Registration Dossier

Administrative data

Workers - 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:
DNEL (Derived No Effect Level)
Value:
4 µg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
3
Dose descriptor:
LOAEC
AF for dose response relationship:
3
Justification:
LOAEC to NOAEC
AF for differences in duration of exposure:
1
Justification:
acutal biomonitoring data was used
AF for interspecies differences (allometric scaling):
1
Justification:
acutal biomonitoring data was used
AF for other interspecies differences:
1
Justification:
acutal biomonitoring data was used
AF for intraspecies differences:
1
Justification:
acutal biomonitoring data was used
AF for the quality of the whole database:
1
Justification:
acutal biomonitoring data was used
AF for remaining uncertainties:
1
Justification:
acutal biomonitoring data was used
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:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected

Additional information - workers

In worker populations exposed via inhalation, a statistically significant increase in mortality from lung cancer was reported in early studies, but this has not been supported in later work. More recent analyses suggest that, in occupational settings, measures protecting against renal/respiratory effects should also be protective of lung cancer (see Section 5.8.2). SCOEL (2010) recommends an Occupational Exposure Level (OEL) equivalent to 4 µg Cd/m3(respirable fraction) as protective against long-term local effects (respiratory effects, including lung cancer). This is based on human data that shows changes in residual volume of the lung for a cumulative exposure to CdO fumes of 500 µg Cd/m3 x years, corresponding to 40 years exposure to 12.5 µg Cd/m3 (LOAEL) (Cortona et al., 1992). Applying an uncertainty factor of 3 (LOAEL to NOAEL) leads to a value of 4 µg/m3. As actual biomonitoring data was used to derive the OEL, and this already integrates inter-individual variation, the proposed

DNELworkers, biomonitoring is therefore equivalent to the OEL, i.e. 4µg Cd/m3

The protection of workers in the Cd-related industry is achieved by the systematic implementation of a carefully designed integrated risk management system, outlining measures to control worker exposure and combining measurements of both exposure and effect. The system is aimed at prevention of exposure and protection against early manifestation of (subclinical) effect at the level of the critical organ, the kidney. The system is described in detail in the industry guidance document “Management of the risk related to the chronic occupational exposure to cadmium and its compounds” (ICdA 2006).This management scheme is based on EU directives for workers protection (Chemicals Agents directive and Carcinogen and Mutagen Directive) and the medical section is based on the principles and thresholds of the existing Swedish regulations (see Arbetsmiljoverkets AFS 2005:6) as well as the official Guidelines for Occupational Medical examinations of the German Social Accident Insurance. Today it is applied throughout the complete cadmium-related industry in Europe.

 

It involves essentially 3 areas of action that are implemented together:

 

1) Ensuring workplace cleanliness by controlling the Cd-concentration in the workplace air and implementing proper cleanliness procedures:

·        Firstly, technical measures must be taken to comply with the EU OEL of 4 µg respirable Cd/m3proposed by SCOEL. This OEL is taken forward as a DNEL. The OEL of 4µg Cd/m3 is applicable to Cd and Cd-compounds in general, unless the limited solubility of a given Cd-compound is documented.

·        Workplace cleanliness is obtained by:

o   ensuring thatprocedures are designed, written and implemented so as to make sure cleanliness is obtained at workstations, work sections, traffic and storage areas, upper areas, building structures and various horizontal surfaces, as well as air suction ducts.

o   implementing procedures for process control.

 

2) Implementing the proper set of personal and collective hygiene procedures:

General industrial hygiene programmes are to be implemented, as required by EU Directive 98/24/EC on protection of workers from chemical agents and EU Directive 2004/37/EC on protection of workers from carcinogens and mutagens at work, and other referenced systems on best practice : IPPC-BREF notes, BIMSCH or equivalent, ICH-Q7, FAMI-QS, ISO9000, ISO 13.100 or alike:

·        General industrial hygiene practice, including but not limited to:

o   use of dual section change rooms with separated storage areas for personal and work clothes,

o   company supplied and regularly washed work clothes,

o   mandatory hand-washing before meals,

o   mandatory end of shift showers ,

o   smoking, snacking and drinking restricted to dedicated areas,

o   regular training on chemical risks,

·        Collective protection measures and use of warning & safety signs

·        Minimizing the number of workers exposed or likely to be exposed

 

3) Medical follow up of individual parameters of exposure and effect:

When working with cadmium, protection of the worker is ensured by complementing risk reduction measures (see sections 1 and 2 above) with a medical follow up including the surveillance of biological indicator at the individual level. These measures include:

·        Medical follow-up of the worker involving regular measurement of biological indicators of both exposure and effect:

·        Biological indicators of exposure: measurement of Cd in urine (µg Cd/g Creatinine) and Cd in blood (µg Cd/L) to assess integrated systemic exposure of the individual, both cumulative and recent,

·        Biological indicators of effect: measurement of early (subclinical) indicators of tubular (kidney) dysfunction. Well-established biological indicators (BI) for Cd-effect are urinary protein excretion measurements: e.g. beta-2 microglobulin (β2-MG), retinol binding protein (RPB), alpha-1 microglobulin (α1-microglobulin or protein HC).

 

This specific medical supervision (for details see ICdA 2006 – part II, section 4) is complementing the technical and hygiene measures taken. It integrates exposure through all possible routes by assessing the Cd-body burden (by means of Cd-U and Cd-B measurement) and assesses early biological indicators (BI) of (subclinical) renal effect (by means of urinary protein excretion measurement: β2-MG, RBP or protein HC). As such it ensures that the risk to Cd-exposed workers is fully controlled.

