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Effects on fertility

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
Additional information

Introductionto read-across matrix

A comprehensive data gap analysis was conducted for the entire substance portfolio of the REACH Metal Carboxylates Consortium (RMC), covering 10 metal carboxylates in total. This literature screening effort included:

 

  • all available proprietary studies from the REACH Metal Carboxylates Consortium (RMC)
  • detailed literature searches in online databases
  • screening of human health review articles
  • rigorous quality and reliability screening according to Klimisch criteria, where those criteria apply

 

During the literature search and data gap analysis it became obvious that the overall database on substance-specific human health hazard data for the metal carboxylates is too scant to cover all REACH endpoints. Therefore, the remaining data gaps had to be covered by either experimental testing or read-across from similar substances.

 

Selected endpoints for the human health hazard assessment are addressed by read-across, using a combination of data on the organic acid counterion and the metal (or one of its readily soluble salts). This way forward is acceptable, since metal carboxylates 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 tests (please refer to the water solubility data in section of the IUCLID and chapter of the CSR). Once the individual constituents 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 the toxicity of the “individual” constituents. Since synergistic effects are not expected for this group of metal carboxylates, the human health hazard assessment consists of an individual assessment of the metal cation and the organic anion.

 

The hazard information of the individual constituents was obtained from existing REACH registration dossiers via a license-to-use obtained by the lead registrant. These registration dossiers were submitted to ECHA in 2010 as full registration dossiers, and are thus considered to contain relevant and reliable information for all human health endpoints. All lead-registrant dossiers were checked for completeness and accepted by ECHA, i.e. a registration number was assigned.

 

Oxygen-free inorganic zirconium(IV) substances (ZrX4) are highly hygroscopic and rapidly decompose in damp atmosphere or water under formation of zirconyl compounds (ZrOX2and ZrO(OH)X). These zirconyl compounds further show an ageing under formation of zirconium dioxide (ZrO2). The zirconium dioxide is an inert metal oxide with a very low water solubility (<55µg/L) and is also the naturally occurring mineral baddeleyite.

The water solubility test (according to OECD 105 and under GLP, as presented under the respective endpoint in this dossier) with zirconium propionate confirmed the above described decomposition of inorganic zirconium salts under formation of insoluble zirconium dioxide. After 24h stirring at a loading of 100mg/L, the zirconium concentration of the samples was at 11.89 µg Zr/L.

It is concluded that localtoxicological effects of inorganic zirconium salts might be exerted solely due to the caustic properties of the concentrated resulting acid in the decomposition reaction (in this case propionic acid). Potential, local effects caused by zirconium propionate are addressed by substance-specific test data, whereas systemic effects are addressed by reading-across to the decomposition products, namely the propionate anion and zirconium dioxide.

 

Based on the above information, unrestricted read-across is considered feasible and justified.

 

Although the term „constituent“ within the REACH context is defined as substance (also being part of a mixture), the term constituent within this hazard assessment is meant to describe either part of the metal carboxylate salt, i.e. anion or cation.

 

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 dioxide
(CAS# 1314-23-4)

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

No data

 

Not classified

NOAEL(sub-chronic, dog)= 2060 mg/kg bw/day

 

Not classified

No data

 

Not classified

 

Zirconium

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 notoxicity data on adverse effects on sexual function and fertilityis 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 propionateis 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 propionateis 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: not reprotoxic (weight of evidence)

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

Effects on developmental toxicity

Description of key information

No information for zirconium on adverse effects on development of the offspring is available, adequate for risk assessment and classification and labelling purposes. A test proposal was issued by the registrant for zirconium dioxide. Upon availability of the testing results for zirconium dioxide, the registrant ensures that the dossier for zirconium propionate and the risk assessment will be updated without undue delay.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no study available (further information necessary)
Additional information

Introductionto read-across matrix

A comprehensive data gap analysis was conducted for the entire substance portfolio of the REACH Metal Carboxylates Consortium (RMC), covering 10 metal carboxylates in total. This literature screening effort included:

 

  • all available proprietary studies from the REACH Metal Carboxylates Consortium (RMC)
  • detailed literature searches in online databases
  • screening of human health review articles
  • rigorous quality and reliability screening according to Klimisch criteria, where those criteria apply

 

During the literature search and data gap analysis it became obvious that the overall database on substance-specific human health hazard data for the metal carboxylates is too scant to cover all REACH endpoints. Therefore, the remaining data gaps had to be covered by either experimental testing or read-across from similar substances.

