion
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
5
Dose descriptor:
other: NOEC
Value:
2 mg/m³
AF for dose response relationship:
1
Justification:
The dose response relationship is considered unremakable, therefore no additional factor is used.
AF for differences in duration of exposure:
1
Justification:
Irritation is considered to be mainly conc. dependent. No assessment factor for differences in duration is required.
AF for interspecies differences (allometric scaling):
1
Justification:
Local effects, dose in experimental animal study is expressed as concentration.
AF for other interspecies differences:
1
Justification:
There is no evidence for species differences in general mode of actions or kinetics.
AF for intraspecies differences:
5
Justification:
ECHA REACH Guidance: default factor for worker
AF for the quality of the whole database:
1
Justification:
The quality of the whole data base is considered to be sufficient and uncritical.
AF for remaining uncertainties:
1
Justification:
The approach used for DNEL derivation is conservative. No further assessment factors are required.
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
8 µg/cm²
Most sensitive endpoint:
skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - workers

 

Worker exposure: Long-term exposure – systemic effects

 

Inhalation exposure:

In order to derive the worker DNEL (long-term inhalation exposure), the NOAEL of 7 mg/kg bw/day of the chronic oral toxicity study (Hunter, 1976) is considered to represent the appropriate dose descriptor for systemic effects related to long-term inhalation to Bronopol.

A factor of 1 was assumed for route to route (oral to inhalation) extrapolation.

In order to derive a worker DNEL and under the assumption of a daily exposure period of 8 hours for 5 days per week,

the oral NOAEL is converted into an inhalation NOAEC according to the following formula:

inhalation NOAEC

= oral NOAEL × 1/sRV(rat) × ABSoral(rat)/ABSinhalation(human) × sRV(human)/wRV(human) × Exposure time (rat)/ Exposure time (human)

with:

oral NOAEL: 7 mg/kg bw/day

sRV(rat): 0.38 m³/kg bw (8 hours) [standard respiratory volume of the rat]

ABSoral(rat)/ABSinhalation(human): 1 [ratio of oral absorption in the rat to inhalative absorption in the human]

sRV(human)/wRV(human): 6.7 m³/10 m³ [ratio of human standard respiratory volume to worker respiratory volume]

Exposure time (rat)/Exposure time (human) [ratio of experimental exposure time in rat (7 days/week) and exposure time in workers (5 days/week)]

Accordingly, the oral NOAEL of 7 mg/kg bw/day is transformed in an inhalation NOAEC of 17.3 mg/m³.

 

Dermal exposure:

Based on a subacute dermal toxicity with rabbits (Davies, 1973), a dermal NOAEL of 5 mg/kg bw/day is deemed. However, in this study neither signs of systemic toxicity nor mortality were observed. The NOAEL estabilished in an oral repeated dose study in rats (Hunter, 1976) of 7 mg/kg bw/day is therefore considered to represent the most appropriate dose descriptor. This value is converted into a dermal NOAEL according to the following formula:

dermal NOAEL

= oral NOAEL × ABSoral(rat)/ABSderm(rat) × ABSderm(rat)/ABSderm(human) × Exposure time (rat)/ Exposure time (human)

with:

oral NOAEL: 7 mg/kg bw/day

ABSoral(rat)/ABSderm(human): 1/0.25 [ratio of oral absorption in the rat to dermal absorption in the human]

under consideration of the default dermal absorption value for humans of 25 % indicated in the EFSA Guidance on Dermal Absorption (2012).

Exposure time (rat)/Exposure time (human) [ratio of experimental exposure time in rat (7 days/week) and exposure time in workers (5 days/week)]

Accordingly, the oral NOAEL of 7 mg/kg bw/day is transformed in a dermal NOAEL of 39.2 mg/kg bw/day.

