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EC number: 289-214-5
CAS number: 86261-90-7
Combined repeated dose study in rats (OECD TG 422), gavage: NOAEL parental toxicity: 100 mg/kg bw/day in males and 300 mg/kg bw/day in females (due to increased organ weights; GLP, Rohm & Haas 2002)
The toxicity of ureido methacrylate after
repeated oral dosing was assessed by a subacute study which was
performed with rats for 8 weeks.
The possible toxic effects, including
potential neurotoxicity, of the test substance, ureido methacrylate
(purity unknown), were evaluated in a GLP conform combined repeated dose
study with a Reproduction/ Developmental screening test in rats
following OECD test guideline 407 (Rohm & Haas 2002). The test substance
was administered orally by gavage to four groups of 12 male and 12
female Crl:CD BR rats once daily for eight weeks. Dose levels were 0,
100, 300, and 1000 mg a.i./kg bw/day, administered at a dosage volume of
5 mL/kg. The control group received the vehicle, double-distilled water,
on a comparable regimen at a dosage volume of 5 ml/kg. Males and females
of the same treatment group were mated 1:1 two weeks after the beginning
of the treatment.
During the treatment period, each rat was
observed twice daily for morbidity or mortality. General clinical
observations were made at least once daily. Body weight was determined
weekly for males throughout this study. Females were weighed weekly
until cohabitation, on Gestation Days (G) 0, 3, 6, 9, 12, 15, 18, and
20, and on Postnatal Days (PND) 0 and 4. Food consumption was determined
weekly for male and female animals until cohabitation. Food consumption
was not measured for either sex during cohabitation due to the inability
to ascribe consumption to individual animals. Females feed consumption
was measured from G0-7, G7-14, G14-21 and from PND 0-4 during lactation.
The weekly feed consumption was resumed for males after the mating
period and continued throughout the study. Functional Observational
Battery (FOB) and motor activity evaluations were performed on week 5
(males) and week 7 (females). After eight weeks,
overnight fasted animals were euthanized and necropsied. Hematology and
clinical chemistry measurements were performed on all animals at
terminal necropsy. Animals were fasted overnight and blood samples were
collected just prior to terminal necropsy. Microscopic examination of
the studied organs were performed for 5 (randomly selected) parental
animals/sex in the high dose group and control group. All tissues
exhibiting gross pathological changes were examined microscopically.
Treatment-related decreases in hemoglobin
(6%), hematocrit (7%), and mean cell volume (4%) were noted in males at
1000 mg a.i./kg bw/day. In addition, platelet counts were increased
(14%) at this level. Treatment-related increases in absolute and
relative kidney weights (10-11%) and in absolute and relative liver
weights (20%) were noted in both sexes at 1000 mg a.i./kg. Absolute and
relative liver weights were also increased (12-16%) in males at 300 mg
a.i./kg. Other effects were considered as incidental and not
treatment-related. Microscopic examinations in the relevant organs
revealed no complementary effects seen in liver and kidney weights,
these observations are considered as not adverse.
Based on the results of this study, the
NOAEL (no-observed-effect level) for systemic toxicity of ureido
methacrylate administered orally is 100 mg a.i./ kg bw/day in males and
300 mg a.i./ kg bw/day in females.
Additionally, data were adopted by
read-across from a reliable chronic 2-year toxicity study of methyl
methacrylate (CAS 82-60-6) in rats and from a two-generation
reporduction toxicity study (see IUCLID section 7.8) in rats. Due to the
structural similarities, the comparable results can be expected for
ureido methacrylate. In addition, 3 subacute studies with methyl
methacrylate are reported.
Twenty-five male and female Wistar rats (P
parental generation) were administered with MMA at 0; 50; 150 and 400
mg/kg body weight/day in an OECD 416 2 generation reproductive toxicity
study (BASF, 2009). At least 73 days after the beginning of treatment, P
animals were mated to produce a litter (F1). Mating pairs were from the
same dose group and F1 animals selected for breeding were continued in
the same dose group as their parents. Groups of 25 males and 25 females,
selected from F1 pups to become F1 parental generation, were treated
with the test substance at dosages of 0; 50; 150 and 400 mg/kg body
weight/day post weaning, and the breeding program was repeated to
produce F2 litter. No signs of systemic toxicity were observed other
than slightly reduced body-weight gain at 150 mg/kg bw/d and above in
the 2-gen study. Reduced body weights were judged to be the direct
result of reduced food intake and therefore not an adverse finding.
Consequently, the NOAEL was confirmed at the highest dose studied (450
Twenty-five male and female Wistar rats were
administered three doses of methyl methacrylate in the drinking water
for two years (Borzelleca et al. 1964). Initial doses of 6, 60 or 2000
ppm were partially raised to 7, 70 and 2000 ppm after 5 months.
A special design was employed to reduce the
volatilization and measurements which showed that the methyl
methacrylate concentrations remained within 15% of the nominal
concentration for 72 hours. Body weight depression was also observed at
2000 ppm but it did not persist beyond the first few weeks of the study.
Significant depression of fluid consumption was observed at 2000 ppm,
although this tended to regress at the end of the study. Individual
observations of depressed food consumption tended to parallel periods of
depressed growth. There were significantly increased kidney ratios for
female rats at 2000 ppm. These effects were believed to be a consequence
of reduced food intake and reduced body weights, and in the absence of
any histopathology, were considered as not biologically relevant.
Therefore the NOAEL is considered to be >= 2000 ppm, corresponding to
124.1 mg/kg bw/day and 164 mg/kg bw/day, for males and females,
respectively, on the basis of treatment specific fluid consumption rates
and body weights.
In 3 subacute toxicity studies, results
comparable to the findings of the chronic 2 year study with methyl
methacrylate were observed. Edward (1975) reported a NOAEL of >18800 ppm
in rats after 5 weeks oral administration. Husain (1985) and Ghanayem
(1986) both showed a NOAEL of 200 mg/kg bw/day after 28 d respectively
14 days oral exposure of rats.
Conclusion for hazard assessment:
Data from read across with methyl
methacrylate show a NOAEL of 124.1 mg/kg bw/day (chronic exposure) and
of about 200 mg/kg bw/day after subacute exposure in rats. The NOAEL of
a subacute study (OECD 422) with ureido metharcrylate was found to be
100 mg/kg bw/day. Due to the structural similarities of both
methacrylates a similar mode of action can be assumed. Thus, data from
both methacrylates show comparable NOAELs after chronic and subacute
exposure. Thus, for ureido methacrylate also a NOAEL in the range of the
subacute study is expected also after longer subchronic exposure. In
conclusion, DNELs are derived from the subacute study with ureido
methacrylate applying a factor of 6 for extrapolation from subacute to
chronic which is believed to be a worst case assumption. No further
subchronic testing with allyl methacrylate is needed for animal welfare
In accordance with column 2 of REACH Annex
IX, the test repeated dose toxicity after inhalation (required in
section 8.6) does not need to be conducted as a repeated dose toxicity
study for oral (28 days, OECD 422) application is available. In addition
read across to subchronic oral studies with methyl methacrylate was
In accordance with column 2 of REACH Annex
IX, the test repeated dose dermal toxicity (required in section 8.6)
does not need to be conducted as a repeated dose toxicity study for oral
(28 days, OECD 422) application is available. In addition read across to
subchronic oral studies with methyl methacrylate was done.
Based on the results obtained, there is no
indication given for classification regarding repeated dose toxicity
according to 67/548/EEC and Regulation (EC) No 1272/2008 (GHS, CLP).
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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