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Toxicological information

Repeated dose toxicity: inhalation

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Administrative data

Endpoint:
repeated dose toxicity: inhalation
Remarks:
other: studies of different durations in animals and humans
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The Scientific Committee on Occupational Exposure Limits (SCOEL) is is a committee of the European Commission.

Data source

Reference
Reference Type:
review article or handbook
Title:
Recommendation from the Scientific Committee on Occupational Exposure Limits for Copper and its inorganic compounds. SCOEL/SUM/171 March 2013
Author:
SCOEL
Year:
2013
Bibliographic source:
Scientific Committee on Occupational Exposure Limits; DRAFT for consultation March-September 2013. Employment, Social Affairs & Inclusion (EC); Ref. Ares(2013)340506 - 15/03/2013

Materials and methods

Test guideline
Qualifier:
no guideline available
Principles of method if other than guideline:
The evaluation is based on ACGIH 2001, ATSDR 2004 (peer-reviewed), HCN 1999, Greim 2004, Greim 2006, ECB 2000, Schneider and Kalberlah 1999, WHO 1998, WHO 2002 and the references cited in these reviews and a literature update (time period 2004-2012).
GLP compliance:
no
Remarks:
not applicable (it is a review)
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
-Copper

Test animals

Species:
other: animals and humans

Administration / exposure

Route of administration:
inhalation: dust

Results and discussion

Effect levels

open allclose all
Dose descriptor:
other: OEL
Effect level:
0.01 mg/m³ air
Based on:
element
Remarks:
Copper
Sex:
male/female
Basis for effect level:
other: established for humans (for respirable fraction)
Dose descriptor:
other: OEL
Effect level:
0.03 - 0.04 mg/m³ air
Based on:
element
Remarks:
Copper
Sex:
male/female
Basis for effect level:
other: established for humans (for inhalable fraction) based on (5 days exposure/week with a breathing volume of 10 m³/8-hour day). To avoid systemic toxicity, the inhalable exposure to copper should be below this value.

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Human data

Gleason (1968) reported symptoms similar to metal fume fever (Section 3.2) in an unknown number of workers after occupational exposure to copper (fine metal dust, most probably not copper oxide) during polishing of copper plates with aluminium oxide abrasive. The effects (general feeling of discomfort, slight sensations of chills and warmth, stuffiness of the head) were first reported some weeks after the start of exposure. Measured exposure was 0.12 mg Cu/m³ but, according to the author, the workers may sometimes have been exposed possibly to two- to threefold higher concentrations. The effects did not disappear until an exhaust system was installed, which reduced exposure to 0.008 mg Cu/m³. However, the reported symptoms differed from the typical metal fume fever in that there was no acute onset and no acclimatisation. The exposure was to copper dust (metallic copper) with co-exposure to aluminium oxide dust. Metal fume fever is mainly attributed to exposure to metal fumes (oxides). For these reasons, Borak et al (2000) questioned that the effects observed in the Gleason (1968) study were indeed copper-induced metal fume fever and assumed other (unknown) agents to be responsible for the complaints. Suciu et al (1981) examined about 100 workers chronically exposed to 111–464 mg Cu/m³ as copper dust. At the higher concentration levels, the authors reported an increased incidence in respiratory effects, gastrointestinal complaints, neurotoxic symptoms, cardiovascular and peripheral vascular disorders, hepatomegaly and impotence. No control group was included in this study. Finelli et al (1981) observed mild anaemia, hepatomegaly and bronchitis in workers who were exposed to copper dust concentrations of 0.64–1.05 mg/m³. These workers were also exposed to iron, lead and cadmium. A more recent cross-sectional study by Jayawardana (2004) of brass workers reported anorexia, distaste, aches and pain after chronic occupational exposure (exposure concentration not stated, co-exposure with zinc).

Animal data

Drummond et al (1986) exposed CD1 mice and Syrian golden hamsters on 3 hours/day to 0.12 mg Cu/m³ as copper sulphate for 5 days and to 0.13 mg Cu/m³ (MMAD 0.54 μm) for 10 days. These authors examined disturbances of pulmonal defence mechanisms (decreased bactericidal activity in alveolar macrophages, increase in mortality following the concurrent inhalation of Streptococcus bacteria) in mice as well as histological alterations in the respiratory tract (alterations of cilia beats in trachea, reduction of the percentage of normally appearing tracheal tissue with smooth surface and beating cilia) in both species. The exposure concentrations in this study were chosen to obtain the same concentration x time product as in the acute studies of these authors (Section 3.2.2). Inhalation exposure of 22 male and 24 female mice to 0.12 mg Cu/m³ as copper sulphate (5 days, 3 hours/day, MMAD 0.54 μm) induced a small but significantly decreased bactericidal activity of alveolar macrophages only in females (94 % of the control value). Exposure of 22 male and 18 female mice to 0.13 mg Cu/m³ for 10 days (3 hours/day) significantly decreased bactericidal activity of alveolar macrophages to 95 % (males) and 85 % (females) of control values. There was no increase in mortality after 5 days of exposure to 0.12 mg Cu/m³ (n = 47–48 per sex) and inhalation of Streptococcus bacteria (10 colony forming units per mouse). However, a significantly increased mortality of mice (mean of males and females: increase of 28 % compared to controls, n = 48 per sex) was reported following exposure to 0.13 mg Cu/m³ for 10 days and inhalation of Streptococcus bacteria, showing a clear time-dependence of the immunosuppressive effect. There were no effects on cilia beatings or other tissue alterations in hamsters as a result of copper exposure for 5 or 10 days. Tissue alterations in the mouse experiments could not be evaluated due to a poor quality of the respiratory epithelium in control CD1 mice (see Section 3.2.2) (Drummond et al 1986).

