Registration Dossier
Registration Dossier
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EC number: 240-714-1 | CAS number: 16669-27-5
Toxicological information
Endpoint summary
Administrative data
Key value for chemical safety assessment
Effects on fertility
Description of key information
There is no study available on reproductive toxicity for the target substance Docosyl methacrylate. Therefore, read-across from studies performed with the structurally analogous Dodecyl methacrylate and with the primary metabolite Docosan-1-ol (Behenyl alcohol, CAS 661-19-8) was performed. In a study similar to OECD TG 421 performed in rats with Behenyl alcohol, no effects on the female and male reproductive organs, sperm counts or placental weights were detected. The NOAEL for reproductive toxicity was 1000 mg/kg bw/day, which was the highest dose tested. In an OECD TG 422 study performed with Dodecyl methacrylate, the NOAEL for reproductive toxicity in rats was 1000 mg/kg bw/day, while no effects on the reproductive organs and performance were observed.
Link to relevant study records
- Endpoint:
- screening for reproductive / developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- study well documented, meets generally accepted scientific principles, acceptable for assessment
- Qualifier:
- according to guideline
- Guideline:
- other: ICH Harmonised Tripartite Guidelines for Detection of Toxicity to Reproduction for Medicinal Products
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
- Principles of method if other than guideline:
- A fertility and reproduction study in rats administered a maximum dose of 1000 mg/kg bw/day Docosan-1-ol was conducted.
- GLP compliance:
- yes
- Remarks:
- Huntingdon Life Sciences Ltd (Suffolk, England)
- Limit test:
- no
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River (UK) Limited (Margate,Kent, England)
- Age at study initiation: (P) males: 6 to 7 weeks; females: 10 to 11 weeks
- Weight at study initiation: (P) Males:193 and 240 g; Females: 208 and 262 g;
- Housing: TR18 stainless-steel cage (Modular Systems and Developments Company Limited, Hereford, England); during mating period, 1 male and 1 female were
housed in a RB3-modified high-grade polypropylene cage with stainless-steel mesh lids and floors (North Kent Plastic Cages Limited, Erith, Kent, England).
- Diet: ad libitum, expanded rodent diet (Special Diets Services Ltd., Witham, Essex, England) containing no added antibiotic, or other chemotherapeutic
or prophylactic agent
- Water: ad libitum, tap water
- Acclimation period: 6 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18°C
- Humidity (%): 55%
- Photoperiod (hrs dark / hrs light): 12 hours/12 hours - Route of administration:
- oral: gavage
- Vehicle:
- other: 1% w/w Tween 80
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
Whe required amount of behenyl alcohol was weighed into a glass container and heated (approximately 80°C) until molten using an electric mantle.
An appropriate volume of vehicle (1% Tween 80) was heated in a water bath to at least 75°C and then combined with the molten behenyl alcohol under continuous magnetic stirring, to a concentration of 20% behenyl alcohol. The resulting suspension was slowly cooled, with homogenization to a temperature of below 60°C, and then further cooled in a water bath to a temperature of 30°C. The 20% behenyl alcohol suspension was prepared weekly.
The lower concentrations were prepared on the day of use by dilution of the 20% suspension with 1% w/w aqueous Tween 80.
VEHICLE
- aqueous Tween 80
- Amount of vehicle (if gavage): 1%
Animals received the test material or vehicle control formulations by gavage, at volume-dosage of 5 mL/kg bw, using an 8 or 10 choke rubber catheter. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- The composition and stability of behenyl alcohol were documented throughout the study.
- Duration of treatment / exposure:
- Males were treated with Behenyl alcohol daily for 71 days prior to mating, during mating, and until termination. Females were treated with the test
substance for 15 days prior to mating, during mating, and up to Day 17 of gestation. - Dose / conc.:
- 0 mg/kg bw/day
- Dose / conc.:
- 10 mg/kg bw/day
- Dose / conc.:
- 100 mg/kg bw/day
- Dose / conc.:
- 1 000 mg/kg bw/day
- No. of animals per sex per dose:
- 44 (22 males and 22 females)
- Control animals:
- yes, concurrent vehicle
- Positive control:
- none
- Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
DETAILED CLINICAL OBSERVATIONS: Yes / No / No data
- Time schedule:
BODY WEIGHT: Yes
- Time schedule for examinations: twice weekly (males), on Gestation Days 0, 3, 7, 10, 14, 18, and 20 (females)
FOOD CONSUMPTION AND COMPOUND INTAKE:
Prior to mating,food and water consumption for males and females was recorded weekly and daily, respectively. During the gestation
period, food and water consumption was measured only for females during the following time periods: Gestation Days 0 to 2, 3 to 6, 7 to 9,
10 to 13, 14 to 17, and 18 to 19, inclusive.
- Oestrous cyclicity (parental animals):
- 10 days before the mating period began, vaginal smear samples were obtained daily from all females to assess the regularity, as well as the duration of estrous
cycles. - Sperm parameters (parental animals):
- The left vas deferens was ligated to obtain a 5 μL sample from the cauda epididymis to assess for motility according to the following grades:
no sperm motile; few sperm motile; most sperm motile, slow moving; or most sperm motile, fast moving. - Postmortem examinations (parental animals):
- Females:
- killed on Day 20 of gestation by carbon dioxide inhalation, and uterine contents examined
- each female macroscopically examined for evidence of disease or adverse reaction
- number of corpora lutea in each ovary counted
- reproductive tract, including ovaries dissected out
- for each female, the numbers of pre- and post-implantation sites, early and late resorption sites, and viable fetuses, as well as the distribution of fetuses in each uterine horn, examined
- uterus of any female presumed to be nonpregnant was stained using 10% aq (v/v) ammonium sulfide solution and examined for implantation sites
Males:
- reproductive organs weighed - Postmortem examinations (offspring):
- - each fetus weighed, subjected to detailed external examination
- placental weights were recorded and examined macroscopically for any abnormalities
- neck, thoracic, and abdominal cavities were removed from half of the fetuses, the contents of the thoracic and abdominal cavities were examined, and sex was recorded
- fetuses subjected to a skeletal examination - Statistics:
- To test the statistical significance of suggestive intergroup differences, one-way analysis of variance and t test were performed on body weights, body weight
changes, and food and water consumption. Organ weights were evaluated by Dunnett’s or Behren’s-Fisher’s tests. Nested analysis of variance and weighed
t test were conducted on fetal and placental weights. Differences with an associated probability of P<0.05 were deemed to be statistically significant. - Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Description (incidence):
- One male treated with 1000 mg/kg bw/day and demonstrating abdominal distension, pallor, ptosis, irregular respiration, and a decrease in body weight was killed during Week 6.
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
- Reproductive function: oestrous cycle:
- no effects observed
- Reproductive function: sperm measures:
- no effects observed
- Reproductive performance:
- no effects observed
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- reproductive toxicity
- Effect level:
- 1 000 mg/kg bw/day
- Sex:
- male/female
- Basis for effect level:
- other: highest dose tested
- Critical effects observed:
- not specified
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- developmental toxicity
- Generation:
- F1
- Effect level:
- 1 000 mg/kg bw/day
- Sex:
- male/female
- Basis for effect level:
- other: highest dose tested
- Critical effects observed:
- not specified
- Reproductive effects observed:
- no
- Endpoint:
- screening for reproductive / developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Study period:
- 12-Oct-2004 to 06-Dec-2004
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
- Version / remarks:
- adopted on 22 March 1996
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Number: 88 rats (44 males and 44 females)
- Source: Sprague-Dawley, Crl CD® (SD) IGS BR, Caesarian Obtained, Barrier Sustained-Virus Antibody Free, (COBS-VAF®); Charles River Laboratories France, L’Arbresle, France.
