Zirconium propionate

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

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.

 

Toxicity for reproduction– effects on fertility

No toxicity data on adverse effects on sexual function and fertility with zirconium propionate is available, thus the reproductive toxicity will be addressed with existing data on the dissociation products as detailed in the table below. Further details on the reproductive toxicity of the individual constituents are given below.

 

Table: Summary of toxicity data on adverse effects on sexual function and fertility of zirconium propionate and the individual constituents.

	Zirconium	Propionic acid (CAS# 79-09-4)	Zirconium propionate(CAS# 84057-80-7)
Repeated dose toxicity data	Not adverse effects on reproductive organs observed (weight of evidence, animal data)	See section on repeated dose toxicity	See section on repeated dose toxicity
Two-generation reproductive toxicity study	Not reprotoxic (weight of evidence, animal data) Not classified	NOAEL(sub-chronic, dog) = 2060 mg/kg bw/day   Not classified	No data   Not classified

 

Zirconium

The systemic toxic effects of zirconium acetate after repeated oral dosing, as well as any toxic effects on reproduction and development, were investigated in Sprague Dawley rats up to early lactation (day 4 post partum) by Rossiello (2013). The study was performed according to OECD guideline 422 and under GLP principles. Three groups of 10 males and 10 females each received the test item, by oral gavage, at 100, 300 and 1000 mg anhydrous zirconium acetate/kg bw/day. A similar constituted control group received the vehicle alone during the treatment period. The overall dosing period was 32 days for males, which included 2 weeks before pairing and continuously thereafter up to the day before necropsy, and up to 50 days for females, including 2 weeks before pairing and thereafter during pairing, gestation and lactation periods until day 3 post partum.

The parental animals were followed for daily clinical signs, weekly body weight, food consumption, neurotoxicity assessment, oestrous cycle, mating performance, clinical pathology evaluation including haematology and clinical chemistry, and offspring delivery. A detailed macroscopic examination, determination of organ weights, and histopathological examination, including the spermatogenic cycle, were performed. Pups were also checked for sex, body weight, clinical signs and macroscopic observations.

No mortality occurred in the study. No treatment related findings were observed either during the in vivo phase or at post mortem examination of parent animals. Microscopically, a treatment related finding was seen in males receiving 300 and 1000 mg zirconium acetate/kg bw/day consisting of minimal focal vacuolation of squamous epithelium (limiting ridge) of the non-glandular region of the stomach. This change may be attributed to a local irritant effect of the compound administered by oral gavage and since humans do not have a forestomach or structural analogue to the forestomach, this finding is not considered of toxicological relevance. In addition, no abnormalities were found during the evaluation of the spermatogenic cycle. No treatment related effects were observed in the number of oestrous cycle, pre-coital intervals, copulatory and fertility indices between treated and control groups. No significant differences were observed in the number of implantations, corpora lutea, total litter size, pre-implantation loss, pre-birth loss and gestation length between control and treated groups.

No effects were noted on reproduction and development at any dose. On the basis of the results obtained in this study, the NOAEL for reproduction/developmental toxicity was considered to be ≥ 1000 mg/kg bw/day (expressed as anhydrous zirconium acetate, equivalent to ≥530 mg Zr/kg bw/day), i.e., the highest dose tested.

Zirconium dioxide shows a limited toxicological activity as highlighted by the acute toxicity studies via oral (LD50 in rats > 5000 mg/kg) and inhalation route (LC50 in rats > 4.3 mg/L, maximal technically achievable mean concentration), as well as by the repeated dose toxicity studies via inhalation by Spiegl et al. (1956) (30 days NOAEC > 100.8 mg/m3 air and 60 days NOAEC > 15.4 mg/m3 air in cat, dog, guinea pig, rabbit, rat). Furthermore, the toxicokinetic assessment concluded of a low systemic absorption of zirconium dioxide. Absorption factors of 10% were proposed for oral, inhalation and dermal absorption, and it was argued that these factors were probably overestimated.

