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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
10 mg/m³
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance
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
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
23.2 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Dermal
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance and ECETOC Technical Report No. 110
Overall assessment factor (AF):
43.2
Modified dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
No route to route extrapolation is required since a repeated dose dermal toxicity study is available.
AF for dose response relationship:
1
Justification:
The dose response relationship is considered unremarkable, therefore no additional factor is used.
AF for differences in duration of exposure:
6
Justification:
The default extrapolation factor for exposure duration is used: subacute (starting point) to chronic (end point).
AF for interspecies differences (allometric scaling):
2.4
Justification:
The default allometric scaling factor for the differences between rabbits and humans is used.
AF for other interspecies differences:
1
Justification:
There is no evidence for species differences in the general mode of action or kinetics.
AF for intraspecies differences:
3
Justification:
The default value for the relatively homogenous group "worker" is used.
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:
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

General

DNEL derivation for the substance is performed under consideration of the recommendations of ECHA REACH Guidance (2012) and ECETOC (2003). In view of the data used for evaluation, the assessment factor (AS) for dose response relation ship, the AS for quality of whole database factors and the AS for remainign uncertainties are set to a value of 1, and are thus not shown in the calculations presented below.

Acute- systemic effects

The test material is not classified and labelled for acute systemic toxicity, according to Directive 67/548/EEC (DSD) and Regulation (EC) No 1272/2008 (CLP). Thus, DNEL derivation is not required for this endpoint.

Acute/short-term and long-term exposure - local effects

Respiratory irritation and sensitisation: No adverse effects on respiratory system were observed in a short-term inhalation study with a structural analogue substance (free acid of the registered substance). Furthermore, the test item is not classified for skin irritation and skin sensitisation according to Directive 67/548/EEC (DSD) and Regulation (EC) No 1272/2008 (CLP). Thus, no adverse local effects to the respiratory system are expected and no DNEL for local effects on the respiratory system was derived.

Skin irritation/corrosion and sensitization: The test item is not classified for skin irritation and skin sensitisation according to Directive 67/548/EEC (DSD) and Regulation (EC) No 1272/2008 (CLP). Thus, DNEL derivation is not required for this endpoint.

Eye irritation: The test item is not classified for eye irritation according to Directive 67/548/EEC (DSD) and Regulation (EC) No 1272/2008 (CLP). Thus, DNEL derivation is not required for this endpoint.

Long-term exposure – systemic effects inhalation exposure

According to ECHA REACH Guidance (2012), for substances in solid form which potentialy appear as dust, and whereas the derived DNEL inhalation from experimental studies is above the general dust limit (10 mg/m³), the general dust limit should be applied. As the calculated DNEL long term inhalation was determined to be 40.6 mg/m3 (see calculations below), the more conservative DNEL for general dust limit (10 mg/m³) was used as final value.

Demonstration of DNEL calculation from experimental studies (not used as reference value):

A combined chronic toxicity/carcinogenicity feeding study in rats (104 weeks), conducted with a structural analogue substance (free acid of the test item) was chosen as the key study. The NOAEL of the study was considered to be 1500 ppm of the test item, equivalent to a mean daily test substance intake of approximately 69 or 93 mg/kg bw/day in male and female animals, respectively. The lowest NOAEL value of 69 mg/kg bw/day was used as basis for the demonstrative DNEL calculation. Additionally, all supporting studies confirm the findings of the key study and lead to the marginal higher DNELs (please see example calculations below). Thus, the DNEL from the key study represents the lowest value. However, a conservatie appoach was applied and the DNEL for general dust limit (10 mg/m³) was used.

DNEL derivation for the key study

Modification of the starting point: The oral NOAEL was converted to an inhalation NOAEC using a method described in the ECHA guidance document (ECHA, 2010). This method is based on predetermined factors and leads to the same NOAEC value as using the alternative calculation with the standard breathing volume for the specific test animal species.

With the chosen method, the oral NOAEL for the rat is transferred to humans with a factor of 4 for allometric scaling. With help of a standard human body weight (70 kg) and a default human breathing volume referring to the specific conditions of the worker population (i.e., 10 m3 for workers in 8h and light activity), this dose is then translated into an air concentration.