- Age at study initiation: males were 8 weeks old and females were 10 weeks old
- Weight at study initiation: males: mean body weight of 317 g (range: 296 g to 345 g); females mean body weight of 223 g (range: 199 g to 261 g)
- Housing: The animals were individually housed (except during mating) in suspended wire-mesh cages (43.0 x 21.5 x 18.0 cm). A metallic tray containing autoclaved sawdust (SISCA, Alfortville, France) was placed under these cages. During mating, gestation and lactation, the animals were housed in polycarbonate cages (43.0 x 21.5 x 20.0 cm) containing autoclaved sawdust (SICSA, Alfortville, France), with wood shaving as nesting material.
- Diet: ad libitum (SNIFF R/M-H pelleted maintenance diet, batch No. 2764132 (SNIFF Spezialdiäten GmbH, Soest, Germany) distributed weekly)
- Water: ad libitum (tap water (filtered with a 0.22 μm filter)
- Acclimation period: 7 days before the beginning of the treatment period
- Allocation to group: during the acclimation period, the required number of animals were selected according to body weight and/or clinical condition and allocated by sex to the groups, using a stratification procedure based on body weight.
Body weights of the animals assigned to the study at the start of the treatment period were within 20% of the mean weight for each sex. Identification: each animal was individually identified by an ear tattoo.
- Contaminant analyses: The batches of diet and sawdust were analyzed by the suppliers for composition and contaminant levels. Bacterial and
chemical analyses of water are performed regularly by external laboratories. These analyses include the detection of possible contaminants
(sawdust: pesticides and heavy metals; diet and water: pesticides, heavy metals and nitrosamines). No contaminants were present in the diet, drinking water or sawdust at levels which could be expected to interfere with or prejudice the outcome of the study.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2°C
- Humidity (%): 50 ± 20 %
- Air changes (per hr): about 12 cycles/hour of filtered, non-recycled air
- Photoperiod (hrs dark / hrs light): 12h/12h - Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS: The test item dosage formulations were prepared by suspending Lauryl Methacrylate (Lauryl MA; CAS: 142-90-5) in corn oil to achieve the concentrations of 20, 60 and 200 mg/mL and were stored at +4°C, protected from light, for up to 9 days prior to use.
- Administration:
The dosage formulations were administered by gavage using a plastic syringe fitted with a metal gavage tube (length of tube: 7.6 cm), once a day, at approximately the same time. The quantity of dosage formulation administered to each animal was adjusted according to the most recently recorded body weight with the exception that body weights on day 14 post-coitum were used to calculate individual dosages for the pregnant females from day 14 post-coitum through parturition (day 1 post-partum) to avoid overdosing the dams because weight gain from GD 14 to 20 (GD: gestation day) is fetal weight. A constant dosage-volume of 5 mL/kg/day was used. Control animals (group 1) received the vehicle alone. The dosage formulations were stirred continuously throughout the dosing procedure.
VEHICLE
- corn oil
- Lot/batch no. (if required): 122K0131 and 103K0107, supplied by Sigma (Saint-Quentin-Fallavier, France)
- Purity: no data, commercial product - Details on mating procedure:
- - M/F ratio per cage: Mating was monogamous (one male to one female).
- Length of cohabitation: maximum of 14 days
- Proof of pregnancy: The presence of a vaginal plug or sperm in the vaginal smear was taken as positive identification of mating, upon which vaginal smearing ceased.
The day of confirmed mating was designated day 0 post-coitum (p.c.). - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Homogeneity
The results of the analyses demonstrated the homogeneity of each dosage formulation analyzed (5 and 300 mg/mL) just after preparation
(protected from light). Furthermore, there was a satisfactory correspondence between the nominal and the measured concentrations of the test
item in the vehicle.
Stability
The results of the analyses demonstrated the satisfactory stability of the two dosage formulations investigated (5 and 300 mg/mL) over a 9-day
period at +4°C (protected from light).
Concentration
A satisfactory agreement was observed between the nominal and actual concentrations of the test item in the dosage formulations analyzed since
the deviations from nominal concentration were in an acceptable range of ± 10%. - Duration of treatment / exposure:
- Each animal was given the appropriate dosage formulation once a day, at approximately the same time each day, 7 days a week, according to the
following schedule:
in the males:
- 15 days before mating, during the mating and post-mating periods until sacrifice (approximately 6 weeks in total),
in the females:
- 15 days before mating,
- during the mating period,
- during pregnancy and lactation, until day 5 post-partum inclusive (or until sacrifice, for un-mated females).
Day 1 corresponds to the first day of the treatment period. - Frequency of treatment:
- daily, 7 days a week
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- Dose / conc.:
- 100 mg/kg bw/day (nominal)
- Dose / conc.:
- 300 mg/kg bw/day (nominal)
- Dose / conc.:
- 1 000 mg/kg bw/day (nominal)
- No. of animals per sex per dose:
- 10
- Control animals:
- yes, concurrent no treatment
- Details on study design:
- - Dose selection rationale: The oral route was selected as it is a possible route of exposure of the test item in man. The dose levels of 100, 300
and 1000 mg/kg/day were defined on the basis of the 14 day oral toxicity range finding study. - Positive control:
- None
- Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: Yes
MORBIDITY AND MORTALITY:
- Time schedule: Each animal was checked at least twice a day for mortality and signs of morbidity (except during the acclimation period when they
were checked at least once a day).
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Each animal was observed at least once a day at approximately the same time (i.e. after dosing the animals in the morning), for the
recording of clinical signs. Animals were also observed in the afternoon as part of the mortality check and any clinical signs were recorded.
All animals of each group were observed in the cage, in the hand and in the standard arena, by observers unaware of the animal's treatment, before
the first day of treatment and then once a week thereafter.
The animals were randomized in order to ensure "blind" evaluation, except for examination performed before the first day of treatment.
The following parameters were assessed:
- "touch escape" or ease of removal from the cage,
- in the hand: fur appearance, chromodacryorrhea, chromorhinorrhea, salivation, lachrymation, piloerection, eye, exophthalmia, mucous
membrane, reactivity to handling, pupil size (presence of myosis or mydriasis),
- in the standard arena (two-minute recording): grooming, palpebral closure, defecation and urination counts, tremors, twitches, convulsions,
gait, arousal (hypo- and hyper-activity), posture, stereotypy behaviour and breathing, ataxia, hypotonia.
Reactivity to manipulation or to different stimuli (FOB):
In five males and five females per group, the examinations listed below were conducted shortly before terminal sacrifice, and before blood
sampling for clinical pathology. The observer performing the evaluation was not aware of the treatment group of the animal. The animals were
randomly selected in order to ensure "blind" evaluation.
The following measurements, reflexes and responses were recorded:
. touch response,
. forelimb grip strength qualitative approach,
. pupil reflex,
. visual stimulus,
. auditory startle reflex,
. tail pinch response,
. landing foot splay,
. righting reflex,
. at the end of observation: rectal temperature.
Motor activity
Motor activity was measured in five males and five females using automated infra-red sensor equipment, recording individual animal activity over a
one-hour period. The females were evaluated on or near day 17 post-coitum to avoid removal of the dam from her pups after parturition and the
males were evaluated at approximately the same time as the females and near the time of sacrifice.
BODY WEIGHT: Yes
- Time schedule for examinations: The body weight of each male was recorded on the first day of treatment (day 1), then once a week until sacrifice.