Additionally the study by Spiegl et al. (1956) showed no impact on the reproductive organs (at least testes) after inhalation of zirconium dioxide. After exposure of 28 animals (2 dogs, 6 rabbits, 20 rats) to 100.8 mg ZrO2 /m3 during 30 days and 123 animals (4 cats, 8 dogs, 20 guinea pigs, 6 rabbits and 72 rats) to 15.4 mg ZrO2/m3 during 60 days, no abnormal findings were noted for the reproductive organs during the histology realized on the 14 animals (2 dogs, 6 rabbits, 6 rats) exposed to 100.8 mg/m3 and the 46 animals (4 cats, 4 dogs, 18 guinea pigs, 10 rabbits and 10 rats) exposed to 15.4 mg/m3.

 

In a study on another poorly soluble zirconium substance, hydrated zirconium carbonate (HZC) containing 20.9% equivalent ZrO2 in which rats were exposed to diet containing equivalent dose of ZrO2 at level up to 7080 mg/kg bw/d for 17 weeks, no effects were observed on the genital organs Harrisson et al. (1951).

 

It is interesting to mention that in the study by Spiegl et al. (1956), exposure to zirconium tetrachloride dissolved into water, so in the form of zirconium dichloride oxide was as well realized. 124 animals (4 cats, 8 dogs , 20 guinea pigs, 20 rabbits and 72 rats) were exposed during 60 days to ZrCl4 at an equivalent dose of 6 mg Zr/m3. In this study, histology was realized on 60 animals (4 cats, 4 dogs, 17 guinea pigs, 10 rabbits and 25 rats) testicular atrophy on 2 cats was observed.

An additional study on zirconium dichloride oxide (ZOC) was done by oral route by Delongeas et al. (1983). This study showed that a weak fraction of Zr was absorbed after oral exposure for 16 days of rats to ZOC (3000 and 5300 mg/kg). However a small portion of this absorbed fraction could reach the ovaries and induce hypervascularization.

Based on these results we can suppose that there may be a difference between soluble and poorly soluble Zr compounds and conclude that for an insoluble compound of zirconium such as zirconium dioxide the effects on reproductive organs and the toxicity to reproduction are limited. However, this does not provide sufficient data to justify a lower priority for testing for effects on development. Therefore, a teratology study (OECD 414) is proposed. The results of this test will provide data on the effects of the substance on implantation, resorptions, foetal growth, morphological variations and malformations. Consequently, in case of clear negative results, any additional testing is deemed not relevant and it can then be concluded that zirconium dioxide will not be toxic to reproduction. In case of any positive results in the teratogenicity study, more information on toxicity to reproduction would be necessary as well and would subsequently be investigated in an OECD 416 study.

 

Propionic acid

There are no reproductive toxicity studies available for n-propionic acid. Data from a 100 days repeated-dose study in dogs did not result in toxicity to reproductive organs.

 

In a dog study satisfying GLP requirements and OECD 409 TG, propionic acid (> 99% purity) was administered via diet to male and female Beagle dogs (4/sex/dose) for approximately 100 days at diet concentrations of 0, 3000, 10000 and 30000 ppm propionic acid. A recovery period of 6 weeks was allocated for the groups (4/sex/dose) receiving 0 and 3000 ppm propionic acid in the diet. No mortality occurred during the administration period. No substance related clinical signs of toxicity occurred. Calculated from food consumption, the mean daily dose administered were 214.2, 718.9, 2056.3 mg/kg bw for males and 225.1, 749.2, 2071.8 mg/kg bw for females. Dogs from the high-dose group displayed a decrease in appetite, which was attributed as a response due to unpalatability of the diet. This decrease in food consumption however did not seem to significantly affect body weights or body weight gains. No systemic effects were observed even at the highest dose. There were no significant changes in haematology, urinalysis, or clinical chemistry parameters that could be attributed to the test material. Necropsy of dogs after the administration interval revealed no gross lesions. Examination of tissues revealed no lesions except point-of-contact diffuse epithelial hyperplasia of the mucosa of the oesophagus in several high dose dogs. This effect was reversible after a 6 week recovery period. The incidence of focal epithelial hyperplasia in lower dose animals was comparable to controls. There were no effects observed on male or female reproductive organs. The NOAEL for this study for systemic /reproductive organ effects is 3000 ppm propionic acid in the diet or 2056,3 mg/kg bw for male dogs and 2071.8 mg/kg bw for female dogs (BASF, 1988).

