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EC number: - | CAS number: -
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Toxicity to reproduction
Administrative data
- Endpoint:
- screening for reproductive / developmental toxicity
- Remarks:
- based on test type
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- From 27 April to January 2013
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: GLP guideline study with no restrictions.
Cross-referenceopen allclose all
- Reason / purpose for cross-reference:
- reference to same study
- Reason / purpose for cross-reference:
- reference to other study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 012
- Report date:
- 2013
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
- Deviations:
- no
- Principles of method if other than guideline:
- Not applicable
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Reference substance name:
- Reaction mass of N-[2-(2-oxoimidazolidin-1-yl)ethyl]methacrylamide and methacrylic acid
- IUPAC Name:
- Reaction mass of N-[2-(2-oxoimidazolidin-1-yl)ethyl]methacrylamide and methacrylic acid
- Test material form:
- liquid: viscous
- Details on test material:
- - Name of test material (as cited in study report): Reaction mass of N-[2-(2-Oxoimidazolidin-1-yl)ethyl] methacrylamide and methacrylic acid, other name: Sipomer wam II
- Stability under test conditions:
- Storage condition of test material: at room temperature and protected from light
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Laboratories France, l’Arbresle, France.
- Age at study initiation: (P) 10 wks for males, 9 wks for females
- Weight at study initiation: (P) Males: 363-433 g; Females: 189-248 g
- Fasting period before study: no
- Housing: individually housed, except during pairing, in polycarbonate cages (Tecniplast 2154, 940 cm²) with stainless steel lids and containing autoclaved sawdust (SICSA, Alfortville, France). Toward the end of gestation and during lactation with their litter, autoclaved wood shavings (SICSA, Alfortville, France) were provided as nesting material, a few days before delivery and during the lactation period. Each cage contained an object (rat hut) for the enrichment of the environment of the rats. nor applicable
- Diet (e.g. ad libitum): free access to SSNIFF R/M-H pelleted maintenance diet, batch No. 2626975 (SSNIFF Spezialdiäten GmbH, Soest, Germany), which was distributed weekly.
- Water (e.g. ad libitum): free access to bottles containing tap water (filtered with a 0.22 µm filter).
- Acclimation period: 6 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2°C
- Humidity (%): 50 ± 20%
- Air changes (per hr): approximately 12 cycles/hour of filtered, non-recycled air
- Photoperiod (hrs dark / hrs light): 12h/12h
IN-LIFE DATES: From: 30 May 2012 To: 23 July 2012
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- water
- Remarks:
- drinking water, treated by reverse osmosis
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS: The test item was administered as a solution in the vehicle. The test item was mixed with the required quantity of vehicle. The test item dose formulations were prepared on a daily basis and were stored and delivered at room temperature in brown flasks.
DIET PREPARATION
not applicable
VEHICLE
- Justification for use and choice of vehicle (if other than water): not applicable
- Concentration in vehicle: 0; 13.3; 40 and 120/80 mg/mL
- Amount of vehicle (if gavage): constant dosage-volume of 5mL/kg bw/d - Details on mating procedure:
- - M/F ratio per cage: 1/1
- Length of cohabitation: until mating occurs or 14 days have elapsed
- Proof of pregnancy: vaginal plug / sperm in vaginal smear referred to as day 0 of pregnancy
- After ... days of unsuccessful pairing replacement of first male by another male with proven fertility: not applicable
- Further matings after two unsuccessful attempts: no
- After successful mating each pregnant female was caged (how): no data
- Any other deviations from standard protocol: no - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Concentrations of the test item in the dose formulations have been quantified by a validated analytical method.
The validation of the analytical method was conducted in CiToxLAB France/Study No. 38954 VAA and precise details concerning the checked parameters, acceptance criteria and obtained results are documented in the corresponding validation report. The concentration of the test item in samples of each control and test item dose formulation prepared for use in weeks 1, 3 and 5 was determined. - Duration of treatment / exposure:
- in the males:
- 2 weeks before pairing (from study days 1 to 14),
- during the pairing period (3 weeks) (from study day 15 until study days 16 to 28),
- until sacrifice (at least 5 weeks in total) (from study days 17 to 29 until study day 36).
in the females:
- 2 weeks before pairing (from study days 1 to 14),
- during the pairing period (3 weeks) (from study days 15 to 28),
- during gestation (from study days 16 to 29 until study days 36 to 49),
- during lactation until day 4 post-partum inclusive
(from study days 37 to 50 until study days 41 to 54). - Frequency of treatment:
- daily
- Details on study schedule:
- - Age at mating of the mated animals in the study: 12 weeks for males, 11 weeks for females
Doses / concentrations
- Remarks:
- Doses / Concentrations:
0; 66.7; 200 and 600/400 mg/kg bw/d
Basis:
other: based on N-[2-(2-oxoimidazolidin-1-yl)ethyl]methacrylamide and methacrylic acid content.
