Zinc di(acetate)

Genetic toxicity: in vitro

Administrative data

Endpoint:

genetic toxicity in vitro

Remarks:

Type of genotoxicity: gene mutation

Type of information:

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

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: The analogue Phenoxyacetic Acid which has a very similar functional group to Zinc acetate, also has comparable values for the relevant molecular properties for the genetic toxicity endpoint.

Cross-reference

Reason / purpose for cross-reference:

reference to other study

Data source

Reference

Reference Type:

other: read-across

Title:

Unnamed

Year:

2010

Materials and methods

Principles of method if other than guideline:

Read-across approach from published experimental data (L5178Y Mouse Lymphoma Cell Mutation Assay) on the analogue Phenoxyacetic acid.

GLP compliance:

not specified

Type of assay:

other: read-across from a mammalian cell gene mutation assay with an analogue

Test material

Test material information

Constituent 1

Reference substance name:

Phenoxyacetic acid

EC Number:

204-556-7

EC Name:

Phenoxyacetic acid

Cas Number:

122-59-8

IUPAC Name:

phenoxyacetic acid

Details on test material:

- Name of test material (as cited in study report): Phenoxyacetic acid
- Molecular formula (if other than submission substance): C8H8O3
- Molecular weight (if other than submission substance): 152.15
- Smiles notation (if other than submission substance): c1(OCC(O)=O)ccccc1
- InChl (if other than submission substance): InChI=1/C8H8O3/c9-8(10)6-11-7-4-2-1-3-5-7/h1-5H,6H2,(H,9,10)
- Structural formula attached as image file (if other than submission substance): see Fig. in attached report

Results and discussion

Test results

Species / strain:

mouse lymphoma L5178Y cells

Metabolic activation:

with and without

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

cytotoxicity

Remarks:

(at higher doses than precipitating concentrations)

Vehicle controls validity:

valid

Positive controls validity:

valid

Additional information on results:

Based on published experimental data on the analogue Phenoxyacetic acid, which is considered to be not mutagenic on mouse lymphoma cells, with and without metabolic activation, and applying the read-across approach, the substance Zinc Acetate is also considered to be not mutagenic under test conditions.

Remarks on result:

other: all strains/cell types tested

Remarks:

Migrated from field 'Test system'.

Any other information on results incl. tables

Phenoxyacetic Acid is an organic acid which has an acetic functional group on its molecular structure. This is the most reactive part of the molecule. Zinc acetate is a water soluble zinc organic salt which dissociates to metallic and acetic ions.

As indicated in the European Chemical Agency Practical Guide 6 “How to report read –across and categories”, the structural grouping was realized using “OECD QSAR APPLICATION TOOL BOX” version 1.1.0.

 

Zinc acetate is therefore expected to be toxicologically equivalent to Phenoxyacetic Acid (table).