No effects on respiratory function were observed in groups of 8 rabbits after 4–6 weeks of intermittent exposure (5 days/week, 6 hours/day) to 0.6 mg Cu/m³ as copper chloride (only one concentration tested). However, there was an increased density of type-II alveolar cells and of membrane damage in the lung macrophages (Johansson et al 1983, 1984, Lundborg and Camner 1984). In a study by Ginoyan (1976), two groups of rats were exposed to either variable exposure concentrations within a range of 0.01–0.1 or to 1 mg/m³ copper oxide aerosol for 90–100 days (0.008–0.08 and 0.8 mg Cu/m³). At the lower exposure level, there was an increase in serum protein levels. At the higher concentration, increased blood haemoglobin levels and higher erythrocyte counts were observed in addition. These data are insufficiently reported and could therefore not be used for risk assessment. In a 4-week study (OECD guideline 412, whole body, 6 hours/day, 5 days/week) Sprague-Dawley-rats were exposed to 0.17, 0.35, 0.7 or 1.7 mg Cu/m³ as Cu2O (MMAD = 1.725 μm ± 1.73 μm GSD) with a recovery period of 13 weeks. Satellite groups were exposed to the high and low dose to evaluate whether a plateau was observed at week 1, 2 or 3 (ICA 2010). Following 4 weeks of exposure, the test substance related effects included higher blood neutrophil counts in all exposed groups, with a significant increase at ≥ 0.35 mg Cu/m³. This effect is probably related to the inflammation of the lung. At ≥ 0.17 mg/m3, increases in lactate dehydrogenase (LDH) and total protein in the bronchoalveolar lavage fluid (BALF) were observed at the end of week 4 and also following week 1, 2, and 3 of exposure at 2.0 mg/m³ with a plateau. At 0.35 mg/m3, there was a slight increase in total cell count in the BALF, significant at 0.7 mg/m³. The majority of cells present were alveolar macrophages, a small number of lymphocytes, neutrophils, and/or epithelial cells. The increase in total cell count was associated with a higher proportion of neutrophils in all test substance-exposed rats (strong increase of 45 % at 0.17 mg/m3 versus 0–1.1 % in control animals). These effects were also seen in the satellite groups (1.7 mg/m³) at weeks 2 and 3 with a plateau at days 12–19. Macroscopically, enlarged bronchial and/or mediastinal lymph nodes were observed at 0.7 and 1.7 mg/m3. At 0.17 mg/m³, absolute and relative lung weights were increased, which was statistically significant at the next higher dose. At the end of the recovery period this effect was not completely reversible (ICA 2010). After 4 weeks of exposure, there were histopatological findings in lung, lymph nodes (bronchial and mediastinal) and nose (level II, III, IV and V). In the lung, a dosedependent histiocytosis (foamy macrophages; minimal at 0.17 mg/m³ and moderate at 1.7 mg/m³) was observed and a dose-dependent acute inflammation occurred at 0.35 mg/m3 and higher. Lymphoid hyperplasia of bronchial lymph node was observed in the majority of rats at ≥ 0.35 mg/m³ and in 1 female at 0.17 mg/m³. Lymphoid hyperplasia was also present in mediastinal lymph nodes at ≥ 0.35 mg/m³, but with a lower incidence. Minimal to slight subacute inflammmation in nasal levels II and III were present in 3 male rats at 1.7 mg/m³ and in 1 rat at 0.17 mg/m³ (ICA 2010). As nasal levels were investigated only in 5 animals per dose group, a final evaluation of this effect is not possible.

Histopatological findings were reversible within the recovery period. The satellite group at 1.7 mg/m3 showed minimal to slight alveolar histiocytosis, acute inflammation and lymphoid hyperplasia in all rats without a clear time-dependence. According to the study authors, except lung weight and incidence of lymphoid hyperplasia, effects at 1.7 mg/m3 appeared to have a peak prior to completion of the 4-week exposure time. Except lung weights, which were greatly reduced, and still slightly detectable following the recovery period, all test substance related effects were reversible within 13 weeks recovery (ICA 2010). The LOAEL of this study is 0.17 mg Cu/m³ (as Cu2O). A calculation of the human equivalent concentration (HEC) based on the 4-week rat study and using the Multiple-Path Particle Deposition (MPPD) model resulted in a human NO(A)ECHEC of 0.006 mg Cu/m³

Applicant's summary and conclusion

Conclusions:
An OEL of 0.01 mg Cu/m³ for the respirable fraction is proposed. This OEL applies to copper and its inorganic compounds.
Executive summary:

A NOAEL of 0.36 mg/m³ has been estimated for acute sensory irritation in humans. It is not known, whether metal fume fever-like symptoms observed in employees exposed to copper dust at 0.12–0.36 mg/m³ is primarily dependent on concentration or on total dose (concentration × time product). Given all the uncertainties, a scientifically based STEL cannot be recommended. At the recommended OEL of 0.01 mg/m³, no developmental effects are expected to occur. Assuming an oral absorption rate of 30–40 %, which is typical for diets in developed societies (SFC 2003), and an assumed 100 % absorption by inhalation, the daily difference of 0.8 mg/day would correspond to an inhalable air concentration of copper of 0.03–0.04 mg/m³ (5 days exposure/week with a breathing volume of 10 m³/8-hour day). To avoid systemic toxicity, the inhalable exposure to copper should be below this value.