Copper dioleate

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Already evaluated by the Competent Authorities for Biocides and Existing Substance Regulations.

Objective of study:

toxicokinetics

Qualifier:

according to guideline

Guideline:

OECD Guideline 417 (Toxicokinetics)

Deviations:

no

Principles of method if other than guideline:

This was a non-regulatory study carried out to determine the effect of dietary copper compounds on adsorption and excretion of dietary copper in
rats.
No guidelines are available to address this objective.

GLP compliance:

yes

Radiolabelling:

no

Species:

rat

Strain:

Crj: CD(SD)

Sex:

male

Details on test animals or test system and environmental conditions:

- Source: Charles River Laboratories Inc, Raleigh, North Carolina.
- Age at study initiation: Approximately 7 weeks
- Weight at study initiation: Variation did not exceed +/- 20% of the mean weight by dose group.

No additional information provided on test animals, environmental conditions or in-life dates.

Route of administration:

oral: gavage

Vehicle:

other: ultra-pure water/diet slurry

Details on exposure:

Approximately 4 ml/kg bw

No information on preparation of dosing solutions or homogeneity and stability of test material.

Duration and frequency of treatment / exposure:

See details on study design.

Remarks:

Doses / Concentrations:
Main experiments:
Experiment 3: 20 mg Cu/kg bw for each of the six copper substances.
Experiment 4: 20 mg Cu/kg bw as copper hydroxide.

No. of animals per sex per dose / concentration:

Experiment 1A: 4 males
Experiment 1B: 4 males
Experiment 2: 1 male
Experiment 3: 5 males
Experiment 4: 5 males

Control animals:

yes, concurrent vehicle

Details on study design:

Pilot Experiments:
Experiment 1A: Plasma and liver pilot experiment with copper sulphate at concentrations of 0, 5, 20 or 65 mg Cu/kg bw to determine a single appropriate dose level for subsequent experiments. Serial blood samples were removed from the jugular vein cannula (pre-dose, 30 min and at 1, 2, 4, 6, 9, 13, 18, 24, 32, 40 and 48 hours after dose administration). Liver samples from one rat per dose group were also submitted to Cu analysis.
Experiment 1B: Plasma copper and surgical status pilot experiment to assess the potential impact of jugular vein and bile duct cannulation on plasma Cu concentrations of control animals. A water/diet slurry (0 mg Cu/kg bw) was administered to four rats unaltered by surgery, four rats with jugular vein cannulae and four rats with bile duct cannulae. Bile was collected approximately 17 to 0 hours before dosing and 0 - 24 hours and 24 - 48 hours after dosing and tail vein blood was collected approximately 17 and 0 hours before dosing and 24 and 48 hours after dosing.
Experiment 2: Absorption and disposition pilot experiment to test the feasibility of using excreta and tissue Cu burdens to compare bioequivalence from the different test substances. 65 mg Cu/kg as copper hydroxide, copper oxide, copper oxychloride, tribasic copper sulphate and bordeaux mixture or copper sulfate pentahydrate was administered to bile duct cannulated rats. Bile, liver, plasma, post-biliary intestinal content, post-biliary intestine wall, pancreas, urine, faeces and carcass were sampled at 24 hours after administration.

Main Experiments:
Experiment 3: Distribution and excretion experiment with biliary cannulation, to estimate bioavailability by summation of Cu recovery from tissues, carcass, excreted dose in bile and urine. Post exposure period, 24 hours.
Experiment 4: Quantification of the time course of Cu in liver and plasma after oral administration of one representative copper substance, copper hydroxide. Post exposure period, 48 hours.

Details on dosing and sampling:

Experiment 3 samples: Blood, plasma, liver, combined stomach and contents, combined post-biliary intestines and contents, carcass, bile, urine, faeces, and cage wash (collection period: 24 hours).
Experiment 4 samples: Whole blood, plasma, liver (0, 1.5, 3, 6, 9 12, 18, 24, 30, 36, 48 hours).

Examinations: Clinical observations (daily), mortality (daily), body weights (at study initiation and at termination), Cu analysis of dose suspensions, representative food samples, whole blood, plasma, tissues, excreta and cage wash as appropriate.

Copper analysis: Microwave digestion was used to prepare non-aqueous samples. Copper was analysed by ICP-AES. The method detection limit (MDL) and limit of quantitation (LOQ) were 0.0054 and 0,012 ppm, respectively.

