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EC number: 403-590-1
CAS number: 104815-18-1
A toxicokinetic assessment was conducted in accordance with REACH Annex
VIII 8.8.1. The substance Ammonium
naphthalenecarboxamidato(2-)]ferrate (1-) (DL-N33) is a mono-constituent
organometallic with a purity of 95-98% with a typical concentration of
96.6%. There are 23 minor organic impurities; none are present at >1%
with a total typical concentration of 3.4%.
A full ADME toxicokinetic study in the rat with DL-N33 is not available.
In vivo studies in rats covering the oral route are available (acute
oral toxicity, 28-day repeated dose toxicity, screening for
reproductive/developmental toxicity). In vivo studies covering the
dermal route are available (guinea pig maximisation test, skin
irritation study in rabbits). An acute inhalation toxicity study in rats
is available. Further details on endpoints are available in the IUCLID 6
registration dossier. The toxicokinetic analysis is based on the
physicochemical and in vivo toxicological data.
The absorption rates of 50% (oral), 10% (dermal) and 100% (inhalation)
are accepted for chemical risk assessment purposes.
1. Physicochemical properties
In accordance with the ECHA Guidance on Information Requirements and
Chemical Safety Assessment, Chapter R.7C Section R.7.12 (Endpoint
Specific Guidance), the physicochemical properties can provide an
insight into the potential behaviour of DL-N33 in the body.
Absorption - oral
The molecular weight of DL-N33 is 905 g/mol and is outside the range for
favourable oral absorption (<500 g/mol). DL-N33 is highly insoluble in
water (0.007 mg/L at 21°C) and moderately lipophilic (log Kow >4.9)
These characteristics will not facilitate transport via passive
diffusion and absorption of DL-N33 is more likely via the lymphatic
system through micellular solubilisation.
Absorption – dermal
The water insolubility, log Kow and molecular weight of DL-N33 indicate
dermal exposure will be very low.
Absorption – inhalation
DL-N33 has very low volatility (1.3x10-12 Pa at 25 °C) but is also
considered a dusty solid. The particle size distribution report
indicates that 19.2% of particles are <10.2 μm and 3.83% are <5.4 μm).
This indicates that a fraction of the particles are available in the
inhalable fractions of air (<100 μm). Particles with aerodynamic
diameters of above 1-5 μm have the greatest probability of settling in
the nasopharyngeal region whereas particles with aerodynamic diameters
below 1-5 μm are most likely to settle in the tracheo-bronchial or
pulmonary regions. As there are fractions in both these categories, the
substance is likely to be distributed throughout the respiratory tract
upon inhalation. Greater than 50% of particles will be able to penetrate
the alveolar region of the respiratory tract (<15 µm). As an insoluble
dust, DL-N33 could be coughed or sneezed out of the body or swallowed
(refer to oral absorption). Based on the water insolubility and
lipophilicity, it is likely that any absorption will be very low and
occur via micellular solubilisation and the lymphatic system.
Based on the molecular weight and water insolubility, DL-N33 will not be
distributed widely. DL-N33 is expected to be excreted mainly unchanged
in the faeces.
2. Information from other studies in the dossier
In the acute oral toxicity study in Crl:CD(SD)BR rats (OECD 401), no
signs of toxicity were observed other than pilo-erection throughout day
1 and day 2. There were no other clinical signs and recovery was
complete by Day 3. The LD50 (male/female) was >5000 mg/kg bw.
In the sub-acute toxicity study (Annex V; Method B7), DL-N33 was
administered by oral gavage to Charles River Crl:CD(SD)BR rats
(5/sex/group) in 1% aqueous methylcellulose at 0, 62.5, 250 or 1000
mg/kg bw/day for 28 days, 7 days per week. No treatment-related deaths
or clinical signs of toxicity. Mean haemoglobin concentration decreased
(p <0.05) in top dose females relative to controls and was marginally
lower than the lower end of the historical value range. No other
treatment-related effects were observed. No gross or microscopic
treatment-related effects were observed. The NOEL (male/female) was 250
mg/kg bw/day and the NOAEL (male/female) was 1000 mg/kg bw/day.
In the reproduction/developmental toxicity screening test (OECD
421/GLP), DL-N33 was administered to 4 groups of Wistar
Han:RccHanTM:WIST rats (10 animals/sex/group) by gavage in arachis oil
at dose levels of 0, 30, 300 and 1000 mg/kg bw/day, 7 days per week, for
up to eight weeks (including a two week maturation phase, pairing,
gestation and early lactation for females). There were no unscheduled
deaths. There were no treatment-related effects on any parameters in the
study. The NOEL (male/female) was 1000 mg/kg bw/day.
These studies together with the physicochemical data indicate that
absorption via the oral route is likely to be low. For chemical safety
assessment purposes, based on the physicochemical properties and
information in the dossier, an oral absorption rate of 50% is accepted.
In a skin irritation study in rabbits (OECD 404), there were no skin
reactions at any timepoint. In the guinea pig maximisation test (OECD
406), there was evidence of sensitisation in control animals at both
challenge doses (2/19 positive at 25% and 4/19 positive at 50%) so the
positive results in the test groups are doubtful (4/20 at 25% and 5/20
at 50%). Overall, DL-N33 is not sensitising and not a skin irritant so
dermal absorption is considered to be very low. The ECHA guidance
criteria (Chapter R.7C) state that 10% dermal absorption is used when
the molecular weight of the substance is >500 and the log Kow is <-1 or
>4, otherwise 100% dermal absorption is used. The molecular weight of
DL-N33 is 905 g/mol and the log Kow is >4.9 so 10% dermal absorption is
accepted for chemical safety assessment purposes.
In an acute inhalation toxicity study (GLP), groups of Sprague-Dawley
rats (5/sex) were given DL-N33 (whole body) at a dose of 3.37mg/L air
(limit test; maximum attainable concentration) for 4 hours. There were
no mortalities in males or females. Signs of exposure were confined to
staining of the skin, fur and tail by the substance. There was a small
reduction in food and water consumption in male exposed rats on day 1.
The lungs of all treated animals were coloured greyish due to the
substance. Lung to bodyweight ratios were unaffected. No
treatment-related changes were found in tissues examined microscopically
(lungs, liver, kidneys). The LC50 (male/female) was >3.37mg/L air.
These studies together with the physicochemical data indicate that
absorption via the inhalation route is likely to be low. For chemical
safety assessment purposes, an inhalation absorption rate of 100% is
accepted, based on the most conservative approach.
Based on the lack of adverse effects noted in the 28-day repeated dose
toxicity study and reproduction/developmental toxicity screening test,
together with the molecular weight, water insolubility and
lipophilicity, DL-N33 is not distributed widely and is likely to be
excreted mainly unchanged in the faeces.
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.
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