The body weight of each female was recorded 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 and days 1 and 5 post-partum.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption/Compound intake: Yes
The quantity of food consumed by each animal was recorded once a week, over a 7-day period, from the first day of treatment through gestation
(days 0-7, 7-10, 10-14, 14-17 and 17-20 post-coitum intervals) and lactation (days 1-5 post-partum interval). During the mating period, the food
consumption was not recorded for males or females. Food intake per animal and per day was calculated by noting the difference between the food
given and that remaining in the food-hopper at the end of the specified interval.
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No
HAEMATOLOGY: Yes
- Animals fasted: Yes
- How many animals: 10; five males and five females (adults) from each group at terminal sacrifice
- Parameters checked: Lithium heparin tubes: Sodium (Na+), Potassium (K+), Chloride (Cl-), Calcium (Ca++), Inorganic phosphorus (I.PHOS),
Glucose (GLUC), Urea (UREA), Creatinine (CREAT), Total bilirubin (TOT.BIL), Total proteins (PROT), Albumin (ALB), Albumin/globulin ratio (A/G),
Total cholesterol (CHOL), Triglycerides (TRIG), Alkaline phosphatase (ALP), Aspartate aminotransferase (ASAT), Alanine aminotransferase (ALAT),
Tubes without anticoagulant: Biles acids (BIL.AC)
CLINICAL CHEMISTRY: Yes
- Animals fasted: Yes
- How many animals: 10; five males and five females (adults) from each group at terminal sacrifice
- Parameters checked: EDTA tubes: Erythrocytes (RBC), Hemoglobin (HB), Mean cell volume (MCV), Packed cell volume (PCV), Mean cell hemoglobin
concentration (MCHC), Mean cell hemoglobin (MCH) Thrombocytes (PLAT), Leucocytes (WBC), Differential white cell count with cell morphology
. neutrophils (N)
. eosinophils (E)
. basophils (B)
. lymphocytes (L)
. monocytes (M)
Sodium citrate tubes: Prothrombin time (PT), Activated partial thromboplastin time (APTT), Fibrinogen (FIB)
URINALYSIS: Yes
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes
- How many animals: 5; first surviving five males (adults) from each group at terminal sacrifice
- Parameters checked: Quantitative parameters: Volume (VOLUME), pH (pH), Specific gravity (SP.GRAV)
Semi-quantitative parameters: Proteins (PROT), Glucose (GLUC), Ketones (CETO), Bilirubin (BILI), Nitrites (NITR), Blood (BLOOD), Urobilinogen (UROB)
Cytology of sediment Microscopic:
. Leucocytes (WBC)
. Erythrocytes (RBC)
. Cylinders (CYLIN)
. Magnesium ammonium phosphate crystals (AMM.PH)
. Calcium phosphate crystals (CAL.PH)
. Calcium oxalate crystals (CAL.OX.)
. Cells (CELLS)
Qualitative parameters: Appearance (APP), Color (COLOR)
NEUROBEHAVIOURAL EXAMINATION: No - Sperm parameters (parental animals):
- Parameters examined in male parental generation:
Testes and epididymides were weighed for all males.
Special emphasis was paid to the stages of spermatogenesis in the male gonads and histopathology of interstitial testicular cell structure. In
particular, the evaluation identified treatment-related effects such as retained spermatids, missing germ cell layers or types, multinucleated giant
cells or sloughing of spermatogenic cells into the lumen. Examination of the intact epididymis included the head, corpus, and tail, which was
accomplished by evaluation of a longitudinal section. The epididymis was evaluated for leukocyte infiltration, change in prevalence of cell types,
aberrant cell types, and phagocytosis of sperm. PAS and hematoxylin staining were used for examination of the male reproductive organs.
Histopathological examination of the ovary included detection of any relevant changes in the follicular development, follicular atresia and corpora
lutea formation.
Peer review was performed for at least 10% of histological slides of control and high-dose groups in each sex and on all slides from identified target
organs. - Litter observations:
- PARAMETERS EXAMINED
The following parameters were examined in [F1] offspring:
Litter size
The total litter size and numbers of pups of each sex were recorded as soon as possible after birth.
The litters were observed daily in order to note the number of live, dead and cannibalized pups. A detailed external examination of live pups was
performed on days 1 and 5.
Clinical signs
The pups were observed daily for clinical signs or abnormal behaviour.
Body weight
The weight of each pup was recorded on days 1 and 5 post-partum.
- Postmortem examinations (parental animals):
- SACRIFICE
Adults
On completion of the treatment period, after at least 14 hours fasting (parents only), all animals were asphyxiated by carbon dioxide and sacrificed by exsanguination.
The males were sacrificed approximately 2 weeks after the end of the mating period (total treatment period was approximately 6 weeks).
The females and their pups were sacrificed on day 6 post-partum. The female showing no evidence of mating was sacrificed 24-26 days after the last day of the mating period.
A complete macroscopic post-mortem examination was performed on all parent study animals. This included examination of 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 ovaries and uterus of the parent females were examined to determine:
. number of corpora lutea,
. number of implantation sites.
In apparently non-pregnant or un-mated females, the presence of implantation scars on the uterus was checked using an ammonium sulphide
staining technique.
In addition, for any female that was pregnant but did not deliver, the implantation sites were recorded according to the following classification:
. uterine scar: uterine implantation without implant,
. early resorption: evidence of implant without recognizable embryo,
. late resorption: dead embryo or fetus with external degenerative changes,
. dead fetus: non live fetus with discernible digits.
Tissues fixed and preserved
From at least 5 male and female animals per group the following tissues listed below were fixed and preserved in 10% buffered formalin
(except testes and epididymides which were fixed in Bouin's solution) of the control and high-dose groups sacrificed at the end of the treatment
period. Furthermore a microscopic examination was performed on all macroscopic lesions of all the animals of the low- and intermediate-dose
groups sacrificed on completion of the treatment period.
Macroscopic lesions
Adrenal glands Ovaries
Brain Prostate
Caecum Rectumall macroscopic lesions
Colon Sciatic nerve
Duodenum Seminal vesicles (with coagulating glands)
Epidiymides Spinal cord (cervical, thoracic and lumbar)
Heart Spleen, Sternum with bone marrow
Ileum Stomach with forestomach
Jejunum Testes
Kidneys Thymus
Liver Thyroids with parathyroids
Lungs with bronchi Trachea
Lymph nodes (mandibular and mesenteric) Urinary bladder
Uterus (horns and cervix)
Histopathological examination
All tissues required for microscopic examination were embedded in paraffin wax, sectioned at a thickness of approximately four microns and stained with hematoxylin-eosin (except testes and epididymides which were stained with hematoxylin/PAS). A longitudinal section of epididymides was
carried out, including the head, the corpus and the tail parts.
This tissue processing was performed at Histotox under the responsibility of CIT. - Postmortem examinations (offspring):
- SACRIFICE
- The pups were sacrificed by subcutaneous injection of Thiopental sodium. Moribund pups were sacrificed in the same manner.The F1 offspring
were sacrificed at 6 days of age.
GROSS NECROPSY
- Pups found dead or sacrificed on day 6 post-partum were carefully examined externally for gross abnormalities through a macroscopic visceral
examination. - Statistics:
- Standard deviations will be calculated as appropriate. For contiunous the significance of the differences amongst group means will be assessed by
analysis of variance. Differences between each treated group and the control group will be assessed by Dunnett's test using a pooled error
variance. The homogeneity of the data was verified by Bartlett's Test before Dunnett's Test was performed. If the data were found to be
inhomogeneous, a modified T Test (Cochran and Cox) was applied. The non-parametric Kruskal-Wallis analysis of variance was used for litter and sex ratios data. Intergoup differences between the control and treated groups were assessed by the non-parametric version of the Williams test.
