Zinc di(acetate)

Skin sensitisation

Administrative data

Endpoint:

skin sensitisation

Remarks:

in vivo

Type of information:

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

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: The analogue Citric Acid which shares the same functional group with Zinc Acetate, also has comparable values for the relevant molecular properties for the skin sensitisation endpoint.

Cross-reference

Reason / purpose for cross-reference:

reference to other study

Data source

Reference

Reference Type:

other: read-across

Title:

Unnamed

Year:

1989

Materials and methods

Principles of method if other than guideline:

Read-across approach from published experimental data from a skin prick testing on the analogue Citric acid.

GLP compliance:

not specified

Type of study:

other: read-across from a skin prick testing with an analogue

Test material

Test material information

Constituent 1

Reference substance name:

Citric acid

EC Number:

201-069-1

EC Name:

Citric acid

Cas Number:

77-92-9

IUPAC Name:

citric acid

Details on test material:

- Name of test material (as cited in study report): Citric acid
- Molecular formula (if other than submission substance): C6H8O7
- Molecular weight (if other than submission substance): 192.1
- Smiles notation (if other than submission substance): OC(=O)CC(O)(CC(O)=O)C(=O)O
- InChl (if other than submission substance): InChI=1/C6H8O7/c7-3(8)1-6(13,5(11)12)2-4(9)10/h13H,1-2H2,(H,7,8)(H,9,10)(H,11,12)
- Structural formula attached as image file (if other than submission substance): see Fig. in attached report

Results and discussion

In vivo (non-LLNA)

Results

Results 1

Reading:

1st reading

Hours after challenge:

0.25

Group:

test chemical

Dose level:

2.5 %

No. with + reactions:

3

Total no. in group:

91

Clinical observations:

Weals

Remarks on result:

other: Reading: 1st reading. . Hours after challenge: 0.25. Group: test group. Dose level: 2.5 %. No with. + reactions: 3.0. Total no. in groups: 91.0. Clinical observations: Weals.

Results 2

Reading:

rechallenge

Hours after challenge:

0.25

Group:

test chemical

Dose level:

2.5 %

No. with + reactions:

0

Total no. in group:

11

Clinical observations:

No effects

Remarks on result:

other: Reading: rechallenge. . Hours after challenge: 0.25. Group: test group. Dose level: 2.5 %. No with. + reactions: 0.0. Total no. in groups: 11.0. Clinical observations: No effects.

Results 3

Reading:

1st reading

Hours after challenge:

0.25

Group:

negative control

Dose level:

0

No. with + reactions:

0

Total no. in group:

247

Clinical observations:

No effects

Remarks on result:

other: Reading: 1st reading. . Hours after challenge: 0.25. Group: negative control. Dose level: 0. No with. + reactions: 0.0. Total no. in groups: 247.0. Clinical observations: No effects.

Any other information on results incl. tables

Based on the experimental results obtained with the analogue Citric acid (Citric acid, 2.5 % aqueous solution, is not sensitizing for the human skin), the read-across approach was applied and the substance Zinc acetate is also considered to be not sensitizing for the human skin. 

The analogue Citric acid which shares the same functional group with Zinc acetate, also has comparable values for the relevant molecular properties. These properties are:

- a low log Pow value, which is -1.72 for Citric acid, and -1.28 for Zinc acetate,

- a high water solubility, which is 1330 g/L for Citric acid,and 434.78 g/L at 25 ºC for Zinc acetate, and

- similar molecular weights, which are 192.1 for Citric acid, and 183.497 for Zinc acetate.

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.Presented results show that both substances have common (eco)toxicological behavior (table).