CAS Number		Source chemical 122-59-8	Target chemical 127-09-3
CHEMICAL NAME		Phenoxyacetic acid	Zinc acetate
PHYSICO-CHEMICAL DATA
Melting Point		Experimental data: 98.5ºC	Measured data: 237 ºC
Boiling Point		Experimental data: 285ºC	Measured data: 258.2 ºC ± 0.7 ºC
Density		Measured data: 1.22g/mL	Measured data: 1.735
Vapour Pressure		Experimental data: 0.0165 mmHg	Estimated data: 0.000876 Pa at 25 ºC
Partition Coefficient (log Kow)		Calculated data: 1.34	Estimated data: -1.28
Water solubility		Experimental data: 12g/L	Experimental data: 434.78 g/L at 25 ºC
ENVIRONMENTAL FATE and PATHWAY
Aerobic Biodegradation		No data	Read across:   Readily biodegradable
ENVIRONMENTAL TOXICITY
Acute Toxicity to Fish		No data	Experimental results:   LC50 for fish is 2.46mg/L.
Acute Toxicity to Aquatic Invertebrates		No data	Experimental data: The 48h-EC50 of zinc acetate in Daphnia magna was determined to be 3.72 mg/L TWA. The 48h-NOEC was 2.5 mg/L TWA (basis for effect: mobility).
Toxicity to Aquatic Plants		No data	Experimental result: EC50 of zinc acetate measured in 72h was 2.1mg/L. It was showed that algae can adapt to zinc acetate and EC50 value can increase.
MAMMALIAN TOXICITY
Acute Toxicity: Oral		LD50= 3750 mg/kg bw (mouse)	Experimental data on Zinc Acetate dihydrate: The LD50 for Zinc Acetate anhydrous was 663.83 mg/kg bw in rats.
Acute Toxicity: Inhalation		No data	Weight of evidence:   Read-across from experimental data on analogues Calcium Acetate and Zinc Stearate, based on molecular weights:   The estimated LC50 for Zinc Acetate was between 6.49 and 58.04 mg/L (rat).
Acute Toxicity: Dermal		LD50= 5 g/kg bw (mouse)	Key study:   No data
Skin Sensitization		No data	Weight of evidence:   Read-across approach from experimental results on Citric Acid, Glycolic Acid, Sodium Glycolate, Lactic Acid, Ammonium Lactate, Triacetin, and Zinc Stearate, based on functional group:   All this substances were not sensitising for human and guinea pigs. Based on these results, Zinc acetate is considered to be not sensitizing.
Repeated Dose Toxicity		No data	Repeated dose toxicity: oral: Key study: Experimental results with Zinc Acetate dihydrate: A 90-days oral toxicity study in rodents was carried out using 40 females Sprague-Dawley rats which were exposed to dihydrated zinc acetate in drinking water at concentrations of 0, 160, 320, and 640 mg/kg bw/day continuously during 3 months. The NOEL for Zinc acetate anhydrous was estimated to be 133.77 mg/kg bw/day in female rats.
Genetic Toxicity in vitro	-         Gene mutation in bacteria	Negative	Weight of evidence: Experimental results: The bacterial reverse mutation test of zinc acetate shows non-mutagenic effects to any of the 5 strains tested (Salmonella TA1535, TA100, TA1537, TA1538, and TA98) and no toxic effects (determined by reduction of the bacterial lawn in the overlay agar with strain TA100). The dose range of zinc acetate was 50-7200 µg/plate. The assay was performed with and without metabolic activation.
	-         Mammalian gene mutation	Experimental data: Phenoxyacetic acid resulted to be not mutagenic on Chinese hamster ovary cells, with and without metabolic activation. It precipitated at concentrations from 1000 µg/mL. It was lethal for cells at concentrations from 2000 µg/mL.	Weight of evidence: Experimental results: Zinc acetate produced dose-related positive responses in the L5178Y mouse lymphoma assay in the presence and absence of the S-9 metabolic activation system. Read-across from the source chemical Phenoxyacetic acid to the target chemical, based on functional group: Zinc acetate is considered to be not mutagenic. Estimated data from Danish (Q)SAR Database: Zinc acetate was not mutagenic in mammalian cell gene mutation assays on mouse lymphoma L5178Y cells, nor on Chinese hamster ovary cell.
	-         Chromosomal aberration	No data	Weight of evidence: Experimental results: Zinc acetate produced dose-related positive responses in an in vitro cytogenic assay with Chinese hamster ovary cells. The responses were obtained in the presence and absence of the S9 activation system, although the S9 reduced both clastogenic response and the toxicity.   The exposure of unstimulated human lymphocytes (lymphoblastoid cells, TK6) to Zinc acetate does not produce a clastogenic effect. The in vitro mammalian chromosome aberration test of zinc acetate dihydrate was performed with human leukocyte cells without metabolic activation. The results of the study indicate that zinc acetate dihydrate, when zinc is available in the cationic form, shows clastogenic effects. The degree of chromosome damage was directly proportional to the concentrations of Zinc acetate used. The highest dose (1.5x10^-3M) was lethal. The level of clastogenicity was produced for the dose 3.0x10^-4M, at 72 hours after the inoculation at 24 hours. A Danish (Q)SAR prediction with the Multicase model was realized to estimate the mutagenic potential of Zinc acetate on mammalian cells (HGRT (CHO): Chinese hamster ovary cell HGPRT forward mutation assay). The substance Zinc acetate was predicted to be not mutagenic in mammalian cells According to WHO, exposure to zinc does not increase mutation frequencies in the majority of bacterial or mammalian cell culture test systems. The weight of evidence from the in vitro and in vivo genotoxicity tests supports the conclusion that zinc, notwithstanding some positive findings at chromosome levels at elevated doses, has no biologically relevant genotoxicity activity (reviewed by Walsh et al., 1994; WHO, 2001)..
Genetic Toxicity in vivo		No data	No data
Carcinogenicity		No data	Supporting information: Results of assays with Zinc Acetate show that the average number of tumours per animal was not significant (related to the control groups). It was observed that Zinc ions seem to promote the emigration, implantation and outgrowth of circulating tumour cells.
