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Toxicological information

Direct observations: clinical cases, poisoning incidents and other

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Administrative data

direct observations: clinical cases, poisoning incidents and other
Type of information:
experimental study
Adequacy of study:
key study
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Already evaluated by the Competent Authorities for Biocides and Existing Substance Regulations.
Reason / purpose for cross-reference:
reference to other study

Data source

Reference Type:
Gastric response for acute copper exposure.
Araya M., Peňa C., Pizarro F. and Olivares M.
Bibliographic source:
The Science of the Total Environment 303 (2003) 253-257.

Materials and methods

Study type:
study with volunteers
Endpoint addressed:
acute toxicity: oral
Test guideline
no guideline followed
not applicable
Principles of method if other than guideline:
Protocol approved by the Ethical Committee of Research on Human Subjects of INTA, University of Chile.
GLP compliance:

Test material

Constituent 1
Reference substance name:
Cu2+ as Copper Sulphate Pentahydrate
Cu2+ as Copper Sulphate Pentahydrate
Details on test material:
CuSO4.5H2O ultrapure (Merck, Darmastadt, Germany).


Type of population:
30 apparently healthy adults (set based on previous studies that showed 0ne third experienced nausea and 5% vomited)
Aged: 18 – 60 yrs old
Balance male/female
Exclusion criteria: gastrointestinal diseases and/or ingestion of medications that may modify gastric emptying or the capacity to experience nausea
and vomiting.
Ethical approval:
confirmed, but no further information available
Route of exposure:
Reason of exposure:
Exposure assessment:
Details on exposure:
Tap water and copper sulphate pentahydrate in amounts such that the final concentrations were 0 or 10 mg Cu/l. The latter figure being the upper
tolerable upper copper intake established by the US Institute of Medicine (Food and Nutrition Board, Institute of Medicine 2001). They were prepared
during the hour prior to ultrasound evaluation and administered at room temperature. Actual concentration was measured daily by AAS.
Each volunteer underwent 2 trials during which he/she received either placebo or a test solution, in random order, in a double blind fashion. After
overnight fast, subjects answered a health questionnaire to ensure that they were asymptomatic on that day. They then drank the test solution and
were instructed to report any changes perceived, pleasant or unpleasant, identifying specific symptoms or discomfort. During the next 3 hours
participants were under direct supervision and gastrointestinal symptoms were recorded. Individuals were contacted by phone 24 hr later and the
form asking for symptoms was applied again.
Ultrasound echotomography was chosen among the non-invasive techniques available to assess indirectly gastric emptying. Because clinical
experience suggests that the gastric chamber is seldom empty, evaluations were started early in the morning, after over fasting. To help define the
best time intervals and the operational sequence to use for ultrasound image generation, a pilot study on 4 adults was conducted. This assessed the
impact of individuals standing up, lying down, after active walking for 5 mins and after Valsalva manoeuvres. On the basis of these results, images
were generated on standing position, every 15 mins during a 2 hr period.
Prior to drinking test solutions all individuals were assessed by means of cross and longitudinal section images in order to visualise and verify that
the antrum had no detectable liquid content or food remnants. These minimal perimeter and area values were used to calculate the z scores of
subsequent measurements (see below).Then individuals drank (within 1 min) a 300-ml glass containing the test solution. Cross-sectional images of
the maximal diameter of the liquid containing area immediately after (within 3 min) ingestion defined the maximal antral area. During the 2-h
observation period and between measurements subjects remained in a comfortable resting room, specially set for the protocol. Within 3 min after
ingesting the test solution and every 15 min thereafter the maximal antral perimeter and area of the stomach (end variables) were measured by
ultrasound echotomography. Images were obtained with a real time echotomography ‘Siemens Sonoline Elegra’ which has linear and convex
transducers of 3.5 and 5 MHz. The equipment calculates the perimeter and the integrated area of the stomach based on the images contoured by the operator on the echotomographer’s screen. Human error was estimated on the basis of data obtained in five gastric images; on each occasion the
physician in charge of the procedure drew up the contour of each stomach image ten consecutive times. These five image sets were statistically analyzed and yielded a coefficient of variability of 1.8–2.5%.
Other: Nausea and gastrointestinal changes
Medical treatment:
Not applicable.

