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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.822 mg/m³
Most sensitive endpoint:
effect on fertility
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
75
Dose descriptor starting point:
NOAEL
Value:
50 mg/kg bw/day
Value:
61.7 mg/m³
Explanation for the modification of the dose descriptor starting point:

Default (DNEL calculator)

AF for dose response relationship:
1
Justification:
Default (DNEL calculator)
AF for differences in duration of exposure:
6
Justification:
Default (DNEL calculator)
AF for interspecies differences (allometric scaling):
1
Justification:
Default (DNEL calculator)
AF for other interspecies differences:
2.5
Justification:
Default (DNEL calculator)
AF for intraspecies differences:
5
Justification:
Default (DNEL calculator)
AF for the quality of the whole database:
1
Justification:
Default (DNEL calculator)
AF for remaining uncertainties:
1
Justification:
None applicable.
Acute/short term exposure
Hazard assessment conclusion:
exposure based waiving
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.233 mg/kg bw/day
Most sensitive endpoint:
effect on fertility
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
300
Dose descriptor starting point:
NOAEL
Value:
50 mg/kg bw/day
Value:
70 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Default (DNEL calculator)

AF for dose response relationship:
1
Justification:
Default (DNEL calculator)
AF for differences in duration of exposure:
6
Justification:
Default (DNEL calculator)
AF for interspecies differences (allometric scaling):
4
Justification:
Default (DNEL calculator)
AF for other interspecies differences:
2.5
Justification:
Default (DNEL calculator)
AF for intraspecies differences:
5
Justification:
Default (DNEL calculator)
AF for the quality of the whole database:
1
Justification:
Default (DNEL calculator)
AF for remaining uncertainties:
1
Justification:
None applicable.
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

Discussion:

The substance is classified for human health as a skin sensitiser and harmful if swallowed or inhaled.

Acute/short-term systemic effects:

Dermal DNEL:

A dermal DNEL has not been derived for short-term systemic effects. An acute dermal toxicity showed no signs of systemic toxicity and the substance is not classified for acute dermal toxicity. It is considered to be unnecessary to derive an acute systemic dermal DNEL. The substance is a skin sensitiser and causes some skin irritation (based on effects seen in a skin irritation study and dermal toxicity study). It is therefore considered that dermal effects will be characterised by local tissue irritation and sensitising effects rather than by systemic effects due to dermal uptake.

For substances which are classified for skin sensitisation (and have irritating properties to the skin), appropriate PPE should be used by all workers. As a result, direct dermal contact should only occur infrequently or accidentally.

Inhalation DNEL:

An acute inhalation toxicity study was conducted and gave an LC50 of 4.56 mg/L (females only) and the substance has been classified as harmful if inhaled. An acute DNEL should be derived if an acute toxicity hazard has been identified and there is a potential for high peak exposures. If a DNEL for acute inhalation toxicity is established this should only be derived for a specified fraction of the daily exposure duration (usually 15 minutes for workers). For inhalation exposure for periods longer than 15 minutes, the long-term DNEL should be used.

Therefore, it is considered that the derivation of an acute inhalation DNEL is not required, as all worker exposure will be for periods longer than 15 minutes and the estimated vapour pressure of the substance indicates 'peak exposures' will not be significant. The long-term inhalation DNEL for systemic effects is therefore used to assess risk.

Acute/short-term local effects:

Dermal DNEL

The substance is classified as a skin sensitiser. The substance also showed evidence of causing irritation effects in an acute dermal toxicity study (Slight or well-defined erythema was apparent on Days 2, 3 and 4 at the sites of application of the test substance) and in a skin irritation study (a single semi-occlusive application to intact rabbit skin for four hours elicited well-defined to moderate dermal irritation).. However, these studies do not provide adequate dose-response information to derive a DNEL for local effects. Dermal effects will be characterised by local tissue irritation and sensitising effects.

For substances which are classified for skin sensitisation (and have some irritating properties to the skin), appropriate PPE should be used by all workers. As a result, direct dermal contact should only occur infrequently or accidentally.

Inhalation DNEL:

No acute DNEL has been derived for local effects as the acute inhalation toxicity study does not give adequate dose response data. However, there were indications of local effects in the study i.e. due to lung observations noted in the animals it is considered that the deaths noted during the study may have been attributable to local toxicity caused by the test item.