- No. of animals per sex per dose:
- 10
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: in a preliminary study, the test item was given to rats (3/sex/group), by daily oral administration (gavage) for 1 week at 0, 100, 300 or 1000 mg/kg bw/day. At 1000 mg/kg bw/day, all males had marked to severe clinical signs (ptyalism, piloerection, loud breathing, dyspnea, abdominal breathing, chromorhynorrhea, soiled snout and/or hypoactivity); 1/3 females had ptyalism. There was a minimal decrease in mean body weight (-6.7% vs. controls) at the end of the treatment period and a marked decrease in mean food consumption in males only (-25.7% vs. controls).
At necropsy, 1/3 males (1000 mg/kg bw/day) had a thymus reduced in size and stomach wall with red discoloration. One out of 3 females (300 mg/kg bw/day) had an uterus dilated and with a translucent content.
There were no treatment-related findings at 300 or 100 mg/kg bw/day.
Overall, 1000 mg/kg bw/day were considered to be an excessive dose-level. Therefore, 600 mg/kg bw/day were selected as the high-dose level. The low-dose and mid-dose have been selected using a ratio representing a three-fold interval (i.e. 66.7 and 200 mg/kg bw/day).
On study day 5 of the current study, 1/10 high dose males was euthanized for ethical reason and on study day 6, 3/9 surviving males from the same group had loud breathing, abdominal breathing and/or chromorhinorrhea and 1/10 females had piloerection and loud breathing. Therefore, 600 mg/kg/day was proved to be an excessive dose-level. It was thus decided to lower the dose administered to animals from the high-dose group from study day 6 (400 mg/kg/day instead of 600 mg/kg/day). - Positive control:
- not required
Examinations
- Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: once a day before the treatment period and at least twice a day during the treatment period, including weekends and public holidays.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once a day
BODY WEIGHT: Yes
- Time schedule for examinations: male: on the first day of treatment (day 1), then once a week until sacrifice; female: on the first day of treatment (day 1), then once a week until mated (or until sacrifice) and on days 0, 7, 14 and 20 post-coitum (p.c.) and days 1 and 5 p.p..
FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
WATER CONSUMPTION: No - Oestrous cyclicity (parental animals):
- The estrous cycle stage was determined from a fresh vaginal lavage (stained with methylene blue), each morning during the pairing period, until the females are mated.
- Sperm parameters (parental animals):
- Parameters examined in male parental generation: testis and epididymis weight for all tested males
- Litter observations:
- STANDARDISATION OF LITTERS
Not applicable
PARAMETERS EXAMINED
The following parameters were examined in F1 offspring:
number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain, physical or behavioural abnormalities
GROSS EXAMINATION OF DEAD PUPS:
yes, for external abnormalities. No tissues were preserved. - Postmortem examinations (parental animals):
- SACRIFICE
- Male animals: All surviving animals at the end of the pairing period (at least 5 weeks of treatment in total)
- Maternal animals: All surviving animals on day 5 p.p..
GROSS NECROPSY
- Gross necropsy consisted of external and inernal examinations including the external surfaces, all orifices, the cranial cavity, the external surfaces of the brain and spinal cord, the thoracic, abdominal and pelvic cavities with their associated organs and tissues and the neck with its associated organs and tissues. The numbers of corpora lutea and implantation sites were also recorded for females sacrificed as scheduled on day 5 post-partum.
HISTOPATHOLOGY / ORGAN WEIGHTS
The tissues indicated in Table 7.8.1/1 were prepared for microscopic examination and weighed, respectively. - Postmortem examinations (offspring):
- SACRIFICE
Animals were subjected to postmortem macroscopic examinations.
GROSS NECROPSY
- Gross necropsy consisted of external examinations only. No tissues were preserved.
