Zirconium propionate

Endpoint summary

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:

06 December 2021 - 21 December 2021

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

GLP compliance:

yes (incl. QA statement)

Test type:

acute toxic class method

Limit test:

yes

Species:

rat

Strain:

Wistar

Remarks:

Han:WIST rats

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Toxi-Coop Zrt., H-1122 Budapest, Magyar Jakobinusok tere 4B
- Hygienic level at supplier: SPF
- Hygienic level during the study: Standard housing conditions
- Number of animals: 6 animals, 3 animals/group
- Sex: Female, nulliparous and non-pregnant animals
- Age of animals at dosing: Young adult rats, approx. 9-10 weeks old
- Body weight range at dosing: 173-204 g. The maximum difference of individual animal weights from the mean of the treatment group did not exceed 20%.
- Acclimatisation period: At least 19 days
- Animal health: Only healthy animals were used for the test. The health status was certified by the Veterinarian.
- Housing: Group caging (3 animals/cage)
- Cage type: T3H polycarbonate
- Bedding and nesting: “SAFE 3/4-S-FASERN” certified wooden chips and “Sizzle pet” nest material were available to animals during the study.
- Enrichment: Animals were housed by group to allow social interaction and with deep wood sawdust bedding to allow digging and other normal rodent activities.
- Animals received standard laboratory rat diet, ad libitum, and tap water from the municipal supply, as for human consumption from drinking bottles designed for rodents, ad libitum.
- The night before treatment, the animals were fasted. Food, but not water, was withheld overnight. Animals were weighed before dosing. Food was replaced 3 hours after the treatment.

ENVIRONMENTAL CONDITIONS
- Lighting period: 12 hours daily, from 6.00 a.m. to 6.00 p.m.
- Temperature: 20 – 23 °C (target: 22 ± 3 °C)
- Relative humidity: 38 – 61 % (target: 30 – 70 %)
- Ventilation: 15-20 air exchanges/hour

IN-LIFE DATES: From 06 December 2021 to 21 December 2021

Route of administration:

oral: gavage

Vehicle:

methylcellulose

Remarks:

1% methyl cellulose in distilled water

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 200 mg/mL
- Amount of vehicle (if gavage): 10 mL/kg bw
- Justification for choice of vehicle: The test item did not dissolve in distilled water, but formed a homogenous suspension in 1% methyl cellulose solution, which was stable while stirring with magnetic stirrer. Therefore 1% methyl cellulose solution was chosen as vehicle for this study. Details of the vehicle used in the study were as follows:
Component 1
Name: Methylcellulosum
Batch number: 8075546
Manufacturer: Magilab Kft.
Expiry date: 10 July 2022
Component 2
Name: Aqua purificata (Distilled water)
Batch number: 2108-5518
Manufacturer: Parma Produkt Kft.
Expiry date: 18 February 2022

DOSAGE PREPARATION: The test item was freshly formulated in the vehicle at the appropriate concentration (200 mg/mL), in the Pharmacy of NEXTREAT Laboratories on the day of administration. The formulations were stirred with magnetic stirrer up to finishing the treatment.

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: As starting dose level for acute toxicity study, a dose of 2000 mg/kg body weight (bw) was selected based on the results of acute oral toxicity studies with Zirconium and propionic acid.
- Initially three animals were treated at the starting dose of 2000 mg/kg bw (Group 1). As no mortality was observed in this group, a confirmatory group (Group 2) was treated at the same dose level. No mortality was observed in this confirmatory dose group, therefore no further testing was required according to the criteria for termination given in Annex 2d of OECD Guideline No. 423.

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

6 (3 animals per group)

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Clinical observations: Following the end of the dosage, the animals were observed individually once during the first 30 minutes, at 1, 2, 3, 4 and 6 hours after the treatment and once daily for 14 consecutive days thereafter. Individual observations were performed on the skin and fur, eyes and mucous membranes and also respiratory, circulatory, autonomic and central nervous system, somatomotor activity and behaviour pattern. Particular attention was directed to observation of tremors, convulsions, salivation, diarrhoea, lethargy, sleep and coma. The time of death was recorded as precisely as possible.
- Body weight: The body weight of the animals was recorded on Days 0 (prior to dosing), 7 and 14 (prior to necropsy), with a precision of 1 g.
- Necropsy: Animals were subjected to a necropsy and a macroscopic examination. After examination of the external appearance, the cranial, thoracic and abdominal cavities were opened and the appearance of the tissues and organs were observed. All gross macroscopic changes were recorded for each animal.

Statistics:

The method used was not intended to allow the calculation of a precise LD50 value.

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

>= 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

not determinable due to absence of adverse toxic effects

Mortality:

Zirconium propionate did not cause mortality at 2000 mg/kg bw.