 

Zirconium propionate

Since no toxicity data on adverse effects on sexual function and fertility is available for zirconium propionate, information on the individual constituents zirconium and propionic acid will be used for the hazard assessment and, when applicable, for the risk characterisation of zirconium propionate. For the purpose of hazard assessment of zirconium propionate, the point of departure for the most sensitive endpoint of each constituent will be used for the DNEL derivation.

 

Zirconium propionate is not expected to show adverse effects on sexual function and fertility, since the two constituents zirconium and propionic acid have not shown adverse effects on sexual function and fertility in relevant bioassays. Thus, zirconium propionate is not to be classified according to regulation (EC) 1272/2008 as reproductive toxicant: fertility impairment. Further testing is not required. For further information on the toxicity of the individual constituents, please refer to the relevant sections in the IUCLID and CSR.

 

Short description of key information:

Zirconium propionate is not expected to show adverse effects on sexual function and fertility.

 

Justification for selection of Effect on fertility via oral route:

Information from read-across substances:

animal data for zirconium: NOAEL(rat) ≥ 530 mg/kg bw/day

animal data for propionic acid: NOAEL(dog) = 2060 mg/kg bw/day

Effects on developmental toxicity

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.

 

Toxicity for reproduction – developmental toxicity

No toxicity data on adverse effects on development of the offspring with zirconium propionate are available, thus the reproductive toxicity will be addressed with existing data on the dissociation products as detailed in the table below. Further details on the genetic toxicity of the individual constituents are given below.

 

Table: Summary of toxicity data on adverse effects on development of the offspring of zirconium propionate and the individual constituents.

	Zirconium	Propionic acid (CAS# 79-09-4)	Zirconium propionate (CAS# 84057-80-7)
Screening test / Pre-natal developmental toxicity study	NOAEL(rat; mat.) ≥530 mg/kg bw/day   NOAEL(rat; dev) ≥530 mg/kg bw/day   Not classified	NOAEL(rat, mat) ≥300 mg/kg bw NOAEL (rat, dev) ≥300 mg/kg bw   NOAEL(mouse, mat) ≥300 mg/kg bw; NOAEL (mouse, dev) ≥300 mg/kg bw   NOAEL(rabbit, mat) ≥300 mg/kg bw; NOAEL (rabbit, dev) ≥300 mg/kg bw   NOAEL(hamster, mat) ≥300 mg/kg bw; NOAEL (hamster, dev) ≥300 mg/kg bw	No data   Not classified

 

Zirconium

An OECD 422 test (scored for reliability K1) has been performed with zirconium acetate (Rossiello, 2013). The test results indicate that zirconium acetate is a substance of low toxicological potential, as the NOAEL for reproductive/developmental toxicity was considered to be higher than or equal to the highest dose tested: 1000 mg/kg bw/day expressed as anhydrous zirconium acetate, equivalent to 530 mg Zr/kg bw/day. Furthermore no effects were observed in any of the parameters evaluated for pups. In addition, and based on the assessment of all available data, low absorption of zirconium acetate is expected. Also low toxicity is expected based on the available acute and subacute experimental data with zirconium acetate. Therefore, no further testing seems to be required for this substance as no adverse effects or hazards need to be addressed. Due to the extremely low absorption and toxicity, it will be scientifically unjustified to perform a prenatal developmental toxicity study, since this study reasonably requires testing up to doses that cause maternal toxicity. Based on the evaluation and results mentioned above, it is considered acceptable to assume that effects on reproduction or development are not to be expected (if at all) at exposure levels well below the unbound values from the repeated dose toxicity studies.