HISTOPATHOLOGY / ORGAN WEIGTHS
Not applicable as no tissues were preserved. - Statistics:
- Data are compared by one-way analysis of variances and Dunnett test (mean values being considered as normally distributed, variances being considered as homogenous) or by Fischer exact probability test (proportions).
PathData software (version 6.2d2) was used to perform the statistical analysis of organ weight data (level of significance of 0.05 or 0.01). - Reproductive indices:
- pre-implantation loss:
Number of corpora lutea - Number of implantation sites
_____________________________________________ x 100
Number of corpora lutea
post-implantation loss (manually calculated):
Number of implantation sites - Number of live pups
_____________________________________________ x 100
Number of implantations
mating index:
Number of mated animals
_____________________ x 100
Number of paired animals
fertility index:
Number of pregnant female partners
_______________________________ x 100
Number of mated pairs
gestation index:
Number of females with live born pups
________________________________ x 100
Number of pregnant females - Offspring viability indices:
- live birth index:
Number of live born pups
_____________________ x 100
Number of delivered pups
viability index on day 4 post-partum:
Number of surviving pups on day 4 post-partum
_______________________________________ x 100
Number of live born pups
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Mortality at 600/400 mg/kg bw/d. See more details below
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Body weight loss between days 1 and 8 for the males in the highest tested group. Lower body weight gain during the period of days 1 to 15 for the females treated with the top dose. Then mean body weight was comparable to the one of the control group.
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- Body weight loss between days 1 and 8 for the males in the highest tested group. Lower body weight gain during the period of days 1 to 15 for the females treated with the top dose. Then mean body weight was comparable to the one of the control group.
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
- Description (incidence and severity):
- see details below
- Other effects:
- effects observed, treatment-related
- Description (incidence and severity):
- Test substance intake: Decrease in mean food consumption in boh sexes from the high dose-group during the premating period. During the lactation period, lower mean food consumption than in the control group in the high dose group (but not statistically significant).
Reproductive function / performance (P0)
- Reproductive function: oestrous cycle:
- no effects observed
- Reproductive function: sperm measures:
- not examined
- Reproductive performance:
- effects observed, treatment-related
- Description (incidence and severity):
- See tables 7.8.1/3 and 7.8.1/4 and details below
Details on results (P0)
REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS): In the group treated at 600/400 mg/kg/day, the pre and post-implantation losses were higher than in the control group and resulted in a non-statistically significant lower mean number of pups delivered (12.7 vs. 13.2 in the Historical Control Data). This minor difference was mainly due to one litter (with 57.1% of post-implantation loss) and therefore a test item treatment-related effect was considered unlikely.
GROSS PATHOLOGY (PARENTAL ANIMALS): gas distension of the stomach/cecum was found in 3/5 decedents, associated in one male with red and depressed foci which correlated with microscopic gastric erosions. In another decedent male, the thymus was gelatinous, which correlated with interlobular edema, and there was stress-associated thymic lymphoid atrophy and increased apoptotic cell numbers microscopically. In the surviving animals, few macroscopic findings were noted at the end of the treatment period in males but were of those commonly recorded in the Sprague-Dawley rat and none were considered to be related to the test item administration. There were no macroscopic findings in females.
HISTOPATHOLOGY (PARENTAL ANIMALS): The cause of deaths/morbidity in these rats was not evident at microscopic examination. In the surviving animals, there were no test item-related changes in the testis, epididymis, ovaries and oviducts.
Effect levels (P0)
open allclose all
- Dose descriptor:
- NOAEL
- Remarks:
- Parental toxicity
- Effect level:
- 200 mg/kg bw/day (actual dose received)
- Based on:
- other: Dose adjusted for N-[2-(2-oxoimidazolidin-1-yl)ethyl]methacrylamide and methacrylic acid content.
- Sex:
- male/female
- Basis for effect level:
- other: Mortality, clinical signs and effects on body weight and food consumption observed at 600/400 mg/kg bw/d
- Dose descriptor:
- NOAEL
- Remarks:
- Parental toxicity
- Effect level:
- 279 mg/kg bw/day (actual dose received)
- Based on:
- other: Dose of substance as registered (including impurities residual water necessary for stability)
- Sex:
- male/female
- Basis for effect level:
- other: Mortality, clinical signs and effects on body weight and food consumption observed at 557/836 mg/kg bw/d
- Dose descriptor:
- NOAEL
- Remarks:
- Reproductive performance
- Effect level:
- 400 - 600 mg/kg bw/day (actual dose received)
- Based on:
- other: Dose adjusted for N-[2-(2-oxoimidazolidin-1-yl)ethyl]methacrylamide and methacrylic acid content.
