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Administrative data

Endpoint:
health surveillance data
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
No data
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference
Reference Type:
publication
Title:
Comparative assessment of gastrointestinal irritant potency in man of tin (II) chloride and tin migrated from packaging
Author:
Boogard PJ, Boisset M, Blunden S, Davies S, Ong TJ, Taverne JP
Year:
2003
Bibliographic source:
Food and Chemical Toxicology 41: 1663-1670

Materials and methods

Study type:
biological exposure monitoring
Endpoint addressed:
repeated dose toxicity: oral
Test guideline
Qualifier:
no guideline available
Principles of method if other than guideline:
The aim of the study was to determine the dose-response of tin acute gastrointestinal effects in man. Two separate well-controlled clinical studies were performed in order to compare the tolerability of tin added as tin (II) chloride in tomato juice and tin migrated from packaging in tomato soup. Distribution studies were conducted in parallel to get insight on the influence of tin associated with low molecular weight (< 1000 Da) of soluble fraction of food on acute adverse effects.
The first study was a randomised, single centre, double-blind four-way crossover study designed to investigate the tolerability of orally administered tin as tin (II) chloride added to tomato juice.
The second study was a single centre, double-blind, controlled study designed to assess the tolerability of orally administered canned foodstuffs (tomato soup) containing tin migrated from packaging.
A third study was also performed, assessing tin distribution in tomato-based food products. The juice and soup from experiments 1 and 2 respectively and other similar products and other tomato-based products such as spaghetti in tomato sauce were analysed for their tin content.
GLP compliance:
no
Remarks:
Not applicable, performed in compliance with the relevant guidelines for medical experiments and good clinical practice.

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
- Name of test material: Tin (II) chloride dihydrate (CAS no 7772-99-8)
- Analytical purity: Analytical grade

Method

Type of population:
general
Ethical approval:
confirmed and informed consent free of coercion received
Remarks:
Subject gave their witnessed written informed consent
Details on study design:
Both studies were designed as randomised double-blind crossover investigations with approximately equal number of males and females.

The study was performed in compliance with the declaration of Helsinki, Scotland Revision 2000, the ABPI Guidelines for Medical Experiments in Non-patient Human Volunteers, the Report of the Royal College of Physicians on Research on Healthy Volunteers, the CPMP note on the Good Clinical Practice for Trials on Medicinal Products and ICH Harmonised Tripartite Guideline for Good Clinical Practice.

To reduce experimental bias, subjects, all staff and quality assurance personnel except those responsible for the preparation and labelling of the test food dosing solutions were blind to treatment order. A study code was produced whereby the subjects were randomly assigned to one of the treatment sequences following a randomised order using a Latin square design.
The single centre, double-blind, controlled study (Study 2) was carried out to assess the tolerability of orally administered canned foodstuffs (tomato soup) containing migrated tin from packaging.

Results and discussion

Results:
TIN (II) CHLORIDE
At the control level (<0.5 mg/kg of tin (II) ion) in tomato juice, no related AEs were reported, two non-related AEs were noted 0200 (musculo-skeletal system disorders) and 1100 (respiratory system disorders). At 161 mg/kg, four subjects reported four AEs. Two were in category 0600 (gastro-intestinal system disorders), one was related and ranked as mild, the other was non-related and ranked as moderate. The other two were category 0410 (central and peripheral system disorders). Both were mild and non-related. Three subjects reported a total of nine AEs at the dose of 264 mg/kg. Seven AEs were in category 0600 (gastro-intestinal system disorders), two were related and mild, five were related and moderate. Two AEs were assigned to category 0410 (central and peripheral system disorders), one was ranked as mild and the other moderate, both were non-related.
Five subjects were exposed to 529 mg/kg tin (II) ion, four of them reported 13 related AEs in category 0600 (gastro-intestinal system disorders). Five were classified as mild and eight as moderate. After considering the number and frequency of these reported adverse AEs, it was decided to cease treatment at this dose level. Two subjects from this group withdrew their consent following the first treatment period, reducing the number of subjects for the other dose levels to 18 and one subject declined treatment at the highest dose level. No values of clinical significance in eliciting AEs, particularly in the 0600 (gastro-intestinal system disorders) category were observed in the safety parameters.
The proportion of related adverse effects was significantly different between dosing groups (Chi 2 = 2641 at 3 d.f. P<0.001). There was a statistically significant increase of the incidence of AEs with increasing dose of ingested tin (II) chloride freshly added to the juice.
Almost all the values of serum tin concentration in study 1 were below the level of quantification (10 µg/L) and not submitted to statistical analysis.