See details on study design for additional information.

Preliminary studies:

Experiment 1A:
No consistent dose response in plasma Cu concentration was observed over the 48 hour collection period, which was attributed to the bioregulation of copper uptake. Elevated copper concentrations were determined in livers of high dose animals. Generally all dose groups including the vehicle control exhibited a drop in plasma concentrations after dose administration which was attributed to fasting prior to and after administration. For this reason fasting was discontinued in subsequent experiments.

Experiment 1B:
All animals appeared healthy. Plasma copper concentrations were higher in rats with cannulation surgery compared to control rats. This finding was attributed to a generalised inflammatory response which is known to raise levels of ceruloplasmin and thus the carrying capacity of Cu in plasma. Rats without surgery showed the greatest body weight gain during the study followed by jugular vein cannulated rats and then by bile cannulated rats.

Experiment 2:
Absorption for copper sulphate and the five other copper substances ranged from 4.67 to 6.86% of the administered dose, based on the amount of copper measured in bile, liver, pancreas, plasma, and urine. Some distention and fluid retention in the intestinal tract was noted during sample collection. Thus the dose was adjusted to 20 mg/kg bw for the main experiments.
The results of the pilot studies were used to adjust the experimental designs of the main experiments.

Details on absorption:

See remarks on results

Details on distribution in tissues:

See remarks on results

Details on excretion:

See other information on results.

Metabolites identified:

not measured

Experiment 3:

All rats appeared healthy with no signs of infection. The actual dose levels ranged from 21.8 to 24.3 mg Cu/kg bw for the six copper test substances. Control animals received 0.052 mg Cu/kg bw from copper present in the diet. The absorbed dose ranged from 10.7 to 12.9% based on percent of the dose measured in whole blood, liver, carcass, bile and urine. No statistically significant difference in absorption was observed between the six copper test substances. The ranking of copper concentrations in excreta and tissue samples was generally faeces > GI tissue and contents (post-biliary) > stomach and contents > liver > bile > plasma ~ whole blood ~ carcass > urine > cage wash. The total recovery ranged between 109 and 141%, the majority of which was measured in the faeces and in the GI tract tissue and contents. Recovery values in excess of 100% of the administered dose were explained with continued uptake of Cu from normal dietary uptake. Based on the results of this experiment, it was concluded that the six copper test substances have essentially the same relative bioavailability under the conditions of this experiment. The results are summarised in the attached Table 1.

Experiment 4:

Animals of the control and test group received mean measured doses of 0.025 or 24.9 mg Cu/kg bw, respectively. Similar copper concentrations were determined in plasma of the vehicle control and the treatment group. Mean values ranged from 0.7 to 1.1 µg Cu/g plasma and were consistent with values obtained for control animals without surgery in the pilot experiment 1B. Administration with 20 mg Cu/kg bw as copper hydroxide caused clearly elevated copper concentrations in liver. While the time course in the control was essentially unchanged during the 48 hours after dosing, a peak concentration of 10.2 µg Cu/g tissue was reached at 12 hours after administration of the test substance. Background copper concentrations measured in livers of the control rats were approximately one half of the peak concentration found in rats of the treatment group. Overall, 0.96 to 1.85% of the administered dose of 20 mg Cu/kg bw was recovered in the liver. Non-compartmental kinetic analysis of the liver concentration data gave an apparent elimination half-life of 31 hours, estimated from the mean data 12 to 48 hours after administration of the test substance. However, the estimation of the linear elimination half-life ignores the fact that continuing exposure to copper occurs from dietary intake and that systemic uptake is subject to bio-regulatory control. It also ignores thhe natural background level of copper already present, and is therefore not an accurate representation. By subtracting the initial T₀ value, the apparent half-life of the dosed copper is 10.134 hours. The AUC for the 20 mg Cu/kg bw group (343 hr* µg/g) was was 1.4 -fold greater than the AUC for the control group (239 hr* µg/g). Upon study termination, copper concentrations in the liver were equivalent to the control, indicating complete clearance of the administered test substance. The results are presented in the attached Table 2 and Figure 1.

Conclusions:

A relative terminal half-life of 10.134 hours was calculated.