 

It is designed to be applied in a progressive way, based on measurement of integrated exposure, as follows (see Figure below):

 

Figure4. Illustration of Eurometaux/ICdA medical supervision guidance (2006) (BI: biological indicators; C: creatinine) (cfr CSR)

 

Ø Using Cd-U:

-        Cd-U ≤ 2 µg Cd/g creatinine, [2 µg Cd/g creatinine is a conservative threshold (and action level) based on general population studies, as described in Section 5.6.2 (green zone)]:

o   general medical follow-up is conducted along with regular measures of the exposure indicators Cd-U, Cd-B and the subclinical effect BI (urinary protein excretion measurement),

o   no further special action is required beyond proper implementation of the general hygiene procedures and medical surveillance.

-        2 µg Cd /g creatinine < Cd-U ≤ 5 µg Cd/g creatinine, [5 µg Cd/g creatinine is a 2ndthreshold (and action level) based on studies at the workplace, as described in Section 5.6.2 (orange zone)]:

o   general medical follow-up is conducted along with regular measures of the exposure indicators Cd-U, Cd-B and the subclinical effect BI (urinary protein excretion measurement),

o   and a detailed analysis of the related workplace along with an assessment of collective and especially individual hygiene procedures implementation (including training) are conducted by means of an interview with the worker,

-        Above Cd-U > 5 µg Cd/g creatinine (red zone):

o   worker is removed from cadmium exposure.

Ø Using Cd-B:

-        The complementary Cd-B marker is used as follows to identify recent accumulation (approximately within the preceding 3 months window):

o   A rapid increase of Cd-B towards 5 µg Cd/L or the exceedance of an action level of 5 µg Cd/L triggers the same detailed analysis of the related workplace along with an assessment of collective and individual hygiene procedures implementation (including training) by means of an interview with the worker,

o   A rapid increase of Cd-B towards 8 µg Cd/L or the exceedance of an action level of 8 µg Cd/L triggers the removal of the worker from exposure.

Ø Using the effect bio-indicator (β2-M, RBP or protein HC):

-        In all situations, if the effect bio-indicator is exceeding the reference value or shows a consistent pattern of increase, which may lead to approaching the reference value(300 µg/g creatinine for beta-2 microglobulin (β2-MG) and retinol binding protein (RPB) or 700 µg/mmol creatinin (=6188.12 µg/g creatinin) for alpha-1 microglobulin (α1-microglobulin or protein HC)), the worker is removed from cadmium exposure.

The management system has been progressively implemented in the EU Cd industry over the last decades. Workers that may have been exposed to cadmium before its implementation have their situation reviewed by the supervising MD on a case by case basis. In all cases, when subclinical effect biomarkers approach or exceed the reference values (see last point above), workers are removed from exposure.


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:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1 µg/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):
1
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:
hazard unknown but no further hazard information necessary as no exposure expected

Additional information - General Population

Given the wealth of available animal and human data, the calculation of DNELs for general population can be done using different approaches. In the following section, DNELs are derived based on the results of 1) long-term animal testing and 2) monitoring data. The resulting values are then compared and discussed.

DNELgeneral populationderived from animal data

As there iscurrently no conclusive evidence from human studies that cadmium acts as a carcinogen following oral exposure, DNELs for the general population can be calculated based on data from repeated-dose toxicity studies in animals. The lowest oral NOAEL presented in Section 5.11.1 corresponds to 0.12 mg Cd/kg bw/dayfrom a 9 year study in monkey (Masoaka et al., 1994). Using this value as a starting point and applying the default assessment factors proposed in Table R.8-6 of the ‘REACH guidance on information requirements and chemical safety assessment, Chapter R.8’ yields the following results:

Table: Derivation of cadmium DNELgeneral populationbased on animal data

 

Value

Comment

Starting point

0.12 mg/kg bw/day

NOAEL from a 9 year repeated dose oral toxicity study in monkey

Assessment factor

2

Interspecies difference, allometric scaling monkey - human

2.5

Interspecies difference - remaining differences

10

Intraspecies variation, general population

1

Exposure duration (9 years; chronic)

1

Dose-response

1

Quality of whole database

DNELgeneral population

0.0024 mg Cd/kg bw/day

 

The resultingDNELgeneral populationis therefore equivalent to 0.0024 mg (2.4 µg) Cd/kg bw/day.

DNELgeneral populationderived from general population monitoring

As discussed in Section 5.6.2, data from several large general population studies indicate that earlyrenal effects (urinary excretion of low molecular weight proteins, occuring before the onset of overt clinical manifestations of kidney disease) can be detected in the general population for Cd-U around 2 μg Cd/g creatinine. In the Belgian Cadmibel study (Buchet et al., 1990), a urinary excretion of 2 µg/24 h (i.e. roughly 2 µg/g creatinine according to SCOEL, 2010) is estimated to correspond to a mean renal cortex concentration of 50 ppm (wet weight), which in non-smokers would be reached after 50 years of oral ingestion of approximately 1 µg Cd/kg bw/day. This value of 1 µg Cd/kg bw/day can be used as the starting point for estimation of the DNELgeneral population.

As actual biomonitoring data was used to derive the starting point, and this already integrates inter-individual variation and accounts for lifetime exposure. The resultingDNEL general population is therefore equivalent to1 µg Cd/kg bw/day(i.e. ca. 2 µg Cd/g creatinine).

 

Discussion

The DNELgeneral populationderived using either animal or human monitoring data are in good accordance (i.e. 2.4 and 1 µg Cd/kg bw/day, respectively), with the second approach yielding a slightly lower value. As a comparison, the WHO calculate that, in order that levels of cadmium do not exceed 50 µg/g in renal cortex, assuming an absorption rate of 5% and a daily excretion of 0.005% of body burden, total intake should not exceed about1 µg/kg bw/daycontinuously for 50 years (WHO, 1987).