Clinical signs:

other:

Body weight:

lower than 10% body weight loss

Remarks:

There were no effects on body weight or body weight gain that could be attributed to treatment with the test item.

Gross pathology:

There were no macroscopic changes seen at necropsy.

Interpretation of results:

GHS criteria not met

Remarks:

The test substance is not classified according to Regulation (EC) No 1272/2008 (CLP)

Conclusions:

Under the conditions of this study, the acute oral LD50 value of the test item Zirconium propionate was found to be above 2000 mg/kg bw in female Han:WIST rats.
The study result triggers the following classification/labelling:
- Regulation (EC) No 1272/2008 (CLP): Unclassified
- GHS (rev. 7) 2017: Unclassified

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

> 2 000 mg/kg bw

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Additional information

Read-across approach

Selected endpoints for the human health hazard assessment are addressed by read-across, using a combination of data on the metal cation and the organic acid anion. This way forward is acceptable, since metal carboxylates are shown to dissociate to the organic anion and the metal cation upon dissolution in aqueous media. No indications of complexation or masking of the metal ion through the organic acid were apparent during the water solubility and dissociation tests (please refer to the water solubility and dissociation in sections 4.8 and 4.21 of IUCLID). Once the individual transformation products of the metal carboxylate become bioavailable (i.e. in the acidic environment in the gastric passage or after phagocytosis by pulmonary macrophages), the “overall” toxicity of the dissociated metal carboxylate can be described by a combination of the toxicity of these transformation products, i.e. the metal cation and carboxylate anion according to an additivity approach.

 

Zirconium propionate is the zirconium metal salt of propionic acid, which readily dissociates to the corresponding zirconium cation and propionate anions. The zirconium cation and the propionate anion are considered to represent the overall toxicity of zirconium propionate in a manner proportionate to the free acid and the metal (represented by one of its readily soluble salts). 

 

A detailed justification for the read-across approach is added as a separate document in section 13 of IUCLID.

 

Acute toxicity

An acute oral toxicity study with zirconium propionate is available. Acute dermal and inhalation toxicity will be addressed with existing data on the dissociation products as detailed in the table below. Further details on the acute toxicity of the individual constituents within the framework of regulation (EC) 1907/2006 are given below.

 

Table: Summary of acute toxicity data of zirconium propionate and the individual constituents.

	Zirconium	Propionic acid (CAS# 79-09-4)	Zirconium propionate (CAS# 84057-80-7)
Acute oral toxicity	LD50(rat) > 3700 mg Zr/kg bw	LD50(rat) = 3455 mg/kg bw (weight of evidence data)	LD50 >2000 mg/kg bw (measured) LD50 3563 mg/kg bw (read-across)
Acute inhalation toxicity	LC50 > 3.2 mg Zr/L	LC50 > 20 mg/L air	waived, since the substance is used and placed on the market in a non-inhalable form
Acute dermal toxicity	LD50 > 870 mg Zr/kg bw	waived due to the corrosive properties of propionic acid	LD50 >1776 mg/kg bw (read-across)

 

Under the assumption that the constituents of zirconium propionate show their toxicological profile individually upon dissolution, the acute oral toxicity of zirconium propionate can be calculated using the equation given in regulation (EC) 1272/2008, Annex I, Section 3.1.3.6.1. The calculated oral LD50 for zirconium propionate is 3563 mg/kg bw, hence the substance is not to be classified according to regulation (EC) 1272/2008 for acute oral toxicity as well as for specific target organ toxicity, single exposure (STOT SE). The predicted LD50 based on data for the two transformation products agrees well with the measured acute oral LD50 for zirconium propionate. It can therefore be concluded that read-across for the two transformation products together with the additivity approach to predict the (eco)toxicological effects of the target substance is conservative and no synergistic effects are expected between the transformation products.

 

Conduct of an acute dermal toxicity study is unjustified as the physicochemical properties of the substance do not suggest a significant rate of absorption through the skin (cf. Annex VIII section 8.5 Column 2 of regulation (EC) 1907/2006) and no acute dermal toxicity has been observed for zirconium (LD50 > 870 mg Zr/kg).

 

For further information on the toxicity of the individual constituents, please refer to the relevant sections in the IUCLID and CSR.

Justification for classification or non-classification

The experimentally measured oral LD50 for zirconium propionate is > 2000 mg/kg, hence the substance is not to be classified according to regulation (EC) 1272/2008 for acute oral toxicity as well as for specific target organ toxicity, single exposure (STOT SE).

Conduct of an acute dermal toxicity study is unjustified as the physicochemical properties of the substance do not suggest a significant rate of absorption through the skin (cf. Annex VIII section 8.5 Column 2 of regulation (EC) 1907/2006) and no acute dermal toxicity has been observed for zirconium (LD50 > 870 mg Zr/kg).