Executive summary:

Materials and Methods:

Based on the results of three pilot experiments two main experiments were conducted, a distribution and excretion experiment with biliary cannulation to estimate the bioavailability of copper from six different test substances, and an experiment investigating the time course of copper in liver and plasma after oral administration of one representative copper substance, i.e. copper hydroxide. The sudy was conducted accoring to EC method B.36 (87/302/EEC) and OECD 417 (1984).

Results and Discussion:

The results of the main experiments showed that five forms of copper were similarly absorbed to copper sulphate, following oral administration to bile cannulated rats. The absorbed dose ranged from 10.7 to 12.9% based on percent of the dose measured in whole blood, liver, carcass, bile and urine. The ranking of copper concentrations in excreta and tissue samples was generally faeces > GI tissue and contents (post-biliary) > stomach and contents > liver > bile > plasma ~ whole blood ~ carcass > urine > cage wash. Administration of 20 mg Cu/kg bw as copper hydroxide had no effect on copper plasma levels. In contrast, increased concentrations of copper in liver were observed with a peak of 10.2 µg Cu/g tissue at 12 hours after administration. Thereafter copper concentrations decreased to control levels upon study termination. A relative terminal half-life of 10.134 hours was calculated.

Summary of absorption data for dietary copper

Reference	Animal model	Identity of copper	Dietary Cu			Duration of treatment/ measurement	Analytical method	Absorption of Cu (% of intake)		Other information	Study rating
			mg/kg feed	μg/d	mg/kgBW/da			Apparent	True
Himmelstein (2003)^d	Sprague Dawley rat (male)	Copper (I) oxide Copper oxychloride Copper sulphate Copper hydroxide	20 mg/kg BW (single oral dose – by gavage)			Measurement of Cu in tissues and excreta for 24h after dosing	ICP	10.7 – 12.9% of intake (absorption calculated as sum of Cu in whole blood, liver, carcass, bile and urine)		Cu levels in tissues and excreta similar for all substances.	3
Himmelstein (2003)^d	Sprague Dawley rat (male)	Copper hydroxide	20 mg/kg BW (single oral dose)			Measurement of Cu in whole blood, plasma and liver for 48h after dosing	ICP			Apparent half-life 10h	3

Values reported are mean values ± (if specified) standard deviation

NR – not reported

Reference 2

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Already evaluated by the Competent Authority for Biocides.

Reason / purpose for cross-reference:

reference to other study

Objective of study:

absorption

excretion

metabolism

Qualifier:

no guideline available

Principles of method if other than guideline:

There are no guidelines available that address the objective of this study. The study protocol was reviewed and approved by the Human Subjects
Review Committee of the University of California, Davis; and by the US Department of Agriculture Human Studies Review Committee.

GLP compliance:

not specified

Radiolabelling:

yes

Remarks:

63Cu from cupric oxide powder

Species:

human

Sex:

male

Details on test animals or test system and environmental conditions:

11 Healthy men. Recruitment, selection, exclusion criteria and procedures for informal consent have been described in Turnlund et al,. (2004). Two subjects did not complete the study, and their data are not included.
The participants ranged in age from 26 to 49 yrs. Mean height was 175 ± 7 cm. Body weight averaged 74 ± 13 kg at the beginning of the metabolic period A (MP-A) and 76 ± 13 kg at the beginning of MP-B; without significant difference between the two periods.

Route of administration:

other: Oral: feed and intravenous injection.

Vehicle:

other: Oral: water or tracer solution; Injection: tracer infusion

Details on exposure:

Diet: A 3-d rotating menu containing at least the recommended amounts of all known essential nutrients was used in both live-in parts of the study.
The daily energy content of the basic diet was 2200 kcal (9.2 MJ) with 87 g (15-16% of energy) from protein; 55 % of energy from carbohydrate and
30% from fat. The polyunsaturated-to-saturated fatty acid ratio was 1.10; and the diet contained 196 mg cholesterol/d. The energy was adjusted for
each volunteer, based on body weight and diet records; so that each volunteer would maintain his initial weight throughout the study. This was done by adding energy drink that contained maltodextrin, cornstarch, sugar, sugar, whipping cream, cottonseed oil and water. If a subject gained or lost
> 1 % of his baseline weight, his energy drink was adjusted accordingly. Baseline weights were the average of weights taken on days 2 – 4 of the study. Body weights remained relatively constant; averaging 74 kg in MP-A and 76 kg in MP-B.
The diet contained 1.61± 0.05 mg Cu – menu day 1; 1.49 ± 0.03 mg Cu – menu day 2; 1.77 ± 0.03 mg Cu – menu day 3. The mean daily copper intake was 1.62 ± 0.14 mg/d, In MP-b the mean daily copper intake was 7.76 ± 0.14 mg Cu/d (7.75 ± 0.05 mg Cu – menu day 1; 7.63 ± 0.03 mg Cu – menu day 2; 7.91 ± 0.04 mg Cu – menu day 3). A solution containing CuSO4 was added to the extra energy drink of each meal to achieve the dietary copper intake. The solution also contained added Zn to maintain the RDA for this element.