The criterion for statistical sigificance was p<0.05. The mean values, standard deviations and statistical analysis were calculated from actual
values in the computer without rounding off. - Clinical signs:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Other than hypersalivation (ptyalism), all signs at 300 and 1000 mg/kg bw/day for males and females were observed during the first week of the premating dosing period only. Hypersalivation, seen shortly after dosing, was observed in a number of males and females receiving 300 or 1000 mg/kg bw/day in a dosage-related manner (based on incidence) starting in week 2 of dosing. As dosing continued through gestation and lactation the number of females exhibiting hypersalivation decreased. Hypersalivation was considered to be a reaction of the animals to the dosing procedure and not a toxic response of Lauryl methacrylate. This conclusion is supported by the lack of similar and/or related findings at time periods other than just following dosing. Incidences of chromodacryorrhea, piloerection and loud breathing were sporadic and not dose-related.
A mass was observed on a right mammary gland of one female (100 mg/kg/day) from day 19 post-coitum until necropsy. Based on the age of the animal, the single incidence, the lack of dose response and the duration of dosing, a relationship to treatment was excluded. - Mortality:
- no mortality observed
- Description (incidence):
- There were no premature deaths during the study.
- Body weight and weight changes:
- effects observed, non-treatment-related
- Description (incidence and severity):
- The body weight loss between days 29 and 36 for the males in all groups is the result of the 14-hour fasting procedure (for blood collection) prior to the final weight collection on day 36. Females given 1000 mg/kg bw/day gained 18% less weight than the controls between day 0 and day 7 post-coitum. This variation was not considered to represent an adverse effect since the differences from controls were not statistically significant, were only observed for the 0-7 interval, and were of minor amplitude. No other treatment-related effects on body weight were noted.
- Food consumption and compound intake (if feeding study):
- effects observed, non-treatment-related
- Description (incidence and severity):
- Males: The food consumption of treated males was similar to that of the controls during the study.
Females: There was no effect of treatment on group mean food consumption during the premating or lactation periods. Between day 7 and day 10 post-coitum, all groups given Lauryl MA consumed less food than the controls, with no dose-relationship trend, achieving statistical significance at 100 and 1000 mg/kg bw/day (-17%, p<0.05 and -25%, p<0.001, respectively). Due to the lack of dose response and lack of consistency with other time periods in the study, these differences in food consumption were not considered of toxicological importance. - Food efficiency:
- not specified
- Ophthalmological findings:
- not specified
- Haematological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- There was no treatment-related effect on any of the hematological parameters examined. When compared with the mean control values, a lower value in total white cell count was recorded for females in the 1000 mg/kg bw/day group (4.95 vs 7.34 g/L: -33%, not statistically significant). This change was not considered related to treatment with the test item because of the great variability and the great inter-individual variations of this parameter and the lack of effects on other related parameters (differential cell counts).
- Clinical biochemistry findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- There was an increase in blood glucose concentration in male rats given 1000 mg/kg bw/day (7.63mmol/L, p<0.01) when compared with the controls (5.78 mmol/L); a relationship to the treatment with the test item cannot be excluded. However, this variation was not considered to be of toxicological im portance since the number of animals/group was limited to five, all values were within historical data
range (mean: 6.69 mmol/L, [5.22-9.04 mmol/L]) and there were no histopathological findings in the liver.
All other differences were considered not to be relevant since either no clear dose-relationship was evident (increased triglyceride and cholesterol plasma concentration in test item-treated females), or differences were slight (decrease in plasmatic protein concentration and increase in liver enzyme activities in females). - Urinalysis findings:
- no effects observed
- Description (incidence and severity):
- There was no effect of treatment on pH, specific gravity or volume of urine produced by the males in any group.
- Behaviour (functional findings):
- no effects observed
- Description (incidence and severity):
- Motor activity:
There were no differences in the measured motor activity (horizontal and rearing movements) which could be attributed to treatment with the test item. Detailed clinical observations and reactivity to manipulation or different stimuli (FOB). There was no evidence of disturbance of either autonomal or physiological functions at any dose-level. - Organ weight findings including organ / body weight ratios:
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
- Description (incidence and severity):
- Microscopic examination of the testes : No treatment-related abnormalities were found in Lauryl MA the treated animals. The tailed and round spermatids were unaffected and the different stages of spermatogenic cycle were undisturbed by the treatment with the test item. Sloughing of spermatogenic cells into tubular lumen and vacuoles in seminiferous tubules were noted with minimal severity and equal incidence in control and test item treated animals. These findings are commonly recorded as spontaneous changes in the rat and were considered to be of no toxicological importance. Moreover, minimal degeneration of seminiferous tubules was noted in one male given 1000 mg/kg bw/day. As this finding can be found in the untreated rat with similar incidence and severity, it was considered of no toxicological importance.
Microscopic examination of the ovaries and uterus: The microscopic examination of the ovaries and uterus did not reveal any treatment-related effects on these organs. The microscopic changes noted in both control and test item-treated animals correlated well with their status (post-partum).
Other organs and tissues: No treatment-related microscopic findings were noted at the end of treatment in the organs which were examined microscopically. All microscopic findings reported were those which commonly occur in the rat of this strain and age and were considered to be of no toxicological importance. - Reproductive function: oestrous cycle:
- no effects observed
- Reproductive function: sperm measures:
- no effects observed
- Reproductive performance:
- no effects observed
- Description (incidence and severity):
- There was no effect of treatment on mating at any dose-level. The male and female fertility indices were unaffected by treatment; all mated females, except one given 1000 mg/kg bw/day, were pregnant with live fetuses. The duration of gestation was similar between the control and test item-treated groups. There was no effect of treatment on the mean number of live-born pups or on pup death after birth.
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day (nominal)
- Sex:
- male/female
- Basis for effect level:
- other: highest dose tested
- Critical effects observed:
- not specified
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- Coldness to the touch was noted in seven pups (one litter) in the control group and four pups (three litters) at 1000 mg/kg bw/day. This sign was considered not to be related to treatment since it was observed at a greater incidence in the control group. The other clinical signs (anouria in one pup from the control group, necrosed forelimb in one pup from the 300 mg/kg/day group) were considered not to be treatment-related as they were isolated findings.
- Mortality / viability:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- There was no effect of treatment on mean pup body weight or body weight gain for males or females.
- Sexual maturation:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- No relevant findings were observed in the pups sacrificed on day 6 post-partum or in the pups found dead.
- Histopathological findings:
- not examined
- Other effects:
- no effects observed
- Description (incidence and severity):
- The sex ratios on days 1 and 5 post-partum were similar in the control and test item-treated groups, and close to a theoretical value of 50%.
- Key result
- Dose descriptor:
- NOEL
- Generation:
- F1
- Effect level:
- >= 1 000 mg/kg bw/day (nominal)
- Sex:
- male/female
- Basis for effect level:
- other: highest dose tested
- Critical effects observed:
- not specified
- Reproductive effects observed:
- no
Referenceopen allclose all
- no differences observed in number of corpora lutea, pre- and postimplantation sites, early and late resorptions, and viable fetuses.
- absolute and relative weights of reproductive organs similar between treatment groups and control group
- evaluation of sperm number and motility revealed no findings attributable to treatment
- placental weights were not affected by treatment
- absolute and relative weights of reproductive organs similar between treatment groups and control group
- evaluation of sperm number and motility revealed no findings attributable to treatment
- placental weights were not affected by treatment
Upon macroscopic, internal, and skeletal examinations of the fetuses, no variations were observed that were not comparable to historical control values. There were no observed effects related to treatment. Fetal weights were not affected by treatment. Fetal sex ratios were comparable between all treatment groups and the control group.