 

Assessment factors:

The following assessment factors are used for the derivation of worker DNELs for dermal or inhalation exposure to Bronopol:

Interspecies factor (rat to human): 4 [dermal route] or 1 [inhalation route]

Intraspecies factor (worker): 5

Exposure duration factor: 1 (chronic)

Quality of whole database factor: 1

 

The resulting worker DNELs are:

 

- Worker DNEL (inhalation exposure – long-term systemic)

= 17.3 mg/m³ / (1 × 1 × 5 × 1 × 1) = 17.3 mg/m³ / 5 = 3.5 mg/m³

 

- Worker DNEL (dermal exposure – long-term systemic)

= 39.2 mg/kg bw/day / (4 × 5 × 1 × 1 × 1) = 39.2 mg/kg bw/day / 20 = 2.0 mg/kg bw/day

 

 

Worker exposure: Short-term exposure – systemic effects

 

Inhalation exposure:

Since peak exposure via the inhalation route may occur (e.g. transfer of substance or preparation), a worker-DNEL acute for inhalation route - systemic is set for a reference period of 15 minutes at 3 times (default) of the worker-DNEL long-term inhalation route - systemic.

 

Dermal exposure:

Since for the dermal route setting of an acute DNEL based on the available lethality data (LD50 rat) was considered to involve too large uncertainties, the long-term DNEL for systemic effects (2.0 mg/kg bw/day) was used to deem an acute DNEL by multiplying the long-term DNEL with a default factor of 3. Nevertheless, no systemic adverse effects (clinical signs) were noticed in an in vivo skin irritation study in rabbits.

 

Thus, the resulting worker DNELs are:

 

- Worker DNEL (inhalation exposure – short-term systemic)

= (3.5 mg/m³ × 3) = 10.5 mg/m³

 

- Worker DNEL (dermal exposure – short-term systemic)

= (2.0 mg/kg bw/day × 3) = 6.0 mg/kg bw/day

 

 

Worker exposure: Long-term exposure – local effects

 

Inhalation exposure:

No quantitative data are available for long-term local effects. However, the test substance is classified for skin and eye irritation and therefore a hazard for the inhalatory route has to be expected. Some quantitative data are available for short-term local effects based on an acute inhalation toxicity study (Collins, 1986). For the test substance, local irritation effects were observed after direct exposure.

Based on the available data, a NOEC of 0.038 mg/L (38 mg/m³) is deemed for local effects in rats due to inhalation exposure. The NOECcorr is calculated as follows: NOAECcorr = 38 mg/m³ x ((4h/d) / (8h/d)) x ((6.7 m³ (8h) / 10 m³ (8h)) = 38 mg/m³ x 0.5 x 0.67 = 12.7 mg/m³

 

Dermal exposure:

The NOAEL for skin irritation established in a subacute repeated dose dermal toxicity study (Davies et al., 1973) of 2 mg/kg bw/day is considered to represent the appropriate dose descriptor for DNEL derivation.

 

Assessment factors:

The following assessment factors are used for the derivation of worker DNELs for long-term local dermal or inhalation exposure to Bronopol:

Dose response relationship: 1

Exposure duration factor: 1 (irritation is considered to be mainly conc. dependent)

Interspecies allometric factor: 1 (local effects)

Interspecies factor: 1

Intraspecies factor (worker): 5

Quality of whole database factor: 1

Remaining uncertainties: 1

 

Thus, the resulting worker DNELs are:

 

- Worker DNEL (inhalation exposure – long-term local)

= 12.7 mg/m³ / (1 × 1 × 1 × 1 × 5 × 1 × 1) = (12.7/3) mg/m³ = 2.5 mg/m³

 

- Worker DNEL (dermal exposure – long-term local)

= 2 mg/kg bw/day / (1 × 1 × 1 × 1 × 5 × 1 × 1) = 2 mg/kg bw/day / 3 = 0.4 mg/kg bw/day

which corresponds to 8 µg/cm²/day (0.67 mg/kg bw/day x 2.5 kg bw / 127.0 cm²)

 

with

rabbit body weight: 2.5 kg

body surface area of New Zealand White rabbits: 1270 cm² (according to Salomon and MacKenzie, 2007)

calculation was conducted with the 10 % value of body surface area, i.e. 127 cm².

 

Reference

Salomon CM and MacKenzie KM (2007). The Rabbit. In: Gad SC (editor). Animal models in toxicology. Taylor and Francis, Bocy Raton, London, New York.