Corrected inhalatory NOAEC for workers = 69 mg/kg bw/day / 4 x 70 kg / 10 m3/person = 121.7 mg/m3

The worker DNEL (long-term exposure) is then calculated using following assessment factors (AF):

AF for differences in duration of exposure: 1

AF for interspecies differences (allometric scaling): 1 (covered by route to route extrapolation)

AF for interspecies differences:1

AF for intraspecies differences (worker): 3

Worker DNEL (long-term inhalation exposure) = 121.7 mg/m³ / 3

= 40.6 mg/m³

DNELs calculated for the supporting studies (not used as reference values):

Further supporting studies conducted with the structural analogue substance using a range of mammalian species (dogs, rats and mice) were conducted. As shown below, these studies support the use of the worst case DNEL derived from the key study, as only marginal higher DNEL values are derived from these studies.

1) Supporting DNEL value derived from the 13-Week Dietary Toxicity Study in Rats:

NOAEL = 352 mg/kg bw/day

Inhalatory NOAEC for workers = 352 mg/kg bw/day / 4 x 70 kg / 10 m3/person = 616 mg/m3

(factor of 4 used for allometric scaling rat to human)

Used AF:

AF for intraspecies differences (worker): 3

AF for difference in duration of exposure (subchronic to chronic): 2

Worker DNEL (long-term inhalation exposure) Worker DNEL = 616 mg/m³ / (3*2)

= 103 mg/m3

2) Supporting DNEL derived from the 13-Week Pilot Feeding Study in Mice:

NOAEL = 287 mg/kg bw/day

Inhalatory NOAEC for workers = 287 mg/kg bw/day / 7 x 70 kg / 10 m3/person = 287 mg/m3

(factor of 7 used for allometric scaling mice to human)

Used AF:

AF for intraspecies differences (worker): 3

AF for difference in duration of exposure (subchronic to chronic): 2

Worker DNEL (long-term inhalation exposure) = 287 mg/m³ / (3*2)

= 48 mg/m³

3) Supporting DNEL derived from the 13 -Week Feeding study in dogs

NOAEL 58 mg/kg bw/day

Inhalatory NOAEC for workers = 58 mg/kg bw/day / 1.4 x 70 kg / 10 m3/person = 290 mg/m3

(factor of 1.4 used for allometric scaling dog to human)

Used AF:

AF for intraspecies differences (worker): 3

AF for difference in duration of exposure (subchronic to chronic): 2

Worker DNEL = 290 mg/m³ / (3*2)

= 48 mg/m³

6) Calculated DNEL derived from the 52-Week Feeding study in dogs

NOAEL 26 mg/kg bw/day

Inhalatory NOAEC for workers = 26 mg/kg bw/day / 1.4 x 70 kg / 10 m3/person = 130 mg/m3

(factor of 1.4 used for allometric scaling dog to human)

Used AF:

AF for intraspecies differences (worker): 3

Worker DNEL = 130 mg/m³ / (3)

= 43 mg/m³

Dermal exposure:

In order to derive the worker DNEL (long-term dermal exposure), the NOAEL assessed in the key 21 day dermal toxicity study in the rabbit conducted with the test item was identified as the relevant dose descriptor (NOAEL = 1000 mg/kg bw/day).

The worker DNEL (long-term dermal exposure) is calculated using following AF:

AF for differences in duration of exposited (subacute to chronic): 6

AF for interspecies differences (allometric scaling): 2.4

AF for interspecies differences:1

AF for intraspecies differences (worker): 3

Considering the above mentioned AFs, the following worker DNEL is calculated as follows:

Worker DNEL (dermal exposure) = 1000 mg/kg bw/day / (6 x 2.4 x 3 x 1) = 1000 mg/kg bw/day / 43.2

= 23.2 mg/kg bw/day

References

- ECHA (2012). Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health.Version 2. ECHA-2010 -G-19 –EN.

- ECETOC (2010). Technical Report 110. Guidance on assessment factors to derive a DNEL.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
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
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
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:
no hazard identified
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

Since no exposure is intended for the general population no DNEL was derived.