Results and discussion

Clinical signs:
Thirty-one subjects participated in the study. One subject vomited shortly after ingesting the 10 mg Cu/l solution and was excluded from analysis.
Thus, 15 women (33 ± 12 years) and 15 men (37 ± 12 years) were analyzed. Nobody presented symptoms after drinking water without added copper while nine subjects (3 men and 6 women) presented nausea after receiving the 10 mg Cu/l solution. Nausea was mild to moderate, short and occurred a few minutes after drinking the test solution. None of the individuals reported additional symptoms in the questionnaire completed 24 hours after
trial. As expected, antral area and perimeter showed a direct, significant correlation (Pearson r test = 0.96, P<0.001).For this reason results are
shown referred only to area. At time 0, 20, 60 and 120 min, mean area ± SD (cm2) in the control situation was 7.0 ± 2.4, 13.7 ± 5.9, 11.0 ± 3.7 and
8.9 ± 3.9, while after ingestion of the 10 mg Cu/l solution the same figures were 7.0 ± 2.3, 20.1 ± 8.5, 13.1 ± 6.3 and 8.4 ± 3.9. Fig.1 shows mean Z
score, SEM and fitted curves for antral area over time for the control and test situations. The group receiving drinking water with 10 mg Cu/l
presented greater areas during the first 60 min of observation. When curves were compared using the linear mixed-effects model fit by REML, the
likelihood ratio test rejected the null hypothesis of no effect of copper on antral area over time (L. Ratio =23.98, P<0.0001). There were no statically
significant differences bygender or by gastrointestinal symptom report/no report.
Results of examinations:
In this study we favoured the use of a non-invasive, reasonably accessible technique, because the main question focused on comparing the
pattern of gastric emptying after drinking copper/no copper containing solutions rather than obtaining a precise measurement of gastric
emptying proper. Analysis of changes of antral area showed that presence of copper in the stomach induced a significant delay in decreasing
antral area, which suggests delaying of gastric emptying. Although comparison of both curves yielded significant differences for the entire curves the effect was clearly given by the changes observed during first 60 min after ingestion, after which the behaviour of both curves became similar. Itis interesting that the effect on antral area is greatest in the early minutes after copper ingestion, coinciding with the timing of nausea appearance.
Effectivity of medical treatment:
Not Applicable.
Outcome of incidence:
See other information on results.

Any other information on results incl. tables

See attached Figure 1.

Applicant's summary and conclusion

In conclusion, although indirect the results of this study support the hypothesis that acute exposure to copper in water modifies the first phase of
gastric emptying. This effect is maximal after few minutes after copper ingestion and coincides with the time of nausea appearance, which is the
earliest effect after acute exposure to copper doses up to 12 mg Cu/l (as copper sulphate).The mechanisms by which copper rapidly induces gastric mucosal response (nausea, emptying pattern, permeability) represents an interesting challenge to answer.
Executive summary:

Materials and Methods:

Early effects of acute copper exposure in humans consists mainly of nausea and altered gastric permeability. To assess effects on gastric response 30 apparently healthy volunteers underwent 2 controlled trials receiving a solution with (10 mg Cu/l) and without (<0.01 mg Cu/l) copper sulphate after overnight fasting, in random order. Ultrasonography was chosen to follow indirectly the gastric emptying pattern for 120 min. Measurements were expressed as z scores [z = (mean-Xi)/SD].


Results and Discussion:

Results showed that nobody presented symptoms after drinking water without added copper, while 9 subjects presented nausea after receiving 10 mg Cu/l solution. The group receiving drinking water with 10 mg Cu/l presented greater antral areas during the first 60 mins of observation. Individual and mean fitted curves for antral area, calculated and compared using the linear mixed effects model fit by REML, showed a group effect of copper on antral area over time (L. Ratio = 23.98, P<0.0001); the effect was due to delay in decreasing antral area in copper treated group during the first hour after ingestion. No differences were found by gender or nausea. Results show a copper effect on gastric response suggesting that acute exposure to copper in water modify the first phase of gastric emptying.