 

 

Worker exposure: Short-term exposure – local effects

 

Inhalation and dermal exposure: 

The worker-DNELs long-term for dermal and inhalation local are considered to cover all relevant scenarios including acute exposure.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.6 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
10
Dose descriptor starting point:
NOAEL
Value:
7 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
6.1 mg/m³
Explanation for the modification of the dose descriptor starting point:

There are no adequate experimental data on the inhalation route available. Therefore, the worker-DNEL long-term for inhalation route - systemic is derived from the NOAEL of 7 mg/kg bw/day, obtained in the key chronic oral repeated dose study in Wistar rats. The NOAECcorr. is calculated as follows:

- standard respiratory volume rat = 1.15 m³/kg/24h

- absorption (oral, rat) = 100 % (based on experimental data, a vitrually complete absorbtion is expected)

- absorption (inhalative, human) = 100 % (default)

- experimental exposure time = 7 days/week

- exposure time worker = 7 days/week

--> modified dose descriptor (corrected inhalatory NOAEC) = 7 mg/kg bw/day * (1/1.15m³/kg/d) * (1/1) * (7 exposure days/week; rat/7 exposure days/week; worker) = 6.1 mg/m³

AF for dose response relationship:
1
Justification:
ECHA REACH Guidance: starting point for the DNEL calculation is a NOAEL
AF for differences in duration of exposure:
1
Justification:
ECHA REACH Guidance: default value for chronic exposure
AF for interspecies differences (allometric scaling):
1
Justification:
ECHA REACH Guidance: no additional factor needed for extrapolation from oral to inhalation route
AF for other interspecies differences:
1
Justification:
There is no evidence for species differences in general mode of actions or kinetics
AF for intraspecies differences:
10
Justification:
ECHA REACH Guidance: default factor for the general population
AF for the quality of the whole database:
1
Justification:
ECHA REACH Guidance: good quality of data base
AF for remaining uncertainties:
1
Justification:
ECHA REACH Guidance: default factor
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.8 mg/m³
DNEL related information
DNEL extrapolated from long term DNEL

Local effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Value:
0.6 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
10
Dose descriptor:
other: NOEC
Value:
38 mg/m³
AF for dose response relationship:
1
Justification:
The dose response relationship is considered unremakable, therefore no additional factor is used.

AF for differences in duration of exposure:
1
Justification:
Irritation is considered to be mainly conc. dependent. No assessment factor for differences in duration is required.
AF for interspecies differences (allometric scaling):
1
Justification:
Local effects, dose in experimental animal study is expressed as concentration.
AF for other interspecies differences:
1
Justification:
There is no evidence for species differences in general mode of actions or kinetics.
AF for intraspecies differences:
10
Justification:
ECHA REACH Guidance: default factor for general population
AF for the quality of the whole database:
1
Justification:
The quality of the whole data base is considered to be sufficient and uncritical.
AF for remaining uncertainties:
1
Justification:
The approach used for DNEL derivation is conservative. No further assessment factors are required.
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.6 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.7 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):
40
Dose descriptor starting point:
NOAEL
Value:
7 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
28 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

There are no adequate experimental data on the dermal route available. Therefore, the worker-DNEL long-term for the dermal route - systemic is derived from the NOAEL of 7 mg/kg bw/day, obtained in the key chronic oral repeated dose study in Wistar rats. The NOAELcorr. is calculated as follows:

- absorption (oral, rat) = 100 % (default)

- absorption (dermal, human) = 25% (ESFA Guidance on Dermal Absorption, 2012)

- experimental exposure time = 7 days/week

- exposure time worker = 7 days/week

--> modified dose descriptor (corrected dermalNOAEC) = 7 mg/kg bw/day * (1/0.25) * (7 exposure days/week; rat/7 exposure days/week; worker) = 28 mg/m³

AF for dose response relationship:
1
Justification:
ECHA REACH Guidance: starting point for the DNEL calculation is a NOAEL
AF for differences in duration of exposure:
1
Justification:
ECHA REACH Guidance: chronic exposure
AF for interspecies differences (allometric scaling):
4
Justification:
ECHA REACH Guidance: default for rat to human extrapolation
AF for other interspecies differences:
1
Justification:
There is no evidence for species differences in general mode of actions or kinetics.
AF for intraspecies differences:
10
Justification:
ECHA REACH Guidance: default factor for the general population
AF for the quality of the whole database:
1
Justification:
ECHA REACH Guidance: good quality of data base
AF for remaining uncertainties:
1
Justification:
ECHA REACH Guidance: default factor
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.1 mg/kg bw/day
DNEL related information
DNEL extrapolated from long term DNEL

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4 µg/cm²
Most sensitive endpoint:
skin irritation/corrosion
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
10
Dose descriptor:
other: NOEC
Value:
2
AF for dose response relationship:
1
Justification:
The dose response relationship is considered unremakable, therefore no additional factor is used.