Reproductive Toxicity		TOXICITY TO REPRODUCTION: No data DEVELPMENTAL TOXICITY / TERATOGENICITY: No data	TOXICITY TO REPRODUCTION: Weight of evidence: Read-across from the analogue Citric Acid, based on molecular weights: A study on rats and mice daily treated by feed before, during, and after mating. For Zinc Acetate, the NOAEL is calculated to be equal or greater than 3582.06 mg/kg bw/day (basis for effect: number of pregnancies, number of young born, or survival of young). A fertility test on female rats daily treated by feed for several months. For Zinc Acetate, the NOAEL is calculated to be 859.69 mg/kg bw/day, and LOAEL greater than 859.69 mg/kg bw/day for reproductive effects. Read-across from the analogue Citric Acid, sodium salt, based on molecular weights: A fertility study on female rats daily treated by feed for several months. For Zinc Acetate, the NOAEL is calculated to be 64.28 mg/kg bw/day, and LOAEL greater than 64.28 mg/kg bw/day for reproductive effects. Read-across from the analogue Zinc sulfate, based on molecular weights: A prospective study which started at booking and continued till discharge of mother and baby from the maternity hospital. Mothers were randomly assigned to receive zinc supplementation (as capsule, 0.3 mg Zinc/kg bw/day as Zinc sulfate) or placebo in a double blind trial. 494 Mothers were followed up till the end of pregnancy. Applying the read-across approach, the NOAEL with the substance Zinc acetate is calculated to be equal or greater than 0.84 mg/kg bw/day (for maternal and neonatal toxicity). Experimental data on Zinc Acetate: The toxic effect of Zinc acetate on the functions of various tissues and organs in male rats was studied. Two groups of rats received zinc acetate (4 mg/kg bw/day and 8 mg/kg bw/day). Test substance was administrated intraperitoneally to rats once every two days, seven times in total. The NOAEL was equal or greater than 8 mg/kg bw/day (reproduction effects in male rats). A model of BALB/c mice received Zinc acetate in drinking water concentrations of 500 and 1000 mg/L during the periods of gestation, lactation and post-weaning. The exposure of up to 372 mg zinc/kg bw/day in mice prior to and throughout pregnancy did not result in changes in reproductive index (for parents and developmental toxicity).   DEVELOPMENTAL TOXICITY / TERATOGENICITY: Weight of evidence: Experimental data on Zinc Acetate: Zinc acetate (10 mg/kg bw, i.p.) was administered to pregnant CD-1 mice at 48, 24 or 0 hr prior to GD 9 administration of LPS (0, 0.025, 0.05 mg/kg bw). Animals were killed on GD 10. At 24 hr post LPS, maternal liver Zinc and MT levels increased with dose. Zinc treatment also induced MT. LPS caused embryolethality, including full-litter resorption (10% and 40% at 0.025 and 0.05 mg/kg bw). Zinc co-administration exacerbated the effects of LPS (60% and 100% fully resorbed at 0.025 and 0.05 mg/kg bw of LPS) while 24 or 48 hr Zinc pretreatment had a protective effect (5% and 4% fully resorbed at 0.025 and 0.05 mg/kg bw of LPS). Read-across approach from experimental results obtained with analogue Sodium Acetate, based on molecular weights: Pregnant CD-1 mice were treated with Sodium Acetate by oral gavage on days 8-12 of gestation. Day 20 of gestation was considered postnatal day 1 (PD1). On PD1 and 3, the litters were counted and weighed as a unit. By read-across approach, for Zinc Acetate the NOAEL is calculated to be equal or greater than 1118.47 mg/kg bw/day (based on maternal toxicity: mortality, pregnancy and resorption; and on neonatal effects: mortality and body weight). Read-across from the analogue Citric Acid, based on molecular weights: A study on rats and mice daily treated by feed before, during, and after mating. For Zinc Acetate, the NOAEL is calculated to be equal or greater than 3582.06 mg/kg bw/day (basis for effect: number of pregnancies, number of young born, or survival of young). Read-across from the analogue substance Calcium Formate, based on molecular weights: A three-generation drinking water study was performed. For Zinc Acetate, the NOAEL is calculated to be equal or higher than 282.06 mg/kg bw/day (overall effects). Read-across from Acetic Acid, based on molecular weights: A one-generation study was performed on female mice, rats and rabbits with Acetic Acid. The read-across approach was applied and the NOAEL with the substance Zinc acetate is calculated to be equal or greater than 2446.63 mg/kg bw/day for maternal and developmental toxicity in mice, rats, and rabbits. Read-across approach from experimental results obtained with analogue Zinc Sulfate, based on molecular weights: A prospective study started at booking and continued till discharge of mother and baby from the maternity hospital. Mothers were randomly assigned to receive zinc supplementation (as capsule, 0.3 mg Zinc/kg bw/day as Zinc sulfate) or placebo in a double blind trial. 494 Mothers were followed up till the end of pregnancy. The read-across approach was applied and the NOAEL with the substance Zinc acetate is calculated to be equal or greater than 0.84 mg/kg bw/day (for maternal and neonatal toxicity). Read-across approach from experimental results obtained with analogue Zinc Aspartate, based on molecular weights: The effects of the oral application of Zinc aspartate in pregnancy women is investigated in a randomly selected study group of 179 patients and a control group of 345 patients. The read-across approach was applied and the NOAEL with the substance Zinc acetate is calculated to be equal or greater than 0.16 mg/kg bw/day (for maternal and developmental toxicity). Read-across approach from experimental results obtained with analogue Zinc Sulfate, based on molecular weights: Based on the experimental results obtained with the analogue Zinc sulfate on Wistr rats, and the molecular weights, the read-across approach was applied and the NOEL with the substance Zinc acetate is calculated to be equal or higher than 48.44 mg/kg bw/day (for maternal and neonatal toxicity).

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information):
negative

The substance Zinc Acetate is considered to be not mutagenic on mouse lymphoma cells, with and without metabolic activation.

Executive summary:

Based on published experimental data on the analogue Phenoxyacetic acid (repoted under endpoint record 07.06.01_012 Phenoxyacetic acid), which is considered to be not mutagenic on mouse lymphoma cells, with and without metabolic activation, and applying the read-across approach, the substance Zinc Acetate is also considered to be not mutagenic under test conditions.