Use of this information is subject to copyright laws and may require the permission of the owner of the information, as described in the ECHA Legal Notice.
EC number: 281-897-8
CAS number: 84057-80-7
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:
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
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.
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
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)
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
Two-generation reproductive toxicity study
NOAEL(sub-chronic, dog)= 2060 mg/kg bw/day
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
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
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.
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
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).
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
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
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.
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.
Pre-natal developmental toxicity study
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
Not classified – data lacking
No data available. A testing proposal
is issued by the registrant of zirconium dioxide.
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.
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:
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
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.
not to be classified according to regulation (EC) 1272/2008 or
67/548 EC as
reproductive toxicant: fertility impairment.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
Sellel veebilehel kasutatakse küpsiseid, et tagada lehe parim kasutus.
Welcome to the ECHA website. This site is not fully supported in Internet Explorer 7 (and earlier versions). Please upgrade your Internet Explorer to a newer version.
Do not show this message again