AF for differences in duration of exposure:
1
Justification:
Irritation is considered to be mainly conc. dependent. No assessment factor for differences in duration is required.
AF for interspecies differences (allometric scaling):
1
Justification:
Local effects, dose in experimental animal study is expressed as concentration.
AF for other interspecies differences:
1
Justification:
There is no evidence for species differences in general mode of actions or kinetics.
AF for intraspecies differences:
10
Justification:
ECHA REACH Guidance: default factor for general population.
AF for the quality of the whole database:
1
Justification:
The quality of the whole data base is considered to be sufficient and uncritical.
AF for remaining uncertainties:
1
Justification:
The approach used for DNEL derivation is conservative. No further assessment factors are required.
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4 µg/cm²
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:
0.18 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):
40
Dose descriptor starting point:
NOAEL
Value:
7 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

There is no need to modify the dose descriptor starting point, since the same routes of exposure, absorption rates and exposure times apply for the animal experiment and the human exposure:

- absorption (oral, rat) = 100 % (default)

- absorption (oral, human) = 100 % (default)

- experimental exposure time = 7 days/week

- default exposure time of the general population = 7 days/week.

AF for dose response relationship:
1
Justification:
ECHA REACH Guidance: starting point for the DNEL calculation is a NOAEL
AF for differences in duration of exposure:
1
Justification:
ECHA REACH Guidance: chronic exposure
AF for interspecies differences (allometric scaling):
4
Justification:
ECHA REACH Guidance: default for rat to human extrapolation
AF for other interspecies differences:
1
Justification:
There is no evidence for species differences in general mode of actions or kinetics.
AF for intraspecies differences:
10
Justification:
ECHA REACH Guidance: default factor for the general population
AF for the quality of the whole database:
1
Justification:
ECHA REACH Guidance: good quality of data base
AF for remaining uncertainties:
1
Justification:
ECHA REACH Guidance: default factor
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.5 mg/kg bw/day
DNEL related information
DNEL extrapolated from long term DNEL

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - General Population

EXPOSURE: GENERAL POPULATION

 

SYSTEMIC – LONG TERM

 

Inhalation exposure:

In order to derive the general population DNEL (long-term inhalation exposure), the NOAEL of 7 mg/kg bw/day of the chronic oral toxicity study (Hunter, 1976) is considered to represent the appropriate dose descriptor for systemic effects related to long-term inhalation exposure to Bronopol.

A factor of 1 was assumed for route to route (oral to inhalation) extrapolation.

In order to derive a general population DNEL and under the assumption of a daily exposure period of 24 hours, the oral NOAEL is converted into an inhalation NOAEC according to the following formula (assuming identical absorption for both routes):

inhalation NOAEC human (24 h)

= (oral NOAEL x default human bw) / (AF x default human breathing volume) with:

oral NOAEL: 7 mg/kg bw/day

AF: allometric factor, Rat to Human: 4

default human bw: 70 kg bw

default human breathing volume: 20 m³/person

Accordingly, the oral NOAEL of 7 mg/kg bw/day is transformed in an inhalation NOAEC of 6.1 mg/m³.

 

Dermal exposure:

Based on a sub-acute dermal toxicity with rabbits (Davies, 1973), a dermal NOAEL of 5 mg/kg bw/day is deemed. However, in this study neither signs of systemic toxicity nor mortality were observed.

The NOAEL established in an oral repeated dose toxicity study in rats (Hunter, 1976) of 7 mg/kg bw/day is therefore considered to represent the most appropriate dose descriptor.

This oral NOAEL of 7 mg/kg bw/day is converted into a dermal NOAEL according to the following formula:

dermal NOAEL

= oral NOAEL × ABSoral(rat)/ABSderm(rat) × ABSderm(rat)/ABSderm(human)

with:

oral NOAEL: 7 mg/kg bw/day

ABSoral(rat)/ABSderm(human): 1/0.25 [ratio of oral absorption in the rat to dermal absorption in the human]

under consideration of the default dermal absorption value for humans of 25 % indicated in the EFSA Guidance on Dermal Absorption (2012).