Table 1: Mean Reproductive parameters of rats treated with Behenyl alcohol
Dose (mg behenyl alcohol/kg body weight) |
||||
| 0 | 10 | 100 | 1000 | |
| Number of pregnant animals | 22 | 22 | 22 | 21 |
| Corpora lutea count | 17.8 (2.7) | 18.4 (4.0) | 18.7 (2.3) | 18.9 (2.4) |
| Implantations | 17.2 (2.6) | 17.0 (3.2) | 18.1 (1.8) | 18.0 (2.3) |
| viable young male | 8.4 (2.9) | 8.4 (2.3) | 8.5 (2.5) | 8.6 (2.6) |
| viable young female | 8.0 (3.0) | 7.5 (2.6) | 8.5 (2.2) | 8.3 (2.2) |
| viable young total | 16.4 (3.2) | 15.9 (3.5) | 17.0 (2.3) | 16.9 (2.2) |
| early resorptions | 0.82 (0.90) | 1.09 (1.04) | 1.14 (1.07) | 1.05 (1.02) |
| late resorptions | 0.00 (0.00) | 0.0 (0.00) | 0.00 (0.00) | 0.00 (0.00) |
| total resorptions | 0.82 (0.90) | 1.09 (1.04) | 1.14 (1.07) | 1.05 (1.02) |
| Pre-Implantation loss (%) | 3.3 | 8.3 | 3.2 | 5.8 |
| Post-Implantations loss (%) | 4.7 | 6.4 | 6.3 | 5.8 |
Numbers in parentheses represent standard deviations.
Effect on fertility: via oral route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 1 000 mg/kg bw/day
- Study duration:
- subchronic
- Species:
- rat
- Quality of whole database:
- GLP study according OECD TG 422 (Read Across)
Effect on fertility: via inhalation route
- Endpoint conclusion:
- no study available
Effect on fertility: via dermal route
- Endpoint conclusion:
- no study available
Additional information
There is no study available on reproductive toxicity for the target substance Docosyl methacrylate. Therefore, read-across from a study performed with the structurally analogous Dodecyl methacrylate (CAS 142-90-5) was utilized. Furthermore read-across from a study with the primary metabolite Docosan-1-ol (Behenyl alcohol, 661-19-8) was performed.
In a study similar to OECD TG 421, reproductive effects of the metabolite Behenyl alcohol were investigated in Sprague-Dawley rats. Males were treated with Behenyl alcohol daily for 71 days prior to mating, during mating, and until termination. Females were treated with the test substance for 15 days prior to mating, during mating, and up to Day 17 of gestation. Doses of 10, 100 and 1000 mg/kg bw/day were administered by oral gavage. No mortality, clinical signs, changes in body weight or food consumption and no histopathological findings were observed in the parental animals. No differences were observed in the number of corpora lutea, pre- and postimplantation sites, early and late resorptions, and viable fetuses. Absolute and relative weights of reproductive organs were similar between treatment groups and control group. Evaluation of sperm number and motility revealed no findings attributable to treatment. Placental weights were not affected by treatment. The NOAEL for reproductive toxicity for male and female rats was 1000 mg kg/bw/day, which was the highest dose tested (Iglesias et al., 2001).
In a further study according OECD TG 422 three groups of 10 male and 10 female Sprague-Dawley rats received the test item, Dodecyl methacrylate, by daily oral (gavage) administration for 15 days before mating, through mating, gestation and the beginning of the lactation period (until day 5 post-partum, p.p.). The dose-levels were 100, 300 and 1000 mg/kg bw/day. Another group of 10 males and 10 females received the vehicle, corn oil, alone, under the same experimental conditions and served as a control group. At 1000 mg/kg bw/day, hypersalivation was recorded in males and females, lower body weight gain was recorded in females during the GD 0-7 interval and increased plasma glucose concentrations were recorded in males. At 300 mg/kg bw/day, a few animals had hypersalivation. At the lowest dose of 100 mg/kg bw/day, no treatment-related effects were detected. Hypersalivation was not considered to be a sign of toxicity. There were no substance-induced effects on the male and female reproductive performance, or on the progeny of the parental rats at any dose-level. There were no treatment-related findings at histopathological examination or on mating at any dose-level. The male and female fertility indices were unaffected by treatment; all mated females, except one given 1000 mg/kg bw/day, were pregnant with live fetuses. The duration of gestation was similar between the control and test item-treated groups. There was no effect of treatment on the mean number of liveborn pups or on pup death after birth. There were no external pup abnormalities in the control or test item-treated groups. There was no effect of treatment on mean pup body weight or body weight gain for males or females. The sex ratios on days 1 and 5 post-partum were similar in the control and test item-treated groups. No relevant findings were observed in the pups sacrificed on day 6 post-partum. The NOEL for reproductive toxicity was ≥1000 mg/kg bw/day (SAM UNTER 05 -044).
In conclusion, based on studies in experimental animals, there is no evidence for reproductive/developmental toxicity of Docosyl methacrylate.
Effects on developmental toxicity
Description of key information
There is no study available on developmental toxicity for the target substance Docosyl methacrylate. Therefore, read-across from studies performed with the primary metabolites Docosan-1-ol (Behenyl alcohol, CAS 661-19-8) and Methacrylic acid (CAS 79-41-4) were utilized. In a study similar to OECD TG 414 pregnant female rats were exposed to methacrylic acid by whole-body inhalation on days 6 through 20 of gestation. No significant increase in embryo/fetal lethality or fetal malformations was observed. The NOAEC for developmental toxicity was ≥ 300 ppm, which was the highest dose tested. In a further study, pregnant rabbits were exposed from day 6 to day 19 of gestation via oral gavage to Docosan-1-ol (Behenyl alcohol). No external, visceral, and skeletal malformations between the control and the treated groups were observed. The NOAEL for developmental toxicity was 2000 mg/kg bw/day, which was the highest dose tested.
Link to relevant study records
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study with acceptable restrictions
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- GLP compliance:
- not specified
- Limit test:
- no
- Species:
- rat
- Strain:
- Sprague-Dawley
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: IFFA Credo Breeding Laboratories, France
- Age at study initiation: not specified
- Weight at study initiation: 180-200 grams
- Housing: mated females were housed in clear polycarbonate cages with stainless steel wire lids and hardwood shavings for bedding
- Diet: food pellets, ad libitum, except during exposure
- Water: tap water, ad libitum, except during exposure
- Acclimation period: 2 weeks
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21±2 °C
- Humidity (%): 50± 5%
- Photoperiod (hrs dark / hrs light): 12 hours/12 hours
- Route of administration:
- inhalation
- Type of inhalation exposure (if applicable):
- whole body
- Vehicle:
- unchanged (no vehicle)
- Details on exposure:
- Exposures were whole body and conducted in a 200 L glass/stainless-steel inhalation chamber with dynamic and adjustable laminar air flow (6-20 m3/h). Chamber temperature was 23°C, and the relative humidity was 50%. Air was passed through a heated bubbler containing test material. The vaporized material was then introduced into the exposure chambers.
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Concentrations were monitored continuously with a GC, and were determined once during each 6 hr exposure by collecting the material and analyzing against a standard using GC.
