Reaction products of sodium glucoheptonate with zinc sulfate and sodium hydroxide

Direct observations: clinical cases, poisoning incidents and other

Administrative data

Endpoint:

direct observations: clinical cases, poisoning incidents and other

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH
Please refer to read-across statement attached under section 13 of this IUCLID file.

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
The rationale for the analogue approach is the high structural similarity between the source and the target substance and the expected identical behaviour in the human or animal body. This is based on the fact, that they both are metal complexes consisting of zinc and sugar-like carbohydrates that are believed to share the same absorption, distribution and metabolic pathways.
In respect to acute oral toxicity the source and the target substances are expected to bear the same toxicity potential based on their 1) structural similarity, 2) the same behaviour in the acidic envzincment in the stomach and proximal duodenum (dissociation), 3) the same oxidation status of the zinc ion after absorption, 4) the same metabolic fate of gluconic acid and glucoheptonic acid and finally 5) its identical limited elimination mechanisms.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)

Source Chemical: Zinc gluconate
CAS 4468-02-4
MW 591.15 (dimer)
The molecular formula is C12H28O18Zn2
The purity of the source substance is not specified.

Target Chemical: Zinc glucoheptonate complex (HGA:Zn-1:1), CAS 1820760-03-9,
MW 619.2 g/mol (dimer)
The molecular formula is C14H32O18Zn2

Information on purity of the registered substance is provided in the target record under "Test material" as confidential. The calculation of a hazard value for zinc glucoheptonate is based on 75 % content of zinc glucoheptonate in the registered product. Another component is Na2SO4. Sodium is a macroelement occuring in surface waters and in living organisms in considerable amounts. Sulfur species are also found in living organisms. Thus, these cations and anions are considered not to impact the toxicity of zinc glucoheptonate.

3. ANALOGUE APPROACH JUSTIFICATION
Zinc gluconate (source) and zinc glucoheptonate complex (HGA:Zn-1:1) (target) are structurally very similar. Both - the source and the target substance - contain the same types of hydrocarbon constituents (sugar residues), which are only variable in carbon chain length. In case of zinc gluconate two gluconic acid-chains (C6H11O7-) are involved and in case of zinc glucoheptonate it is two glucoheptonic chains (C7H10O8).
After oral intake of these substances the low pH in the upper GI tract will provoke dissociation releasing gluconic acid / glucoheptonic acid and zinc, respectively. Therefore, at low pH values both substances are not able to participate in complexation of metal cations (Alekseev et al., 1998).
This dissociation has been confirmed in a lot of investigations, which show gluconate and glucoheptonate complexes to be more stable at alkaline conditions, while the complexes were not stable enough to be detected at acidic conditions (Escandar et al., 1996; Sawyer, 1964; Gyurcsik and Nagy, 2000; Alekseev et al., 1998).
In the posterior parts of the GI tract, in the small intestines, where pH raises, new complexes can be formed, impacting any additional absorption of both substances again in a similar way. This however is not of great importance as the major absorption of zinc takes place in the upper GI tract, where the pH values are low.
The released free gluconate or glucoheptonate anions, however, can further sequester luminal or mucosal metal affecting the absorption. The impact of this on absorption of metals has been addressed by a lot of investigations, which showed that gluconate complexes actually enhanced absorption of metals increasing their bioavailability. Absorption of the nutrient metals was higher from gluconates than from the soluble inorganic compounds (i.e. Cousins, 1985, please refer to the detailed read-across statement attached in IUCLID section 13.). Therefore, gluconate-metal complexes are used for food fortification. Absorption of nutrient metals from glucoheptonate complexes seems to be equal to that from gluconate complexes (i.e. Durisova et al., 1985, please refer to the detailed read-across statement attached in IUCLID section 13.).
All this shows that the metal cation originated from the gluconate /glucoheptonate complexes is subjected to a more or less independent fate of absorption into the systemic circulation – independent from the organic moiety and will underlie normal physiological pathways responsible for metal uptake.
Substantiating these facts, it has generally been shown by a substantial body of evidence, that the toxicity profiles of chelate compounds in general depend mainly on metal ion, its affinity to this metal, and their ability to supply or to sequester it from the body. In the OECD SIDS report is mentioned “Evidence from the reviewed literature suggests that the eventual toxicity of the gluconate salts would be attributable to the cation rather than to the gluconate moiety of these substances. Acute toxicity responses to the various gluconate salts are comparable with other salts of the same metals and long-term toxicities seem related to the tissue deposition of these metals. Because toxicological effects of these gluconates appear to be related to their cationic components, safe and acceptable levels in foods are limited only by the nature of the specific cations.” (Life Science Research Office, 1978, cited in OECD SIDS (2004)). Moreover, lactonisation occurs at low pH values (i.e. observed under pH 3.8 in case of Ca gluconate complexes) that would hinder complexation (Pallagi et al., 2010).
“Absorption of zinc takes place in the small intestine and appears to be a carrier-mediated transport process which is not saturated under normal physiological conditions. At high intakes, zinc is also absorbed through a non-saturable process or passive diffusion.” (Sandström, 1992, cited by EFSA, 2006). Subsequently, after absorption, the sugar residues, which differ by one methyl rest, will both be metabolised by the pentose phosphate pathway (also called the phosphogluconate pathway and the hexose monophosphate shunt) for the synthesis of the same 5-carbon sugars. In fact, no toxicity is attributed to gluconate or glucoheptonate moiety up to considerable amounts.
Taken together, both substances are expected to have an identical toxicodynamic and toxicological behaviour, which is based on the fact that these similar structures are metabolised by the same pathways, leading to the same substances.
Please refer also to the extended-read-across statement attached in section 13 of this IUCLID file.

