Bis(D-gluconato-O1,O2)zinc

Endpoint summary

Description of key information

Acute oral toxicity:

The acute oral toxicity of zinc gluconate was investigated in 2 groups of fasted 5 male and 5 female rats of the WISW-strain. Any signs of reaction and mortalities were recorded during the 14-day observation period, animals which died and those killed terminally were subjected to necropsy. In the tested dosage the sample did not induce any clinical-toxicological symptoms. Post-dosing weight gains (2 week values) of all animals did not show essential differences. No mortali ties were observed. Nothing abnormal was found in the animals necropsied on day 14. The determination of the oral LD50 is > 5g/kg.

Acute inhalation toxicity:

A study was conducted in Sprague-Dawley female rats to determine pulmonary injury after acute inhalation exposure to the zinc chloride.

Animals were exposed to the test material at a concentration of 600, 940, 1,220 and 1,950 mg Zn/m3 (molar ratio of Zn: ZnCl2 is 1:2.1) for 10 min. Animals showed respiratory distress. Clinical examination of lung showed discolouration (dark red), varying degrees of congestion, patchy discolouration, oedema and interstitial emphysema, atelectasis, hyperaemia and haemorrhages. Based on the results, the acute inhalation LD50 of the test material was calculated to be approximately 2,000 mg ZnCl2/m3 in rats.

This result is used in a read-across approach for Zinc gluconate. The LC50 identified for ZnCl2 have been derived for zinc gluconate, using the following molecular weight : Zinc chloride (ZnCl2) = 136.296 ; Zinc gluconate (ZnC12H22O14) = 455.682. Consequently, the result is given as LD50 = 6686.65 mg of ZnGlc /m3.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1985

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

GLP compliance:

yes

Test type:

acute toxic class method

Limit test:

yes

Specific details on test material used for the study:

The test compound "zinc gluconate granular" was supplied by the sponsor.
The sample is a white fine granular.
Storage at normal room-temperature, in darkness.

Species:

rat

Strain:

Wistar

Remarks:

Substrain : SPF TNO ; Color : white

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Firma Winkelmann, Versuchstierzucht, 4791 Borchen 1, Gartenstraße 300
- Weight at study initiation: male = 194,1 - 219,2 g ; female = 146,5 - 183,0 g
- Housing: Collection caging (Cage type: Macrolon type III/max. 5 rats)
- Diet : ad libitum (Pellets, 2.4 cm large, 1.0 cm diameter ; Producer: Ssniff Versuchstierdiäten GmbH 4770 Soest/Westfalen ; composition detailed in the report)
- Water : ad libitum (Aqua fontana as for human consumption)
- Acclimation period: About 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20°C ± 2°C
- Humidity (%): 50 - 85 %
- Photoperiod (hrs dark / hrs light): 12 hours daily, from 7.00 a.m. - 7.00 p.m. with fluorescent light, 120 Lux

Route of administration:

oral: gavage

Vehicle:

CMC (carboxymethyl cellulose)

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 0.5%
- Justification for choice of vehicle: standard vehicle

MAXIMUM DOSE VOLUME APPLIED: 5.0 g/kg (volume = 0.73 to 0.91ml at maximum dose)

CLASS METHOD
- Rationale for the selection of the starting dose: highest dose following the range finding study

Doses:

5.0g/kg (only one dose applied according to the range finding study results).

No. of animals per sex per dose:

2 groups of fasted 5 male and 5 female rats.

Control animals:

not specified

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of weighing: The body weights are recorded at day 0 (beginning of the experiment) and at day 14 (terminal necropsy) on the surviving animals.
- Frequency of observations: Records were made according to the following intervals: ca. 20', 1 h, 2 + 3 h, 6 h, 24/48 h, 7/14 days p.a.
- Necropsy of survivors performed: yes
- Other examinations performed: Necropsies performed on all animals at termination exhibited no gross pathological findings.