- Details on mating procedure:
- Mating: 2-3 females were caged with one male rat
The onset of gestation was based upon the presence of sperm in the vaginal smear and this was designated gestation day 0. After confirmation of mating, females werereturned to an individual cage. - Duration of treatment / exposure:
- 6 hours per day
- Frequency of treatment:
- day 6 to 20 of gestation
- Duration of test:
- mated females were exposed 6 hr/day on days 6 through 20 of gestation
- Dose / conc.:
- 50 ppm
- Remarks:
- 55.3 ± 8.1 ppm analytical concentration
- Dose / conc.:
- 100 ppm
- Remarks:
- 101.5 ± 16.9 ppm analytical concentration
- Dose / conc.:
- 200 ppm
- Remarks:
- 207.3 ± 24.7 ppm analytical concentration
- Dose / conc.:
- 300 ppm
- Remarks:
- 316.0 ± 36.7 ppm analytical concentration
- No. of animals per sex per dose:
- 19-25 pregnant females per dose
- Control animals:
- other: yes, concurrently to filtered room air
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: No data
DETAILED CLINICAL OBSERVATIONS: / No data
BODY WEIGHT: Yes
FOOD CONSUMPTION Yes
for the intervals GDs 6-13 and 13-21
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 21
- Organs examined: uterus
- Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes - Fetal examinations:
- Live fetuses were weighed, sexed, and examined for external anomalies. 50% of the live fetuses were preserved in Bouin's solutionand examined for internal soft-tissue changes. The remaining fetuses were fixed in ethanol (70%), eviscerated and then processed for skeletal staining with alizarin red S.
- Statistics:
- The number of CL, implantation sites,and live fetuses, maternal food consumption and various body weights were analyzed by ANOVA, followed by Dunnett'st-test. the percentage of non-live implant, resorptions,and males and the proportion of fetuses with alterations ineach litter were evaluated by Kruskal-Walles test followed by Dixon-Massey test. Rates of pregnancy and percentage of litters with any malformations or external, visceral, or skeletal variations were analyzedusing Fisher's test. Where appropriate, least squares analysis was performed. The level of significance was p < 0.05.
- Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Exposure to 300 ppm led to significant decreases in maternal weight gain. Absolute weight gain was significantly reduced at 300 ppm.
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- Exposure to 300 ppm led to significant decreases in maternal food consumption.
- Pre- and post-implantation loss:
- no effects observed
- Early or late resorptions:
- no effects observed
- Dead fetuses:
- no effects observed
- Key result
- Dose descriptor:
- NOAEC
- Effect level:
- 200 ppm
- Basis for effect level:
- other: maternal toxicity
- Abnormalities:
- not specified
- Fetal body weight changes:
- no effects observed
- Reduction in number of live offspring:
- no effects observed
- Details on embryotoxic / teratogenic effects:
- There were no significant changes in number of implantations and live fetuses, in the incidence of non-live implants and sorptions, or in fetal weights across groups. One fetus of 200 ppm and two of the 300 ppm group showed different types of malformations. There was no consistent pattern of changes to suggest any treatment-related effects. The difference of fetuses with external, visceral, and skeletal variations did not differ between the control and the treated groups. No significant increase in embryo/fetal lethality or fetal malformations was observed after exposure. While maternal toxicity was observed, methacrylic acid caused no evidence of developmental toxicity up to 300 ppm.
- Key result
- Dose descriptor:
- NOAEC
- Effect level:
- >= 300 ppm
- Sex:
- male/female
- Basis for effect level:
- other: teratogenicity
- Abnormalities:
- not specified
- Developmental effects observed:
- no
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- study well documented, meets generally accepted scientific principles, acceptable for assessment
- Qualifier:
- according to guideline
- Guideline:
- other: ICH Harmonised Tripartite Guidelines for Detection of Toxicity to Reproduction for Medicinal Products
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Principles of method if other than guideline:
- An embryonic developmental study in rabbits administered a maximum dose of 2000 mg/kg bw/day Docosan-1-ol was conducted.
- GLP compliance:
- yes
- Remarks:
- Huntingdon Life Sciences Ltd (Suffolk, England)
- Limit test:
- no
- Species:
- rabbit
- Strain:
- New Zealand White
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Froxfield SPF Rabbits Limited (Hampshire, England)
- Age at study initiation: approximately 18 to 26 weeks
- Weight at study initiation: 3.29 - 4.98 kg
- Fasting period before study:
- Housing: housed individually in suspended stainless-steel cages (type TR6) mounted in batteries (Modular Systems
and Developments Company Limited, Hereford, England) and equipped with an undertray, lined with absorbent paper
- Diet: ad libitum, standard rabbit diet (Special Diets Services Ltd., Witham, Essex, England) containing no added antibiotic, or other chemotherapeutic or prophylactic agent
- Water: ad libitum, tap water
- Acclimation period: minimum of 1 week prior to the initiation of dosing
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18°C
- Humidity (%): 55%
- Photoperiod (hrs dark / hrs light): 12 hours/12 hours
- Route of administration:
- oral: gavage
- Vehicle:
- other: 1% w/w aqueous Tween 80
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
The required amount of test item was weighed into a glass container and heated (approximately 80°C) until molten using an electric mantle.
An appropriate volume of vehicle (1% Tween 80) was heated in a water bath to at least 75°C and then combined with the molten behenyl alcohol under continuous magnetic stirring, to a concentration of 20% behenyl alcohol. The resulting suspension was slowly cooled, with homogenization to a temperature of below 60°C, and then further cooled in a water bath to a temperature of 30°C. The 20% behenyl alcohol suspension was prepared weekly. The lower concentrations were prepared on the day of use by dilution of the 20% suspension with 1% w/w aqueous Tween 80.
VEHICLE
- aqueous Tween 80
- Amount of vehicle (if gavage): 1%
Animals received the test material or vehicle control formulations by gavage, at volume-dosages of 10, 0.625, 2.5, or 10 mL/kg bw for rabbits using a 20 choke rubber catheter. - Details on mating procedure:
- Insemination procedure:
- mated with New Zealand white males
- following insemination, each female was injected intravenously with 25 IU of luteinizing hormone (Profasi,Serono) to ensure successful ovulation
- day of insemination designated as Day 0 of gestation
- all animals were examined on Day 6 of gestation, prior to dosing, and determined to be suitable for use in the study - Frequency of treatment:
- daily from Day 6 to Day 19 of gestation
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- Dose / conc.:
- 125 mg/kg bw/day (nominal)
- Dose / conc.:
- 500 mg/kg bw/day (nominal)
- Dose / conc.:
- 2 000 mg/kg bw/day (nominal)
- No. of animals per sex per dose:
- 22
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: These doses were selected based on a previously conducted range-finding study providing a maximum dose of 2000 mg Behenyl alcohol/kg bw/day.
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
BODY WEIGHT: Yes
Body weight gains were measured daily.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
Food consumption was recorded during the following time periods: Days 1 to 5, 6 to 12, 13 to 19, 20 to 23, and 24 to 28, inclusive.
WATER CONSUMPTION: Yes
Water consumption were measured daily.
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 29
- Organs examined: each animal was macroscopically examined
- Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Fetal examinations:
- - External examinations: Yes
- Soft tissue examinations: Yes
- Skeletal examinations: Yes
- Head examinations: Yes - Statistics:
- To test the statistical significance of suggestive intergroup differences, one-way analysis of variance and t test were performed on body weights, body weight
changes, and food and water consumption. Organ weights were evaluated by Dunnett’s or Behren’s-Fisher’s tests. Nested analysis of variance and weighed
t test were conducted on fetal and placental weights.
Differences with an associated probability of P<0.05
were deemed to be statistically significant. - Clinical signs:
- effects observed, non-treatment-related
- Description (incidence and severity):
- There were no remarkable clinical observations, with the exception of pale feces observed in the majority of females treated daily with 2000 mg/kg bw/day.
- Mortality:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- Food and water consumption of all dose groups were comparable to those of control rabbits throughout the duration of the study.