The amount of copper was the only variable between MP-A and MPB.

During the free living period subjects were encouraged to consume supplements containing 7 mg Cu/d as CuSO4. The supplements were divided between the morning and evening meals. Subjects kept dietary records for 5 days before the study and for 5 d during the free living period. The
NUTRITION DATA SYSTEM FOR RESEARCH version 4.01 (Nutrition Coordinating Center, University of Minnesota. 1998) was used to estimate copper intake from these records. Copper intake was estimated to be an average of about 1.6 mg/d from these records.

ISOTOPE PREPARATION AND ADMINISTRATION: A copper solution containing enriched 63Cu was prepared from cupric oxide powder with 63CU
abundance of 99.89 % (Oak Ridge National Laboratory, Oak Ridge, TN). The solution was used to prepare the isotope diluent, oral tracer and infused
tracer solutions. The oral tracer solution – 0.27 mg 63Cu/g solution in MP-A and 2.25 mg 63Cu/g solution in MP-B. These tracers were added to the supplemental drinks of 3 subjects 1 hour before each meal on the 7th day of each metabolic period, for total oral doses of 0.82 mg 63Cu in MP-A and 6.74 mg 63Cu in MP-B. The solution replaced the natural copper solutions (0.88 mg Cu in MP-A, 7.03 mg Cu in MP-B) added on the other days of the study. 63Cu solution (5 g) containing 0.46 mg 63Cu was infused into the arm veins of 6 subjects over a period of 1 min. The infusion took place 15
mins after breakfast began on the 7th day of each metabolic period.
Dysprosium (Dy); a faecal marker not absorbed by the body was administered on the day of the oral and intravenous isotopes were administered to
confirm the completeness of the faecal collections. It was prepared for administration by dissolving high purity Dy2O3 in HCL. The pH was adjusted
with NaOH, and the solution was diluted. The solution (1 g) containing 0.67 mg Dy was added to the extra energy drink at each meal on day 7.

Duration and frequency of treatment / exposure:

The subjects lived in the Western Human Nutrition Research Center’s metabolic research unit (MRU) for 18 d (MP-A) on specific diet; followed by a 129-d free-living period when they consumed their normal diets along with Cu supplements. They returned to the MRU for another 18 d (MP-B) and the diets were supplemented with Cu.

Remarks:

Doses / Concentrations:
During the 18 d (MP-A) the diet contained 1.6 mg Cu/d; then in the 129-d free-living period subjectsconsumed their normal diets along with Cu
supplements containing 7 mg Cu/d. During the final 18 d (MP-B) study period and the diets were supplemented with 6.2 mg Cu/d for a total of 7.8 mg Cu/d.

No. of animals per sex per dose / concentration:

11 males; dietary and infusion additions during MP-B were given to 6 subjects at each event.

Control animals:

yes, historical

Details on study design:

This study was part of a larger study on the effect of long-term high copper intake on indexes of copper status, immune function and antioxidant
status. The subjects lived in the Western Human Nutrition Research Center’s metabolic research unit (MRU) for 18 d (MP-A) while consuming a diet
containing 1.6 mg Cu/d; followed by a 129-d free-living period when they consumed their normal diets along with Cu supplements containing 7 mg Cu/d. They returned to the MRU for another 18 d (MP-B) and the diets were supplemented with 6.2 mg Cu/d for a total of 7.8 mg Cu/d. They were
supervised by the nursing staff at all times whilst living in the MRU. During the free-living period, they returned to the center once every 2 wks to
receive a supply of supplements, verify compliance, monitor body weight and vital signs and report any concerns. Body weights and vital signs were measured daily throughout the confined portions of the study.
The protocol of the study is shown in Figure 1 (attached). Complete urine and stool collections were made throughout the live-in part of the study.