If significant inhalation occurred, it is anticipated that local effects would be likely based on the sensitising and irritant properties of the substance i. e. irritation of the respiratory tract would be a likely local effect.

Long-term expousre - systemic effects:

Dermal DNEL

A DNEL has been derived for long-term systemic effects by the dermal route. The substance is a skin sensitiser and shows evidence of causing some skin irritation. Therefore, effects following dermal exposure will be characterised by local irritant and sensitising effects related to duration, quantity and concentration of the substance, rather than by systemic toxicity due to dermal uptake. Appropriate PPE should be used by all workers and therefore repeated substantial dermal exposure is unlikely.

However, a dermal DNEL for long-term systemic effects has been derived by route-to-route extrapolation from an oral NOAEL. A 90 -day repeated dose oral toxicity study resulted in a NOAEL (for systemic toxicity) of 50 mg/kg bw/day.

Based on this result the dermal NOAEL is assumed to be 50 mg/kg bw/day, assuming the same oral and dermal absorption of the substance as a worst case.The following assessment factors were then appllied:

- allometric scaling for interspecies differences (4 for rats)

- remaining interspecies differences (default factor 2.5)

- intraspecies differences (default factor of 5 for workers)

- study duration extrapolation (2 for subchronic to chronic)

Overall assessment factor: 100

The DNEL is therefore 50 mg/kg bw/day / 100 = 0.5 mg/kg bw/day

This long-term systemic dermal DNEL is used in the quantitative assessment of risk for systemic toxicity to workers via the dermal route.

Inhalation DNEL

No long-term inhalation study is available do derive a inhalation DNEL for long-term systemic effects.

However, a inhalation DNEL for long-term systemic effects has been derived by route-to-route extrapolation from an oral NOAEL. A 90 -day repeated dose oral toxicity study resulted in a NOAEL (for systemic toxicity) of 50 mg/kg bw/day.

The corrected inhalation dose descriptor of 44.05 mg/m3 was calculated in accordance with the ECHA Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterisation of dose [concentration]-response for human health.

The conversion of an oral rat NOAEL into a corrected inhalatory NOAEC to assess human inhalatory exposure was performed using the modification of starting point equation as given in Figure R. 8-3 (see below) for workers (in the case of 8 hour exposure/day). This corrected dose descriptor was based on worst case assumptions for absorption (i.e. the absorption percentage for the oral route is half that for the inhalation route). The inclusion of this factor means that 50% absorption was assumed for oral absorption and 100% absorption assumed for inhalation. This leads to the most conservative corrected dose descriptor.

Default parameters for rats and human (for 8 hour exposure) were used for the modification of starting point under the allometric scaling principles given in Table R. 8-2 of the above ECHA guidance.

Figure R.8-3 Modification of the starting point:

Conversion of an oral rate N(L)OAEL into a correct inhalatory N(L)OAEC to assess human inhalatory exposure:

For workers (in case of 8h exposure/day):

Corrected inhalatory N(L)OAEC = oral N(L)OAEL x (1 / sRVrat) x (ABSoral-rat / ABSinh-human) x (sRVhuman / wRV)

 

 

Corrected inhalatory N(L)OAEC= 50 mg/kg bw/day x (1 / 0.38 m3/kg/d) x (1 / 2) x (6.7 m3(8h) / 10 m3(8h))

                                                         = 44.05 mg/m3

 

Where:

ABS: Absorption

sRV: standard Respiratory Volume

wRV: worker Respiratory Volume (light activity)

 

Default parameters:

sRVrat (8 h) : 0.38m3/kg bw

sRVhuman (8 h) : 6.7 m3/ person

wRV (8 h): 10 m3/ person

The following assessment factors were then applied:

- remaining interspecies differences (default factor 2.5)

- intraspecies differences (default factor of 5 for workers)

- study duration extrapolation (2 for subchronic to chronic)

Overall assessment factor: 25

 

 

Conversion of corrected inhalatory NOAEC into a long-term DNEL (inhalation) of workers:

 

DNEL (inhalation)= Inhalatory NOAEC / Overall assessment factor = 44.05 mg/m3/ 25 = 1.76 mg/m3

This long-term systemic inhalation DNEL is used in the quantitative assessment of risk for systemic toxicity to workers via the inhalation route.