- Gross pathological findings:
- effects observed, non-treatment-related
- Pre- and post-implantation loss:
- no effects observed
- Dead fetuses:
- no effects observed
- Details on maternal toxic effects:
- No intergroup differences suggestive of statistical significance were observed in the number of corpora lutea, pre- and postimplantation sites, early
and late resorptions, and viable fetuses. Fetal and placental weights were not affected by treatment up to 2000 mg/kg bw/day. A total of 3 females, treated with 0, 125, and 500 mg/kg bw/day, respectively, were observed to have a total litter loss at necropsy. The uterus of each of these females revealed early resorptions. - Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 2 000 mg/kg bw/day (nominal)
- Basis for effect level:
- other: highest dose tested
- Abnormalities:
- no effects observed
- Changes in sex ratio:
- no effects observed
- External malformations:
- no effects observed
- Skeletal malformations:
- no effects observed
- Visceral malformations:
- no effects observed
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 2 000 mg/kg bw/day (nominal)
- Sex:
- male/female
- Basis for effect level:
- other: highest dose tested
- Abnormalities:
- no effects observed
- Developmental effects observed:
- no
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Study period:
- 12-Oct-2004 to 06-Dec-2004
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Qualifier:
- according to guideline
- Guideline:
- other: OECD 422
- Deviations:
- no
- Principles of method if other than guideline:
- OECD combined study TG422:
Combined repeated dose toxicity study by the oral route (gavage) with the reproduction/development toxicity screening test. Three groups of 10
male and 10 female Sprague-Dawley rats received the test item, Lauryl MA, by daily oral (gavage) administration for 15 days before mating, through
mating, gestation and the beginning of the lactation period (until day 5 post-partum, p.p.). The dose-levels were 100, 300 and 1000 mg/kg bw/day. The
control group (10 males and 10 females) received the vehicle only (corn-oil). The dosing volume was 5 mL/kg. Clinical signs and mortality were
checked daily. Body weight and food consumption were recorded at designated intervals throughout the study. Detailed clinical observations,
reactivity to different stimuli (Functional Observation Battery; (FOB)) and motor activity were also recorded. Blood was taken from five males and five
females for hematological and blood biochemical investigations at terminal sacrifice (i.e. in week 6 for males and week 7 for females). At the same
time, urine was collected from five males for analysis. Males were sacrificed approximately two weeks (week 6) after the end of the mating period,
females on day 6 p.p. The animals were subjected to a macroscopic examination of the principal thoracic and abdominal organs. Designated organs were weighed and examined microscopically. In addition, the numbers of corpora lutea and implantation sites were recorded for each female. The pups were observed daily for clinical signs, sexed and weighed on days 1 and 5 p.p. After sacrifice on day 6 p.p., the pups were examined for gross abnormalities. - GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
- Species:
- rat
- Strain:
- Sprague-Dawley
- Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS: The test item dosage formulations were prepared by suspending Lauryl Methacrylate (Lauryl MA; CAS: 142-90-5) in corn oil to achieve the concentrations of 20, 60 and 200 mg/mL and were stored at +4°C, protected from light, for up to 9 days prior to use.
- Administration:
The dosage formulations were administered by gavage using a plastic syringe fitted with a metal gavage tube (length of gavage tube: 7.6 cm), once a day, at approximately the same time. The quantity of dosage formulation administered to each animal was adjusted according to the most recently recorded body weight with the exception that body weights on day 14 post-coitum were used to calculate individual dosages for the pregnant females from day 14 post-coitum through parturition (day 1 post-partum) to avoid overdosing the dams because weight gain from GD 14 to 20 (GD: gestation day) is fetal weight. A constant dosage-volume of 5 mL/kg bw/day was used. Control animals (group 1) received the vehicle alone. The dosage formulations were stirred continuously throughout the dosing procedure.
VEHICLE
- corn oil
- Lot/batch no. (if required): 122K0131 and 103K0107, supplied by Sigma (Saint-Quentin-Fallavier, France)
- Purity: no data, commercial product - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Homogeneity
The results of the analyses demonstrated the homogeneity of each dosage formulation analyzed (5 and 300 mg/mL) just after preparation
(protected from light). Furthermore, there was a satisfactory correspondence between the nominal and the measured concentrations of the test
item in the vehicle.
Stability
The results of the analyses demonstrated the satisfactory stability of the two dosage formulations investigated (5 and 300 mg/mL) over a 9-day
period at +4°C (protected from light).
Concentration
A satisfactory agreement was observed between the nominal and actual concentrations of the test item in the dosage formulations analyzed since
the deviations from nominal concentration were in an acceptable range of ± 10%. - Duration of treatment / exposure:
- Each animal was given the appropriate dosage formulation once a day, at approximately the same time each day, 7 days a week, according to the
following schedule:
in the males:
- 15 days before mating, during the mating and post-mating periods until sacrifice (approximately 6 weeks in total),
in the females:
- 15 days before mating,
- during the mating period,
- during pregnancy and lactation, until day 5 post-partum inclusive (or until sacrifice, for un-mated females).
Day 1 corresponds to the first day of the treatment period. - Frequency of treatment:
- daily, 7 days a week.
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- Dose / conc.:
- 100 mg/kg bw/day (nominal)
- Dose / conc.:
- 300 mg/kg bw/day (nominal)
- Dose / conc.:
- 1 000 mg/kg bw/day (nominal)
- No. of animals per sex per dose:
- 10
- Control animals:
- yes, concurrent no treatment
- Details on study design:
- - Dose selection rationale: The oral route was selected as it is a possible route of exposure of the test item in man. The dose levels of 100, 300
and 1000 mg/kg/day were defined on the basis of the 14 day oral toxicity range finding study. - Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
MORBIDITY AND MORTALITY:
- Time schedule: Each animal was checked at least twice a day for mortality and signs of morbidity (except during the acclimation period when they
were checked at least once a day).
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Each animal was observed at least once a day at approximately the same time (i.e. after dosing the animals in the morning), for the
recording of clinical signs. Animals were also observed in the afternoon as part of the mortality check and any clinical signs were recorded.
All animals of each group were observed in the cage, in the hand and in the standard arena, by observers unaware of the animal's treatment, before
the first day of treatment and then once a week thereafter.
The animals were randomized in order to ensure "blind" evaluation, except for examination performed before the first day of treatment.
The following parameters were assessed:
- "touch escape" or ease of removal from the cage,
- in the hand: fur appearance, chromodacryorrhea, chromorhinorrhea, salivation, lachrymation, piloerection, eye, exophthalmia, mucous
membrane, reactivity to handling, pupil size (presence of myosis or mydriasis),
- in the standard arena (two-minute recording): grooming, palpebral closure, defecation and urination counts, tremors, twitches, convulsions,
gait, arousal (hypo- and hyper-activity), posture, stereotypy behaviour and breathing, ataxia, hypotonia.
Reactivity to manipulation or to different stimuli (FOB):
In five males and five females per group, the examinations listed below were conducted shortly before terminal sacrifice, and before blood
sampling for clinical pathology. The observer performing the evaluation was not aware of the treatment group of the animal. The animals were
randomly selected in order to ensure "blind" evaluation.
The following measurements, reflexes and responses were recorded:
. touch response,
. forelimb grip strength qualitative approach,
. pupil reflex,
. visual stimulus,
. auditory startle reflex,
. tail pinch response,
. landing foot splay,
. righting reflex,
. at the end of observation: rectal temperature.
Motor activity
Motor activity was measured in five males and five females using automated infra-red sensor equipment, recording individual animal activity over a
one-hour period. The females were evaluated on or near day 17 post-coitum to avoid removal of the dam from her pups after parturition and the
males were evaluated at approximately the same time as the females and near the time of sacrifice.