- Sex:
- male/female
- Basis for effect level:
- other: Non-statistically significant increase in post-implantation losses in the highest dose group which was mainly due to one litter and therefore considered not to be adverse.
- Dose descriptor:
- NOAEL
- Remarks:
- Reproductive performance
- Effect level:
- 557 - 836 mg/kg bw/day (actual dose received)
- Based on:
- other: Dose of substance as registered (including impurities residual water necessary for stability)
- Sex:
- male/female
- Basis for effect level:
- other: Non-statistically significant increase in post-implantation losses in the highest dose group which was mainly due to one litter and therefore considered not to be adverse.
Results: F1 generation
General toxicity (F1)
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- See details below and in Table 7.8.1/5.
- Mortality / viability:
- mortality observed, treatment-related
- Description (incidence and severity):
- See details below.
- Body weight and weight changes:
- no effects observed
- Sexual maturation:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- See details below and in Table 7.8.1/5.
- Histopathological findings:
- not examined
Details on results (F1)
CLINICAL SIGNS AND GROSS PATHOLOGY (OFFSPRING): There were dose-related increases in the percentages of litters with pups having clinical signs from 200 mg/kg/day. These increases were mainly due to litter Y23635 (200 mg/kg/day) and litter Y23648 (600/400 mg/kg/day) and there were no dose-related increases in the percentage of litters with pups having gross external abnormalities. Therefore a test item treatment-related effect was considered unlikely.
Effect levels (F1)
open allclose all
- Dose descriptor:
- NOAEL
- Remarks:
- toxicity on progeny
- Generation:
- F1
- Effect level:
- 400 - 600 mg/kg bw/day (actual dose received)
- Based on:
- other: Dose adjusted for N-[2-(2-oxoimidazolidin-1-yl)ethyl]methacrylamide and methacrylic acid content.
- Sex:
- male/female
- Basis for effect level:
- other: Viability indexes were slightly reduced in the 200 and 600 mg/kg bw/d groups but still comparable to historical control and therefore considered not to be adverse.
- Dose descriptor:
- NOAEL
- Remarks:
- toxicity on progeny
- Generation:
- F1
- Effect level:
- 557 - 836 mg/kg bw/day (actual dose received)
- Based on:
- other: Dose of substance as registered (including impurities residual water necessary for stability)
- Sex:
- male/female
- Basis for effect level:
- other: Viability indexes were slightly reduced in the 557 and 836 mg/kg bw/d groups but still comparable to historical control and therefore considered not to be adverse.
Overall reproductive toxicity
- Reproductive effects observed:
- not specified
Any other information on results incl. tables
Table 7.8.1/2 : Clinical signs observed in the surviving animals
Sex |
Male |
Female |
||||||
Dose-level (mg/kg/day) |
0 |
66.7 |
200 |
600/400 |
0 |
66.7 |
200 |
600/400 |
Piloerection |
0 |
1 |
0 |
4 |
0 |
0 |
0 |
0 |
Round back |
0 |
0 |
0 |
2 |
0 |
0 |
0 |
0 |
Emaciated appearance |
0 |
0 |
0 |
2 |
0 |
0 |
0 |
0 |
Aggressive behaviour |
1 |
2 |
0 |
1 |
0 |
0 |
0 |
0 |
Loud breathing |
0 |
0 |
0 |
5 |
0 |
0 |
2 (P/G) |
2 (P/G) 3 (L) |
Abdominal breathing |
0 |
0 |
0 |
2 |
0 |
0 |
0 |
0 |
Ptyalism |
0 |
1 |
0 |
8 |
0 |
0 |
0 |
2 (P) 5 (G) |
Aera of hair loss on forelimb, abdomen or neck |
1 |
2 |
1 |
0 |
0 |
1 (P/G/L) |
0 |
0 |
Cutaneous lesion on neck |
1 |
0 |
2 |
1 |
1 (G) |
0 |
0 |
0 |
Abnormal growth of teeth |
0 |
0 |
1 |
0 |
0 |
0 |
0 |
0 |
Chromodacryorrhea |
0 |
0 |
0 |
0 |
1 (P/G) |
0 |
0 |
0 |
P: premating and mating periods, G: gestation period, L: lactation period.