CAS Number		Source chemical 77-92-9	Target chemical 557-34-6
CHEMICAL NAME		Citric acid	Zinc Acetate
PHYSICO-CHEMICAL DATA
Melting Point		Measured data: 153 ºC	Measured data: 237 ºC
Boiling Point		Decomposes	Measured data: 258.2 ºC ± 0.7 ºC
Density		Measured data: 1.665 g/cm3 at 20 ºC	Measured data: 1.735
Vapour Pressure		Estimated data: 5.6E-09 mm Hg	Estimated data: 0.000876 Pa at 25 ºC
Partition Coefficient (log Kow)		Measured data: -1.72	Estimated data: -1.28
Water solubility		Measured data: 1330 g/L	Experimental data: 434.78 g/L at 25 ºC
ENVIRONMENTAL FATE and PATHWAY
Aerobic Biodegradation		Experimental results: Readily biodegradable	Read-across:   Readily biodegradable
ENVIRONMENTAL TOXICITY
Acute Toxicity to Fish		Experimental data: (96 h) LC 50 = 1516 mg/L	Experimental results:   LC50 for fish is 2.46mg/L.
Acute Toxicity to Aquatic Invertebrates		Experimental data: (48 h) EC 50 = 1535 mg/L	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		Experimental data: (72 h) EC 50 = 640 mg/L	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		Experimental data: LD 50 = 5790 – 7100 mg/kg bw (mice) LD 50 = 11700 mg/kg bw (rats)	Weight of evidence: 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		Experimental data:   A 4-hour skin irritation study in rabbits exposed to a solution containing 60% citric acid caused erythema and edema. This study did not assess a lethal dose value. TheLD50 was not provided.	No data
Skin Irritation/Corrosion		Experimental data:   Application of 500 mg Citric Acidto rabbit skin produced moderate irritation in 24 hr.	Weight of evidence:   Experimental data on Zinc Acetate on rabbits, mice, and rats, and read-across approach from experimental data on Calcium Acetate and Zinc Stearate, based on functional group:   Zinc Acetate is considered to be not irritating for skin after a single application of test substance.
Eye Irritation/Corrosion		Experimental data:   Citric Acidtested on rabbit eyes as single drop of 2% to 5% solution in water caused little or no injury. Irrigation for 30 min with 0.5% to 2% solution causes severe injury; the 0.5% solution causes permanent cloudiness of cornea, and the 2% solution causes severe dense opacification.   Application of 750 mg caused severe irritation in the rabbit eye.	Experimental data:    Zinc Acetate is belongs to a group of substances which cause eye corrosion/irritation.
Skin sensitisation		Experimental results:   Citric acid (2.5 % aqueous solution) is not sensitizing for the human skin.   No allergic reactions were seen when 60 patients with hand eczema, all of whom were involved in handling food, were patch tested (covered contact, probably 24 hr) with 2.5% citric acid in petrolatum.	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		Repeated dose toxicity: oral: Experimental results:   In a 150-day study with male New Zealand White rabbits daily treated by feed, theNOAEL was 1500 mg/kg bw/day(based on no effects observed at the only dose tested).   In a 6-week study with male Sprague-Dawley rats daily treated by feed, theNOAEL was 4800 mg/kg bw/day(based on no effects observed at the highest dose tested).	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	Experimental data:   In a bacterial reverse mutation assays usingS. typhimurium(TA97, TA98, TA100 and TA104) in the presence and absence of metabolic activation and up to 2000μg/plate, citric acid was not mutagenic.	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	No data	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.   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 cells.
	-         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		Experimental data:   In a Dominant Lethal assay using male/female rats dosed at 3 g/kg for 5 days, citric acid did not induced germ cell genotoxicity.	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: Experimental data: In a one-generation oral reproductive toxicity study, female rats and mice were daily treated with citric acid before, during, and after mating. The NOAEL was equal or greater than 2500 mg/kg bw/day (basis for effect: number of pregnancies, number of young born, or survival of young). In a fertility study, female rats were exposed to citric acid in their daily diet for several months. TheNOAEL (reproductive toxicity) was 600 mg/kg bw/day(based on no effects observed at the only dose tested).   DEVELOPMENTAL TOXICITY / TERATOGENICITY:   Experimental data:   In a one-generation oral reproductive toxicity study, female rats and mice were daily treated with citric acid before, during, and after mating. The NOAEL was equal or greater than 2500 mg/kg bw/day (basis for effect: number of pregnancies, number of young born, or survival of young).	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

Interpretation of results:

not sensitising

Remarks:

Migrated information

Conclusions:

Zinc acetate is considered to be not sensitizing for the human skin.

Executive summary:

Based on the experimental results (reported under the endpoint record 07.04.01_01 Citric acid) obtained with the analogue Citric acid (Citric acid, 2.5 % aqueous solution, is not sensitizing for the human skin), the read-across approach was applied and the substance

Zinc acetate is also considered to be not sensitizing for the human skin.