Preliminary study:

This preliminary study (range finding) showed no mortalities.
Pairs of two female rats were employed in a preliminary range finding study. The dosages of the single oral administration were 2,5 g/kg and 5,0 g/kg.
In the light of the range finding results and in accordance with the OECD-guidelines, the following dosage was used for the definitive study: 5 g/kg

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 5 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortality observed

Clinical signs:

Any signs of reaction were recorded during the 14-day observation period. At the tested dosage the sample did not induce any clinical-toxicological symptoms.

The evaluation of the clinical-toxicological signs (a modified Irvin-Screening) is done individually and depends on the nature of the signs. If the symptoms persist to the same degree for a longer period of time, this is noted in the corresponding protocoIs .
Only a change of symptoms is recorded. Records were made according to the following intervals: ca. 20', 1 h, 2 + 3 h, 6 h, 24/48 h, 7/14 days p.a.

Body weight:

Body weight changes after the observation period showed a normal weight gain :
mean initial body weight = 132.31g
mean terminal weight = 217.93g

Gross pathology:

No gross pathology observed.

Interpretation of results:

GHS criteria not met

Conclusions:

The determination of the oral LD50 is > 5g/kg.

Executive summary:

The objective of this study was to determine the acute median lethal dosage of "zinc gluconate granular" after its single oral application to rats in accordance with the OECD guidelines.

The acute oral toxicity was investigated in 2 groups of fasted 5 male and 5 female rats of the WISW-strain. Any signs of reaction and mortalities were recorded during the 14-day observation period, animals which died and those killed terminally were subjected to necropsy. In the tested dosage the sample did not induce any clinical-toxicological symptoms. Post-dosing weight gains (2 week values) of all animals did not show essential differences. No mortali ties were observed. Nothing abnormal was found in the animals necropsied on day 14. The determination of the oral LD50 is > 5g/kg.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

5 000 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

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

Adequacy of study:

key study

Study period:

1986

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH
The read-across hypothesis is instantaneous dissociation of zinc gluconate into zinc cations (Zn2+) and gluconate anions in aqueous media (environmental compartments and body fluids). Thus, for endpoints where no zinc gluconate data exist, the assessment of the (eco-) toxicological effects can be based on available data of dissociable zinc compounds and gluconate derivatives.
The assessment of human and environmental toxicology is mainly based on the zinc ion, which is considered to be toxicologically more relevant than the gluconate ion (see complete justification report attached).
All of the zinc based read-across partners have in common that they dissociate into zinc and the respective counter ion in aqueous media as described above. The same is true for all of the gluconate based read-across partners, as they dissociate into the gluconate anion and the respective counter ion in aqueous media.
The gluconate derivatives are tentatively ignored for the purpose of this read-across due to the role of gluconates as common additives or nutritional supplements in food and due to the fact that gluconate/gluconic acid is a ubiquitous metabolic product/substrate in mammals with proven low toxicity. As a normal metabolic product of glucose metabolism, 25–30 g are being produced daily in humans. It can safely be concluded that systemic toxicity need not be expected to arise from gluconates/gluconic acid when assessing the potential effects of zinc gluconate. Nevertheless, the lack of toxicological relevance of gluconates is addressed in sufficient detail in the final read-across report targeted at supporting this dossier.
When resorting to dissociable zinc read-across partners, there is a risk of confounding effects that might actually be attributable to the counter ion. The dissociation products of the aforementioned zinc compounds are glycerol, sulphate and chloride ions. The counter ions of the gluconates are sodium, calcium and manganese. All these ions play an important role in the physiology of man and other species. Considering this information, the respective counter ions (calcium, sodium, manganese) are unlikely to contribute to any confounding effects hence do need to be further addressed in this report.

Taking into account the global approach and the detailed explanation (including data matrix and analysis for each endpoint) provided in the report attached, the present read-across is considered relevant.