Accordingly, the oral NOAEL of 7 mg/kg bw/day is transformed in a dermal NOAEL of 28 mg/kg bw/d.

 

Oral exposure:

In order to derive the general population DNEL (long-term oral exposure), the NOAEL of 7 mg/kg bw/day of the chronic oral toxicity study (Hunter, 1976) is considered to represent the appropriate dose descriptor for systemic effects related to long-term exposure to Bronopol.

 

Assessment factors:

The following assessment factors are used for the derivation of a general population DNELs for exposure to Bronopol:

Interspecies factor (rat to human): 4 [dermal and oral route], 1 [inhalation route]

Intraspecies factor (general population): 10

Exposure duration factor (dermal route): 1 (chronic)

Quality of whole database factor: 1

  The resulting DNELs are:

- General population DNEL (inhalation exposure): 0.6 mg/m³

- General population DNEL (dermal exposure): 0.7 mg/kg bw/d

- General population DNEL (oral exposure): 0.2 mg/kg bw/d

 

 

SYSTEMIC – SHORT TERM

Inhalation exposure:

Since the general population-DNEL long-term for inhalation route - systemic may not ensure a sufficient level of protection, a general population-DNEL acute for inhalation route - systemic is set at 3 times the general population-DNEL long-term for inhalation route - systemic.

 

Dermal exposure:

An acute DNEL was estimated by multiplying the long-term DNEL with a default factor of 3.

 

 

LOCAL – LONG TERM

Inhalation exposure:

Quantitative data are available for short-term local effects based on an acute inhalation toxicity study. For the test substance, local irritation effects were observed after direct exposure. Furthermore, the test substance is classified for skin and eye irritation. Based on the available data, a NOEC of 0.038 mg/L (38 mg/m³) is deemed for local effects in rats due to inhalation. The NOECcorr is calculated as follows: NOECcorr = 38 mg/m³ x ((4h/d) / (24h/d)) = 6.3 mg/m³. This NOECcorr covers also the acute exposure scenario.

 

Assessment factors:

The following assessment factors are used for the derivation of general population DNELs for long-term and short-term local inhalation exposure to Bronopol:

Dose response relationship: 1

Exposure duration factor: 1 (irritation is considered to be mainly conc. dependent)

Interspecies allometric factor: 1 (local effects)

Interspecies factor: 1

Intraspecies factor (general population): 10

Quality of whole database factor: 1

Remaining uncertainties: 1

- General population DNEL long-term and short-term (inhalation exposure): 6.3 mg/m³ / 10 = 0.6 mg/m³

 

Dermal exposure:

The NOAEL for skin irritation established in a subacute repeated dose dermal toxicity study (Davies et al., 1973) of 2 mg/kg bw/day is considered to represent the appropriate dose descriptor for DNEL derivation.

 

Assessment factors:

The following assessment factors are used for the derivation of general population DNEL long-term local for dermal or inhalation exposure to Bronopol:

Dose response relationship: 1

Exposure duration factor: 1 (irritation is considered to be mainly conc. dependent)

Interspecies allometric factor: 1 (local effects)

Interspecies factor: 1

Intraspecies factor (general population): 10

Quality of whole database factor: 1

Remaining uncertainties: 1

 

Thus, the resulting general population DNEL (dermal exposure – long-term local) is:

2 mg/kg bw/day / (1 × 1 × 1 × 1 × 10 × 1 × 1) = 2 mg/kg bw/day / 5 = 0.2 mg/kg bw/day

which corresponds to 4 µg/cm²/day (0.2 mg/kg bw/day x 2.5 kg bw / 127.0 cm²)

with

rabbit body weight: 2.5 kg,

body surface area of New Zealand White rabbits: 1270 cm² (according to Salomon and MacKenzie, 2007),

calculation was conducted with the 10 % value of body surface area, i.e. 127 cm².

 

Reference

Salomon CM and MacKenzie KM (2007). The Rabbit. In: Gad SC (editor). Animal models in toxicology. Taylor and Francis, Bocy Raton, London, New York.

 

 

LOCAL - SHORT TERM

Inhalation and dermal exposure:

The general population-DNELs long-term for dermal and inhalation local are considered to cover acute exposure scenarios.