Details on dosing and sampling:

Suitable precautions to avoid contamination by trace elements were taken.

The copper content of the diet was determined by isotope dilute inductively coupled plasma mass spectrometry (ICP-MS). Four diet composites of each of the 3 menus were analysed twice in each 18 d metabolic period for copper. Complete faecal collections were made throughout the 18 day
periods. Stools were collected and pooled for 3 days and frozen. Diet composites and faecal pools were thawed, homogenised, frozen and
lyophilised. When dry these were weighed, crushed to a fine powder and mixed in large plastic bags, transferred to plastic jars and stored in
desiccators. Blood samples to be analysed for copper 63Cu enrichment were drawn into trace element free tubes containing heparin before
isotope infusion (day 7); at 5, 15, 30 min and 1, 2, 4, 6, 11, 16 hours after administration – and daily from day 8 to 18. Urine was collected in 8 h
or 24 h pools. Subsamples of the 8 h collections were combined into 24 h pools then all 24 h pools combined into 3 d pools. Urine and plasma
samples were stored at -20◦C before copper analysis. Hair was also collected from the back of the heads.

Samples were appropriately prepared before analysis using ICP-MS. The isotope ratio of 63Cu:65Cu was determined in faecal, diet, urine and
plasma samples using ICP-MS with 250 sweeps and 10 replicates. The copper concentration yielded total copper intensities ~ 1 million counts/s
in the analogue mode. The average reproducibility of the 63Cu:65Cu measurement was 0.3%. Corrections were made for natural 63Cu:65Cu levels.

The 63Cu tracer and total copper content of the samples were determined by isotope dilution by the 63Cu:65Cu of 2 duplicate aliquots (with and
without added 63Cu), natural samples of the same matrix and the 63Cu enriched solution, along with the weights of the sample aliquots and the
added isotope diluent, the concentration of the isotope diluent and the total pooled weights.

Urinary and hair copper concentrations were determined by graphite furnace AAS and reported previously (Turnlund et al,. 2004). Faecal samples were analysed for Dy ICP-MS and mean Dy recover was stated as 101.7% for MP-A and 101.3% for MP-B.

Statistics:

Statistical analysis was performed with computer package SAS v8.2. Descriptive statistics; means, SDs and plots were tabulated and compared.
PROC GLM was used to perform ANOVA on the effect of the 2 dietary copper intakes on copper absorption and retention, faecal and urinary 63Cu
excretion and total urinary copper. If a significant F was found, Tukey’s test was used to determine which treatment variable differed. A significance
level of 0.05 was used for all statistical tests.

Preliminary studies:

Copper absorption during each dietary period is shown in Table 1.

Details on absorption:

Copper absorption during each dietary period is shown in Table 1. The fraction absorbed was significantly higher during MP-A (29%) than during
MP-B (16%; SE = 1.0). However, the amount absorbed was significantly less during the MP-A (0.48 mg) than during the MP-B (1.2 mg; SE = 0.05).
True absorption showed similar patterns (Table 1) but the relative differences were less.

Details on distribution in tissues:

N/A

Details on excretion:

The main routes of copper excretion are through the gastrointestinal tract and in the urine. Most of the 63Cu that was excreted appeared in the
stools and only a small fraction was found in the urine. Mean 12-d 63Cu faecal excretion was significantly higher (P<0.05) in MP-B (46%) than in MP-A (27%; SE = 2.3) as shown in Table 1. In contrast, mean cumulative urinary 63Cu excretion was significantly lower in MP-B (1.3%) than in MP-A (2.1%;
SE = 0.14). The patterns of excretion are depicted in Figure 2. The total 12-d 63Cu excretion by both routes was 47% of the infused dose in MP-B
compared with 29% in MP-A, which was significantly lower. However, total urinary copper excretion was significantly higher in MP-B than in MP-A.
Plasma enrichment after the infusion of 63Cu is depicted in Figure 3 (A and B). The pattern of enrichment is similar in both periods, but from 48 h
after the infusion and onward enrichment differed significantly, averaging 1.1% in MP-B and 1.6% in MP-A (SE=0.02).