Long-term exposure - local effects:

Dermal DNEL

No DNEL has been derived for long-term dermal local effects. No long-term dermal study has been conducted and available short-term studies do not give adequate dose-response data.

The substance is a skin sensitiser and shows evidence of causing some skin irritation. Therefore, effects following dermal exposure will be characterised by local irritant and sensitising effects related to duration, quantity and concentration of the substance, rather than by systemic toxicity due to dermal uptake. Appropriate PPE should be used by all workers and therefore repeated substantial dermal exposure is unlikely.

Inhalation DNEL

No DNEL has been derived for long-term inhalation local effects as no long-term inhalation study has been conducted and therfore there is no data on local effects.

Based on the estimated vapour pressure of the substance exposure via inhalation is not anticipated to be at significant levels.

If significant inhalation occurred, it is anticipated that local effects would be likely based on the sensitising and irritant properties of the substance i. e. irritation of the respiratory tract would be a likely local effect.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.145 mg/m³
Most sensitive endpoint:
effect on fertility
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
150
Dose descriptor starting point:
NOAEL
Value:
50 mg/kg bw/day
Value:
21.8 mg/m³
Explanation for the modification of the dose descriptor starting point:

Default (DNEL calculator)

AF for dose response relationship:
1
Justification:
Default (DNEL calculator)
AF for differences in duration of exposure:
6
Justification:
Default (DNEL calculator)
AF for interspecies differences (allometric scaling):
1
Justification:
Default (DNEL calculator)
AF for other interspecies differences:
2.5
Justification:
Default (DNEL calculator)
AF for intraspecies differences:
10
Justification:
Default (DNEL calculator)
AF for the quality of the whole database:
1
Justification:
Default (DNEL calculator)
Acute/short term exposure
Hazard assessment conclusion:
exposure based waiving
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
exposure based waiving
Acute/short term exposure
Hazard assessment conclusion:
exposure based waiving
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
83.3 µg/kg bw/day
Most sensitive endpoint:
effect on fertility
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
600
Dose descriptor starting point:
NOAEL
Value:
50 mg/kg bw/day
Value:
50 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Default (DNEL calculator)

AF for dose response relationship:
1
Justification:
Default (DNEL calculator)
AF for differences in duration of exposure:
6
Justification:
Default (DNEL calculator)
AF for interspecies differences (allometric scaling):
4
Justification:
Default (DNEL calculator)
AF for other interspecies differences:
2.5
Justification:
Default (DNEL calculator)
AF for intraspecies differences:
10
Justification:
Default (DNEL calculator)
AF for the quality of the whole database:
1
Justification:
Default (DNEL calculator)
Acute/short term exposure
Hazard assessment conclusion:
exposure based waiving
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
exposure based waiving
Acute/short term exposure
Hazard assessment conclusion:
exposure based waiving

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
83.3 µg/kg bw/day
Most sensitive endpoint:
effect on fertility
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
600
Dose descriptor starting point:
NOAEL
Value:
50 mg/kg bw/day
Value:
50 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Default (DNEL calculator)

AF for dose response relationship:
1
Justification:
Default (DNEL calculator)
AF for differences in duration of exposure:
6
Justification:
Default (DNEL calculator)
AF for interspecies differences (allometric scaling):
4
Justification:
Default (DNEL calculator)
AF for other interspecies differences:
2.5
Justification:
Default (DNEL calculator)
AF for intraspecies differences:
10
Justification:
Default (DNEL calculator)
AF for the quality of the whole database:
1
Justification:
Default (DNEL calculator)
AF for remaining uncertainties:
1
Justification:
None applicable.
Acute/short term exposure
Hazard assessment conclusion:
exposure based waiving
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

The only DNEL derived for the general population is for long-term system effects via the oral route. This DNEL has been derived in order to assess the risk from indirect exposure of humans via the environment (from release of the substance from manufacturing).

No other DNELs are considered to be relevant as the substance will only be used by industry and not by the public. The substance is consumed in the vulcanisation process, so is not present in the final manufactured rubber products. Exposure to the general public is therefore not anticipated.