MIGRATED TIN
In Study 2, the incidence of AEs considered to be related to the tin intake shows minor differences between the three treatment groups. As one subject was withdrawn for protocol violation, 23 subjects were exposed to a nominal dose <0.5 mg/kg tin in tomato soup: two subjects reported two related, mild adverse events. One was in the 0600 (gastro-intestinal system disorders) category and the other in the 0410 (central and peripheral system disorders) category. At 201 mg/kg tin migrated from packaging, one subject reported a non-related mild adverse event from the 1810 (body as a whole-general disorders) category. Four subjects reported four related adverse events at 267 mg/kg. Two were mild in the 0600 (gastro-intestinal system disorders) and 0500 (psychiatric disorders) categories and two were moderate in 0600 (gastro-intestinal system disorders) category. One subject reported a non-related adverse event in the 0600 (gastro-intestinal system disorders) category.
Comparison of the incidence of related AEs with the Cochran’s Q test showed no difference between the three nominal dose levels (Q > 3.5 at 2 d.f., P> 0.10). No values of clinical significance were reported from the safety parameters measured, throughout the study.

TIN ANALYSIS
Elemental tin concentration in solid and liquid phases revealed marked differences between tomato juice and tomato soup. When sampled within 1 hour of mixing, solid matter contained just 15% of the total tin content whereas in the soup this phase contained just over half of the total tin. The amount of low molecular weight tin species (<1000 Da) in the juice was two times higher than in the soup. However, when sampled after 24 hours, the amount of the total tin associated with the solid matter had risen to about 35 %, demonstrating that absorption/complexation is not instantaneous.

Any other information on results incl. tables

Table 1 Analysis of tin concentration in tomato juice freshly dosed with tin (II) chloride

Nominal concentrations of tin (II) ion (mg/kg)

Tin concentration mg/kg*

% Nominal dose

0

<1-<1

-

150

159-163

106-109

250

263-264

105-106

500

523-535

105-107

*Individual results of two different dosing solutions

Table 2 Distribution of adverse events (AEs) related to tin (II) chloride freshly added to tomato juice

Concentration of tin in juice (mg/kg)

No. of subjects in treatment period

No. of related AEs

Incidence (% of persons with related AEs)

<0.5

18

0

0

161

18

1

5.6

264

18

7

17

529

5*

13

80

*Treatment at this dose level was discontinued based on the frequency and the number of AEs reported.

 

Table 3: Distribution of advers events related to tin migrated from packaging in tomato soup

Concentration of tin in soup (mg/kg)

No. of subjects in treatment period

Number of related AEs

Incidence (% of persons with related AEs)

<0.5

23

3

13

201

23

0

0

267

23

4

17

 

Applicant's summary and conclusion

Conclusions:
Results obtained in study 1 in which tin (II) chloride was freshly added to tomato juice confirm that elevated tin concentrations may cause gastro-intestinal disorders in humans. The absence of adverse effects attributable to tin in study 2 strongly suggest that gastro-intestinal irritation is determined by chemical speciation of the tin rather than simply by its total concentration.
Executive summary:

Controlled studies looking at acute effects of tin migrated from food packaging indicate the threshold for adverse effects exceeds 730 mg/kg.  In the current study tin (II) chloride was added to tomato juice and tin migrated from food packaging in tomato soup.  Results indicate it is the chemical form of tin rather than the concentration that is critical to determine adverse effects.

Dietary intake of tin is primarily due to ingestion of food packed in unlacquered or partially lacquered tinplate cans, slow dissolution of tin results in the formation of soluble and insoluble tin (II) complexes.  The process is controlled by a large variety of factors within the can environment.  The adverse effects level stated by WHO in 2000 were 150 mg/kg for canned beverages and 250 mg/kg for other canned foods – these were lowest levels anticipated to possibly result in gastric intestinal irritation in some individuals. 
Results from the first study in which tin (II) chloride was added to fruit juice (tomato juice selected since tin is found in highest amounts in food stuffs such as tomato-based products, pineapple and fruit juices) confirmed elevated tin concentrations may cause adverse event in humans. But the results of the second study (tin concentrations determined from migrated tin from tinplate in tomato soup can), in which no adverse effects were apparent, indicate it is the species of tin that may be important rather than a simple concentration effect.