4. DATA MATRIX
The table attached in section 13 shows the available data relevant to justify the read-across from the source to the target chemical for the endpoint acute toxicity.

Cross-reference

Reason / purpose for cross-reference:

read-across source

Reference

Endpoint:

direct observations: clinical cases, poisoning incidents and other

Type of information:

other: Report of an acute poisoning incident

Adequacy of study:

weight of evidence

Study period:

1988

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Study type:

poisoning incident

Qualifier:

no guideline available

GLP compliance:

no

Specific details on test material used for the study:

Zinc gluconate (Lozenges), marked as an immune system booster and an aid in shortening the duration of a cold.
Each pill contains 50 mg zinc gluconate.

Type of population:

other: single, 17-year-old male

Subjects:

- Number of subjects exposed: 1
- Sex: male
- Age: 17
- Weight: 83.4 kg
- Known diseases: His medial history was without serious illnesses, medications or hospitalizations. He had no history of prior ingestions and no prior psychiatric history.
- Other: The test subject denied alcohol use beyond occasional drinks on weekends, and denied smoking and drug use.

Ethical approval:

not applicable

Route of exposure:

oral

Reason of exposure:

intentional

Details on exposure:

The total amount of ingested zinc gluconate was approximately 4 g zinc gluconate. This corresponds to 570 mg elemental zinc.

Examinations:

- Urine analysis: Urine toxicology
- Haematology: routine blood chemistry, blood salicylate and acetaminphen concentration
- Other: vital signs (body temperature, blood pressure, respiration rate, heart rate), weight, pharynx, cardiac, chest and abdomen examination. Testing of reflexes and coordination.

Medical treatment:

A bolus of normale saline and phenergan 25 mg was administered intravenous.

Clinical signs:

Within 20 minutes of ingestion, severe nausea and vomiting was reported. Since then the subject had been retching constantly. The subject also reported some dizziness.

Results of examinations:

He was alert and oriented, but vomiting scant mucous and bilious material. Mental status was appropriate. Pharynx was without burns or other lesions. Chest and cardiac exams were unremarkable. His abdomen was soft, nontender, nondistended, with normoactive bowel sounds, and no rebound or guarding. Coordination, deep tendon reflexes, and gait were normal. Routine blood chemistries, blood salicylate and acetaminophen concentrations, and urine toxicology were all normal except for a mild anion gap acidosis, which resolved with hydration. Serum zinc was 4974 µg/dL at 5 hours postingestion. An abdominal film revealed normal gas pattern with no air under the diaphragm and several pill-sized opacities in the small intestine. An ECG revealed normal sinus rhythm with neither QT prolongation nor other significant abnormalities. The remainder of his 6.5-hour urgent care course was unremarkable.