Table 7.8.1/3:Mating and fertility data results
Dose-level (mg/kg/day) |
0 |
66.7 |
200 |
600/400 |
Number of animals paired (M + F) |
10 + 10 |
10 + 10 |
10 + 10 |
8 + 8 (a) |
Number of males mated |
10 |
10 |
10 |
7(b) |
Number of females mated |
10 |
10 |
10 |
7(b) |
Mean number of days taken to mate |
3.1 |
3.8 |
2.4 |
3.6 |
Number of pregnant females |
10 |
10 |
10 |
7 |
Male fertility index(%) |
100 |
100 |
100 |
100 |
Female fertility index(%) |
100 |
100 |
100 |
100 |
(a): one female was sacrificed the first day of pairing period and another one was found dead before the start of the pairing period.
(b):one female was sacrificed after a 5-day pairing period with no evidence of mating.
Table 7.8.1/4:Delivery data results
Dose-level (mg/kg/day) |
0 |
66.7 |
200 |
600/400 |
Number of pregnant females |
10 |
10 |
10 |
7 |
Number of females which delivered |
10 |
10 |
10 |
7 |
Mean duration of gestation (days) |
21.2 |
21.1 |
21.1 |
21.3 |
Mean number ofcorpora lutea |
16.4 |
17.0 |
15.2 |
15.9 |
Mean number of implantations |
16.2 |
16.8 |
14.8 |
15.1 |
Mean pre-implantation loss (%) |
1.1 |
1.3 |
2.9 |
5.1 |
Mean number of pups delivered |
14.6 |
15.0 |
13.5 |
12.7 |
Mean post-implantation loss (%)a |
10.8 |
10.9 |
10.1 |
17.5 |
a: manually calculated, no statistics performed.
Table 7.8.1/5: Clinical signs and gross necropsy results in the offspring
|
Clinical signs |
Gross external abnormalities |
||||||
Dose-level (mg/kg/day) |
0 |
66.7 |
200 |
600/400 |
0 |
66.7 |
200 |
600/400 |
Scab on tail |
|
Y23621-3 |
|
|
|
|
|
|
Dehydration |
|
Y23621-13 |
|
|
|
|
|
|
Emaciated appearance |
|
Y23621-13 |
Y23635-6 Y23635-10 Y23635-12 Y23639-14 |
Y23644-6 |
|
|
Y23635-6 |
|
Hind limb necrosis |
|
|
Y23631-8 |
Y23648-7 |
|
|
Y23631-8 |
Y23648-7 |
Generalized pallor |
|
|
Y23635-6 Y23635-12 |
|
|
|
|
|
Cold to the touch |
|
|
Y23635-6 Y23635-12 Y23639-14 |
Y23648-12 |
|
|
|
|
Hematoma on back/abdomen |
|
|
|
Y23643-9 |
|
|
|
|
Hematoma on hind limb |
|
|
|
Y23648-12 |
|
|
|
|
|
|
|
|
|
|
|
|
|
Number of affected pups |
0 |
2 |
5 |
4 |
0 |
0 |
2 |
1 |
Number of litter examined |
10 |
10 |
10 |
7 |
10 |
0 |
10 |
7 |
Number of affected litters |
0 |
1 |
3 |
3 |
0 |
0 |
2 |
1 |
In brackets: percentage (%) of affected litters.
Applicant's summary and conclusion
- Conclusions:
- Based on the experimental conditions of this study:
- the No Observed Adverse Effect Level (NOAEL) for parental toxicity was considered to be 200 mg/kg/day (based on mortality, clinical signs and effects on body weight and food consumption recorded for both sexes at 600/400 mg/kg/day),
- the NOAEL for reproductive performance (mating, fertility and delivery data) was considered to be 600/400 mg/kg/day,
- the NOAEL for toxic effects on progeny was considered to be 600/400 mg/kg/day. - Executive summary:
The potential effects of the Reaction mass of N-[2-(2-Oxoimidazolidin-1-yl)ethyl] methacrylamide and methacrylic acid, on reproductive and developmental parameters were assessed in an OECD 421 compliant study following daily oral administration (by gavage) to male and female rats from before mating, through mating and, for females, through gestation until day 4post-partum (p.p.).