 

Selected endpoints for the human health hazard assessment are addressed by read-across, using a combination of data on the organic acid counterion and the metal (or one of its readily soluble salts). This way forward is acceptable, since metal carboxylates 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 tests (please refer to the water solubility data in section of the IUCLID and chapter of the CSR). Once the individual constituents 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 the toxicity of the “individual” constituents. Since synergistic effects are not expected for this group of metal carboxylates, the human health hazard assessment consists of an individual assessment of the metal cation and the organic anion.

 

The hazard information of the individual constituents was obtained from existing REACH registration dossiers via a license-to-use obtained by the lead registrant. These registration dossiers were submitted to ECHA in 2010 as full registration dossiers, and are thus considered to contain relevant and reliable information for all human health endpoints. All lead-registrant dossiers were checked for completeness and accepted by ECHA, i.e. a registration number was assigned.

 

Oxygen-free inorganic zirconium(IV) substances (ZrX4) are highly hygroscopic and rapidly decompose in damp atmosphere or water under formation of zirconyl compounds (ZrOX2and ZrO(OH)X). These zirconyl compounds further show an ageing under formation of zirconium dioxide (ZrO2). The zirconium dioxide is an inert metal oxide with a very low water solubility (<55µg/L) and is also the naturally occurring mineral baddeleyite.

The water solubility test (according to OECD 105 and under GLP, as presented under the respective endpoint in this dossier) with zirconium propionate confirmed the above described decomposition of inorganic zirconium salts under formation of insoluble zirconium dioxide. After 24h stirring at a loading of 100mg/L, the zirconium concentration of the samples was at 11.89 µg Zr/L.

It is concluded that localtoxicological effects of inorganic zirconium salts might be exerted solely due to the caustic properties of the concentrated resulting acid in the decomposition reaction (in this case propionic acid). Potential, local effects caused by zirconium propionate are addressed by substance-specific test data, whereas systemic effects are addressed by reading-across to the decomposition products, namely the propionate anion and zirconium dioxide.

 

Based on the above information, unrestricted read-across is considered feasible and justified.

 

Although the term „constituent“ within the REACH context is defined as substance (also being part of a mixture), the term constituent within this hazard assessment is meant to describe either part of the metal carboxylate salt, i.e. anion or cation.

 

Toxicity for reproduction – developmental toxicity

No toxicity data on adverse effects on development of the offspring withzirconium propionateare 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 ofzirconium propionateand the individual constituents.

 

Zirconium dioxide
(CAS# 1314-23-4)

Propionic acid

(CAS# 79-09-4)

Zirconium propionate(CAS# 84057-80-7)

Pre-natal developmental toxicity study

Test proposal

 

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 – data lacking

 

Zirconium

No data available. A testing proposal is issued by the registrant of zirconium dioxide.

 

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 forofzirconium 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.

 

No information for zirconium on adverse effects on development of the offspring is available, adequate for risk assessment and classification and labelling purposes. A test proposal was issued by the registrant for zirconium dioxide.Upon availability of the testing results forzirconium dioxide, the registrant ensures that the dossier for zirconium propionateand the risk assessment will be updated without undue delay.

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

Information from read-across substances:

animal data for zirconium: a test proposal was issued by the registrant for zirconium dioxide

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

Justification for classification or non-classification

Zirconium propionateis 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 propionateis not to be classified according to regulation (EC) 1272/2008 or Directive 67/548 EC as reproductive toxicant: fertility impairment.

No information for zirconium on adverse effects on development of the offspring is available, adequate for risk assessment and classification and labelling purposes. A test proposal was issued by the registrant for zirconium dioxide.Upon availability of the testing results forzirconium dioxide, the registrant ensures that the dossier for zirconium propionateand the risk assessment will be updated without undue delay.

Additional information

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