Metabolites identified:

no

Copper retention:

The average retention based on dietary, urinary and faecal copper for each metabolic period is shown in Table 1. Both faecal and urinary copper were higher when dietary copper was high. Faecal copper averaged 7.1 mg/d in MP-B and 1.6 mg/d in MP-A (SE=0.10). Urinary copper averaged 26 µg/d in MP-B and 20 µg/d in MP-A (SE=0.9). Copper retention was markedly higher in MP-B (0.67 mg/d) than in MP-A (0.06 mg/d; SE=0.27).

 

Copper turnover:

Endogenous copper losses were calculated for fast and slow turnover pools and total endogenous gastrointestinal losses for 9 subjects for the last 12 days of each metabolic study period as described. When dietary copper intake levels were

1.6 mg/d (MP-A); a total of 0.58 mg endogenous Cu/d was eliminated in the stools. Of that 0.18 mg endogenous Cu/d was contributed to by the fast turnover pool and 0.40 mg endogenous Cu/d by the slow turnover pool. When intake was 7.8 mg Cu/d (MP-B); total endogenous gastrointestinal losses were 1.56 mg Cu/d, with 1.04 mg Cu/d contributed by the fast turnover pool and 0.52 mg Cu/d by the slow turnover pool.

 

DISCUSSION:

The current study was undertaken to determine whether after long-term high copper intake, changes in copper status would occur and whether absorption and retention would adapt to long-term high intake.

In this study the Apparent absorption was 29% (0.48 mg Cu/d) when intake was 1.6 mg Cu/d and 16% (1.2 mg Cu/d) when intake was 7.8 mf Cu/d. When these absorption values are corrected for endogenous excretion of absorbed copper over time of sample collection, true absorption was 40 % (o.65 mg Cu/d) compared with 29 % (2.2 mg Cu/d). These data show 2 of the points of regulation. The initial amount absorbed is considerably higher, but a considerable amount is immediately excreted into the gastrointestinal tract; so apparent absorption is less. The amount retained by the intestinal cells when intake is high (the other point of regulation) cannot yet be quantified, but ultimately this is eliminated in the stools along with the unabsorbed dietary copper and endogenous copper.

Retention of copper in this study was 0.06 mg/d; close to 0, when dietary intake was 1.6 mg Cu/d, but increased to 0.67 mg/d when dietary intake was 7.8 mg Cu/d. Therefore, some adaptation to high dietary Cu took place. However, 0.67 mg Cu/d still resulted in a significant amount of retained Cu, and at this rate could double body Cu in 100-150 d.

Conclusions:

Interpretation of results (migrated information): bioaccumulation potential cannot be judged based on study results
This study shows that homeostatic mechanism controlling copper retention in humans is not sufficient to prevent accumulation of copper intake
when intake is high, even over a period of several months.

Executive summary:

Background:Numerous studies have examined the effect of low and adequate intakes of copper on absorption und retention, but little information is available on the regulation of absorption and retention of copper when intake is high.

Objective:A study was conducted in men to determine the effect of long-term high copper intake on copper absorption, retention, und homeostasis.

Design:Nine men were confined to a metabolic research unit (MRU) for 18 d and were fed a 3-d rotating menu containing an average of 1.6 mg Cu/d. They continued the study under free-living conditions for 129 d, supplementing their usual diets with 7 mg Cu/d. They then returned to the MRU for 18 d and consumed the same diet as during the first period, except that copper intake was 7.8 mg/d. The stable isotope 63Cu was fed to 3 subjects und infused into the other 6 on day 7 of each MRU period, and complete urine und stool collections were made throughout the study. Total copper und 63Cu were determined by inductively coupled plasma mass spectrometry. Copper absorption, excretion, und retention were calculated on the basis of dietary, urinary, and faecal copper und 63Cu.

Results:Results were as follows when comparing the high copper intake with the usual intake: fractional copper absorption was significantly lower, but the amount absorbed was significantly higher; excretion of the infused 63Cu was significantly faster; und total retention was significantly higher.

Conclusions:Homeostatic regulation of copper absorption and retention helped to minimize the amount of copper retained with high copper intake but was not sufficient to prevent retention of > 0.6 mg Cu/d.

Reference 3

Endpoint:

basic toxicokinetics, other

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Generally old data, but formally reviewed and accepted under Cosmetic Ingredients Safety Review

Objective of study:

absorption

bioaccessibility (or bioavailability)

distribution

excretion

metabolism

toxicokinetics

GLP compliance:

not specified

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

1

Additional information

10 x compenstion to correct for the difference in dermal and inhalation absorption