Reason / purpose for cross-reference:

read-across source

Mass median aerodynamic diameter (MMAD):

µm

Duration of exposure:

min

Sex:

female

Dose descriptor:

LC50

Effect level:

ca. 2 000 mg/L air

Based on:

test mat. (total fraction)

Remarks:

The result is given as 2000 mg of ZnCl2 /m3

Exp. duration:

10 min

Key result

Sex:

female

Dose descriptor:

LC50

Effect level:

6 686.65 mg/L air

Based on:

other: Zinc Gluconate

Remarks:

The LC50 identified for ZnCl2 have been derived for zinc gluconate, using the following molecular weight : Zinc chloride (ZnCl2) = 136.296 ; Zinc gluconate (ZnC12H22O14) = 455.682. Consequently, the result is given as 6686.65 mg of ZnGlc /m3

Exp. duration:

10 min

Mortality:

Two animals died at 940 and 1,220 mg/m3 while all animals died at highest dose of 1,950 mg/m3 (mg of Zn / m3). For details see table given in the section "any other information on results incl. table".

Clinical signs:

other: Respiratory distress including dyspnoea, decreased locomotor activity, laboured breathing, rhonci and rales observed.

Body weight:

Not reported

Gross pathology:

Entire surface of lungs showed discolouration (dark red), varying degrees of congestion, patchy discolouration, oedema and interstitial emphysema

Other findings:

- Histopathology: Atelectasis, hyperaemia and haemorrhages and oedema observed
- Potential target organs: Lungs

Acute inhalation toxicity of test material in rats

Concentration (mg Zn/m3)*	Mortality after exposure during 10 min (number of deaths/exposed)
600	0/3
940	2/3
1,220	2/3
1,950	3/3

* The molar ratio of Zn: ZnCl2 is 1:2.1 and the ratio Zn:ZnGlc is detailed in the target endpoint

Interpretation of results:

GHS criteria not met

Conclusions:

Based on these results, the acute inhalation LD50 of the test material was calculated to be approximately 2,000 mg ZnCl2/m3 in rats. This result is considered relevant and used in a read-across approach for zinc gluconate. The corresponding result for zinc gluconate is 6686.65 mg of ZnGlc /m3.

Executive summary:

A study was conducted in Sprague-Dawley female rats to determine pulmonary injury after acute inhalation exposure to the test material.

Animals were exposed to the test material at a concentration of 600, 940, 1,220 and 1,950 mg Zn/m3 (molar ratio of Zn: ZnCl2 is 1:2.1) for 10 min. Animals showed respiratory distress. Clinical examination of lung showed discolouration (dark red), varying degrees of congestion, patchy discolouration, oedema and interstitial emphysema, atelectasis, hyperaemia and haemorrhages.

Based on the above results, the acute inhalation LD50 of the test material was calculated to be approximately 2,000 mg ZnCl2/m3 in rats.

This result is used in a read-across approach for Zinc gluconate. The LC50 identified for ZnCl2 have been derived for zinc gluconate, using the following molecular weight : Zinc chloride (ZnCl2) = 136.296 ; Zinc gluconate (ZnC12H22O14) = 455.682. Consequently, the result is given as LD50 = 6686.65 mg of ZnGlc /m3.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LC50

Value:

6 686.65 mg/m³

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

the study does not need to be conducted because inhalation of the substance is likely

Justification for type of information:

JUSTIFICATION FOR DATA WAIVING
According to the §8.5.3, column 2 of the annex VIII of REACh, testing is not appropriate for dermal route since inhalation of the substance is likely and acute toxicity data by inhalation route is provided.

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

According to the §8.5.3, column 2 of the annex VIII of REACh, testing is not appropriate for dermal route since inhalation of the substance is likely and acute toxicity data by inhalation route is provided.

Justification for classification or non-classification

Acute oral toxicity: The determination of the oral LD50 is > 5g/kg. According to the CLP critera, this value does not lead to classification (cut off value of 2000 mg/kg).

Acute inhalation toxicity: The determination of the inhalation LD50 is = 6686.65 mg of ZnGlc /m3. According to the CLP critera, this value does not lead to classification (cut off value of 5.0 mg/L).

Acute dermal toxicity: According to the §8.5.3, column 2 of the annex VIII of REACh, testing is not appropriate for dermal route since inhalation of the substance is likely and acute toxicity data by inhalation route is provided.

All available study do not provide any information leading to acute toxicity. Consequently, it can be considered that the subtance zinc gluconate do not have acute toxicity effect.