 

Propionic acid

There are no data available for n-propionic acid. Calcium propionate is an ion pair, which readily dissociates in water. The dissociation constant shows that at the low pH of the stomach, the important moieties from a toxicological standpoint are the unionized free acid and ionized metal. Because of this, mammalian toxicity data for calcium propionate can serve as surrogate data for the acid. Data for calcium propionate in four species (mouse, rat, hamster, and rabbit) are presented.

 

Calcium propionate was fed to pregnant CD-1 mice and Wistar rats during gestation days 6-15 at dose levels of 3, 14, 65, and 300 mg/kg-bw/day. Pregnant rabbits and hamsters were fed calcium propionate at a doses of 0, 4, 19, 86, and 400 mg/kg-bw/day during gestation days 6-18 (rabbits) or 6-10 (hamsters). Body weights of dams were taken at several intervals during gestation. Dams were observed each day for food and water intake and other measures of appearance and behaviour. Dams were sacrificed on gestation day 17 (mice), 20 (rats), 14 (hamsters), or 29 (rabbits). Numbers of implantation sites, resorption sties, and live and dead foetuses were recorded. Body weights of live pups were also recorded. All pups were examined grossly for external congenital abnormalities. One-third of the foetuses of each litter underwent detailed visceral examinations; two-thirds were examined for skeletal defects. In all species, there was no effect on maternal or foetal survival, or on foetal or litter size. No increase in foetal or skeletal abnormalities was observed. The NOAEL for maternal toxicity and developmental in rats is 300 mg/kg bw. The NOAEL for maternal toxicity and developmental in mouse is 300 mg/kg bw. The NOAEL for maternal toxicity and developmental in rabbits is 400 mg/kg bw and the NOAEL for maternal toxicity and developmental in hamster is 400 mg/kg bw (FDA 1972). The study is acceptable for assessment with restrictions. The authors provided no reason why tests were not performed up to the limit concentration. However, based on the findings from the repeated dose studies, forestomach lesions will be expected to occur at the limit dose.

 

Zirconium propionate

Since no reproductive toxicity study is available for zirconium propionate, information on the individual constituents zirconium and propionic acid will be used for the hazard assessment and, when applicable, for the risk characterisation of zirconium propionate. For the purpose of hazard assessment of zirconium propionate, the point of departure for the most sensitive endpoint of each constituent will be used for the DNEL derivation.

Zirconium propionate is not expected to show adverse effects on development of the offspring, since the two constituents zirconium and propionic acid have not shown developmental toxicity in relevant bioassays. Thus, zirconium propionate is not to be classified according to regulation (EC) 1272/2008 as developmental toxicant. Further testing is not required. For further information on the toxicity of the individual constituents, please refer to the relevant sections in the IUCLID and CSR.

 

Justification for selection of Effect on developmental toxicity: via oral route:

Information from read-across substances:

animal data for zirconium: NOAEL(rat) ≥530 mg/kg bw/day

animal data for propionic acid: NOAEL ≥300mg/kg bw/day

Justification for classification or non-classification

Zirconium propionate is not expected to show adverse effects on sexual function and fertility, since the two constituents zirconium and propionic acid have not shown adverse effects on sexual function and fertility in relevant bioassays. Thus, zirconium propionate is not to be classified according to regulation (EC) 1272/2008 as reproductive toxicant: fertility impairment.

Zirconium propionate is not expected to show adverse effects on development of the offspring, since the two constituents zirconium and propionic acid have not shown developmental toxicity in relevant bioassays. Thus, zirconium propionate is not to be classified according to regulation (EC) 1272/2008 as developmental toxicant.