Three groups of ten male and ten female Sprague-Dawley rats received the test item, Reaction mass of N-[2-(2-Oxoimidazolidin-1-yl)ethyl]methacrylamide and methacrylic acid (batch No. MWAM12059A), daily, by oral administration (gavage), 2 weeks before mating, during mating and, for the males, until sacrifice, for the females, throughout gestation until day 4p.p., at dose-levels of 66.7, 200 or 600/400 mg/kg/day (i.e, 93, 279 and 836/557 mg/kg bw/day in terms of registered substance). An additional group of ten males and ten females received the vehicle control, drinking water, under the same experimental conditions. The dosing volume was 5 mL/kg/day.
Animals were checked daily for clinical signs and mortality. Body weights and food consumption were recorded weekly until mating and then at designated intervals throughout gestation and lactation. The animals were paired for mating after 2 weeks of treatment and the dams were allowed to litter and rear their progeny until day 5p.p.. The total litter sizes and numbers of pups of each sex were recorded after birth. The pups were observed daily for clinical signs of toxicity and pup body weights were recorded on days 1 and 5p.p..
The males were sacrificed after completion of the mating period. Dams were sacrificed on day 5p.p.. Body weights and selected organs weights were recorded and a complete macroscopicpost-mortemexamination performed, with particular attention paid to the reproductive organs.
Microscopic examination was performed on the reproductive organs from control and high-dose males and females at terminal sacrifice and from premature decedents, and on all macroscopic observations in all groups.
Pups, including those found dead before study termination, were also submitted for a macroscopicpost-mortemexamination.
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The test item concentrations in the administered dose formulations analyzed in weeks 1, 3 and 5 remained within an acceptable range of -9.0% to -0.4% when compared to the nominal values. Reaction mass of N-[2-(2-Oxoimidazolidin-1-yl)ethyl]methacrylamide and methacrylic acid was not detected in control samples
As death occurred in one male exposed to the dose of 600 mg/kg bw/d on day 5 (animal sacrificed for ethical reason), the high-dose level was lowered to 400 mg/kg bw/d for the rest of the study period. An another male was euthanized for ethical reason on day 8 and 3/10 females were found dead or sacrificed on day 8, 15 and 20 respectively, at the highest dose-level. Before sacrifice or death, animals suffered of ptyalism, piloerection, hypoactivity, chromorhinorrhea, dyspnea, loud and abdominal breathing and presented a round back and emaciated appearance or were cold to the touch. In the surviving animals clinical signs were observed (piloerection, round back, emaciated appearance, loud and abdominal breathing) and were considered to be related to the test item treatment. In the surviving animals, few macroscopic findings were noted at the end of the treatment period in males but were of those commonly recorded in the Sprague-Dawley rat and none were considered to be related to the test item administration.
With regards to reproductive and developmental parameters, the following observations were made:
Mating and fertility data: there were no effects on the mean number of days taken to mate. All mated females were pregnant.
Delivery data: there were no obvious treatment related effects. In the group treated at 600/400 mg/kg/day, the post-implantation loss was higher than in the control group but with no statistical significance. This difference was mainly due to one litter (with 57.1% of post-implantation loss).
Pups mortality: there were no obvious treatment-related effects on pup mortality.
Pups clinical signs and external abnormalities: there were no test item treatment-related findings.
Pup viability: there were no treatment-related effects on live birth and lactation indexes. In the groups treated at 200 or 600/400 mg/kg/day, the viability indexes were statistically significantly reduced (94.8% and 95.5% respectively,vs.controls) but still comparable to Historical Control Data (94.9%) and therefore considered not to be adverse.
Pup body weight: there were no effects on mean pup body weights and mean pups body weight changes when compared with controls.
Pup sex ratio: there were no treatment-related effects on sex ratio (% of male pups) both on days 1 and 5p.p..
Pathology: At terminal sacrifice, the test item administration did not induce any organ weight or macroscopic changes. There were no significant microscopic findings in the testis, epididymis, ovaries and oviducts.
In conclusion, based on the experimental conditions of this study:
- the No Observed Adverse Effect Level (NOAEL) for parental toxicity was considered to be 200 mg/kg/day (based on mortality, clinical signs and effects on body weight and food consumption recorded for both sexes at 600/400 mg/kg/day),
- the NOAEL for reproductive performance (mating, fertility and delivery data) was considered to be 600/400 mg/kg/day,
- the NOAEL for toxic effects on progeny was considered to be 600/400 mg/kg/day
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