Effectivity of medical treatment:

A bolus of normale saline and phenergan 25 mg was administered intravenous, which resulted in resolution of symptoms

Outcome of incidence:

The condition of the subject improved after the intravenous injection of the bolus of normal saline and phenergan (25mg). Telephone follow-ups at 1 and 4 weeks after the incident revealed no complaints.

Conclusions:

The 17-year old male who ingested 570 mg elemental zinc in the form of tablets (Zinc gluconate (Lozenges) which contain 50 mg zinc gluconate per tablet) experienced within 20 to 30 minutes after ingestion severe nausea and vomiting. After the intravenous injection of a bolus of normal saline and Phenergan (25 mg), the symptoms resolved.
Due to the body weight of 83.4 kg, the TDLo (Lowest published toxic dose) is calculated to be 47 mg/kg bw.

Executive summary:

Zinc gluconate tablets (Lozenges) with a zinc gluconate content of 50 mg per tablet are marketed as immune system booster and aid in shortening the duration of a cold. In an attempt to harm himself, a 17-year-old male ingested 80 to 85 tablets which correspond to a total intake of approximately 570 mg elemental zinc. He experienced severe nausea and vomiting within 30 minutes of the ingestion but without the severe caustic effects and systemic symptoms reported with ingestion of other zinc compounds related to elevated serum zinc. Serum zinc level was 4.97 mg/dL at approximately 5 hours postingestion.

Toxicity following ingestion of zinc-containing products varies with the type of zinc compound and the route of exposure. The relatively low percentage of zinc in zinc gluconate tablets may be a protective factor, and the binding agents in the pharmaceutical preparation may reduce the release of free zinc. However, within the wide range of clinical responses to different zinc preparations, zinc gluconate appears, in this patient, to lie on the more benign end of the spectrum.

Due to the body weight of 83.4 kg, the TDLo (Lowest published toxic dose) is calculated to be 47 mg/kg bw.

Materials and methods

Test material

Test material information

Constituent 1

Reference substance name:

Reaction products of sodium glucoheptonate with zinc sulfate and sodium hydroxide

EC Number:

946-329-1

Molecular formula:

Not specified (UVCB substance).Molecular formula of the main substance:C14H30O22SZn2

IUPAC Name:

Reaction products of sodium glucoheptonate with zinc sulfate and sodium hydroxide

Test material form:

solid: granular

Remarks:

microgranulated

Results and discussion

Any other information on results incl. tables

Calculation of the LD50 for zinc glucoheptonate:

 

A TDLo was reported for the source substances and expressed as mg Zn/ kg bw/d.

 

Molecular weight of zinc glucoheptonate (dimer, containing 2 zinc atoms): 619.2 g/mol

Molecular weight of Zn: 65.39 g/mol

 

The weight of 1 mol zinc glucoheptonate is more than the weight of 1 mol of Zn. Thus, the corresponding amount of zinc glucoheptonate is more than that of Zn:

TDLo for Zn: 47 mg/kg bw

TDLo for zinc glucoheptonate: 47 mg/kg bw of zinc corresponds to (619.2 g/mol x 47 mg/kg bw)/65.39 g/mol /2 = 222.5 mg/kg bw

 

The concentration of zinc glucoheptonate is 75%, therefore, the TDLo value is transformed to a 100 % zinc glucoheptonate concentration: 222.5 mg/kg bw / 75% x 100% = 269.7 mg/kg bw.

 

The calculated LD50 value for zinc glucoheptonate corresponds to a value 296.7 mg/kg bw.

Applicant's summary and conclusion

Executive summary:

The data on zinc gluconate allows estimating a corresponding LD50 for zinc glucoheptonate providing that no toxicity is attributed to gluconate or glucoheptonate ion, that the absorption of zinc from this zinc compounds is 100 % and all zinc became systemically available. 

The TDLo for zinc gluconate is reported to be 47 mg/kg bw which corresponds to a TDLo of 296.7 mg/kg bw for zinc glucoheptonate.

For details regarding the calculation path please see section “Any other information on results incl. tables”.