BODY WEIGHT: Yes
- Time schedule for examinations: The body weight of each male was recorded on the first day of treatment (day 1), then once a week until sacrifice.
The body weight of each female was recorded 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 and days 1 and 5 post-partum.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption/Compound intake: Yes
The quantity of food consumed by each animal was recorded once a week, over a 7-day period, from the first day of treatment through gestation
(days 0-7, 7-10, 10-14, 14-17 and 17-20 post-coitum intervals) and lactation (days 1-5 post-partum interval). During the mating period, the food
consumption was not recorded for males or females. Food intake per animal and per day was calculated by noting the difference between the food
given and that remaining in the food-hopper at the end of the specified interval.
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No
HAEMATOLOGY: Yes
- Animals fasted: Yes
- How many animals: 10; five males and five females (adults) from each group at terminal sacrifice
- Parameters checked: Lithium heparin tubes: Sodium (Na+), Potassium (K+), Chloride (Cl-), Calcium (Ca++), Inorganic phosphorus (I.PHOS),
Glucose (GLUC), Urea (UREA), Creatinine (CREAT), Total bilirubin (TOT.BIL), Total proteins (PROT), Albumin (ALB), Albumin/globulin ratio (A/G),
Total cholesterol (CHOL), Triglycerides (TRIG), Alkaline phosphatase (ALP), Aspartate aminotransferase (ASAT), Alanine aminotransferase (ALAT),
Tubes without anticoagulant: Biles acids (BIL.AC)
CLINICAL CHEMISTRY: Yes
- Animals fasted: Yes
- How many animals: 10; five males and five females (adults) from each group at terminal sacrifice
- Parameters checked: EDTA tubes: Erythrocytes (RBC), Hemoglobin (HB), Mean cell volume (MCV), Packed cell volume (PCV), Mean cell hemoglobin
concentration (MCHC), Mean cell hemoglobin (MCH) Thrombocytes (PLAT), Leucocytes (WBC), Differential white cell count with cell morphology
. neutrophils (N)
. eosinophils (E)
. basophils (B)
. lymphocytes (L)
. monocytes (M)
Sodium citrate tubes: Prothrombin time (PT), Activated partial thromboplastin time (APTT), Fibrinogen (FIB)
URINALYSIS: Yes
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes
- How many animals: 5; first surviving five males (adults) from each group at terminal sacrifice
- Parameters checked: Quantitative parameters: Volume (VOLUME), pH (pH), Specific gravity (SP.GRAV)
Semi-quantitative parameters: Proteins (PROT), Glucose (GLUC), Ketones (CETO), Bilirubin (BILI), Nitrites (NITR), Blood (BLOOD), Urobilinogen (UROB)
Cytology of sediment Microscopic:
. Leucocytes (WBC)
. Erythrocytes (RBC)
. Cylinders (CYLIN)
. Magnesium ammonium phosphate crystals (AMM.PH)
. Calcium phosphate crystals (CAL.PH)
. Calcium oxalate crystals (CAL.OX.)
. Cells (CELLS)
Qualitative parameters: Appearance (APP), Color (COLOR)
NEUROBEHAVIOURAL EXAMINATION: No
SACRIFICE
Adults
On completion of the treatment period, after at least 14 hours fasting (parents only), all animals were asphyxiated by carbon dioxide and sacrificed by exsanguination.
The males were sacrificed approximately 2 weeks after the end of the mating period (total treatment period was approximately 6 weeks).
The females and their pups were sacrificed on day 6 post-partum. The female showing no evidence of mating was sacrificed 24-26 days after the last day of the mating period.
A complete macroscopic post-mortem examination was performed on all parent study animals. This included examination of 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 ovaries and uterus of the parent females were examined to determine:
. number of corpora lutea,
. number of implantation sites.
In apparently non-pregnant or un-mated females, the presence of implantation scars on the uterus was checked using an ammonium sulphide
staining technique.
In addition, for any female that was pregnant but did not deliver, the implantation sites were recorded according to the following classification:
. uterine scar: uterine implantation without implant,
. early resorption: evidence of implant without recognizable embryo,
. late resorption: dead embryo or fetus with external degenerative changes,
. dead fetus: non live fetus with discernible digits.
Tissues fixed and preserved
From at least 5 male and female animals per group the following tissues listed below were fixed and preserved in 10% buffered formalin
(except testes and epididymides which were fixed in Bouin's solution) of the control and high-dose groups sacrificed at the end of the treatment
period. Furthermore a microscopic examination was performed on all macroscopic lesions of all the animals of the low- and intermediate-dose
groups sacrificed on completion of the treatment period.
Macroscopic lesions
Adrenal glands Ovaries
Brain Prostate
Caecum Rectumall macroscopic lesions
Colon Sciatic nerve
Duodenum Seminal vesicles (with coagulating glands)
Epidiymides Spinal cord (cervical, thoracic and lumbar)
Heart Spleen, Sternum with bone marrow
Ileum Stomach with forestomach
Jejunum Testes
Kidneys Thymus
Liver Thyroids with parathyroids
Lungs with bronchi Trachea
Lymph nodes (mandibular and mesenteric) Urinary bladder
Uterus (horns and cervix)
Histopathological examination
All tissues required for microscopic examination were embedded in paraffin wax, sectioned at a thickness of approximately four microns and stained with hematoxylin-eosin (except testes and epididymides which were stained with hematoxylin/PAS). A longitudinal section of epididymides was
carried out, including the head, the corpus and the tail parts.
This tissue processing was performed at Histotox under the responsibility of CIT. - Statistics:
- Standard deviations will be calculated as appropriate. For contiunous the significance of the differences amongst group means will be assessed by
analysis of variance. Differences between each treated group and the control group will be assessed by Dunnett's test using a pooled error
variance. The homogeneity of the data was verified by Bartlett's Test before Dunnett's Test was performed. If the data were found to be
inhomogeneous, a modified T Test (Cochran and Cox) was applied. The non-parametric Kruskal-Wallis analysis of variance was used for litter and sex ratios data. Intergoup differences between the control and treated groups were assessed by the non-parametric version of the Williams test.
The criterion for statistical sigificance was p<0.05. The mean values, standard deviations and statistical analysis were calculated from actual
values in the computer without rounding off. - Clinical signs:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Other than hypersalivation (ptyalism), all signs at 300 and 1000 mg/kg bw/day for males and females were observed during the first week of the premating dosing period only. Hypersalivation, seen shortly after dosing, was observed in a number of males and females receiving 300 or 1000 mg/kg bw/day in a dosage-related manner (based on incidence) starting in week 2 of dosing. As dosing continued through gestation and lactation the number of females exhibiting hypersalivation decreased. Hypersalivation was considered to be a reaction of the animals to the dosing procedure and not a toxic response of Lauryl methacrylate. This conclusion is supported by the lack of similar and/or related findings at time periods other than just following dosing. Incidences of chromodacryorrhea, piloerection and loud breathing were sporadic and not dose-related.
A mass was observed on a right mammary gland of one female dosed 100 mg/kg/day from day 19 post-coitum until necropsy. Based on the age of the animal, the single incidence, the lack of dose response and the duration of dosing, a relationship to treatment was excluded. - Mortality:
- no mortality observed
- Description (incidence):
- There were no premature deaths during the study.
- Body weight and weight changes:
- effects observed, non-treatment-related
- Description (incidence and severity):
- The body weight loss between days 29 and 36 for the males in all groups is the result of the 14-hour fasting procedure (for blood collection) prior to the final weight collection on day 36. Females given 1000 mg/kg bw/day gained 18% less weight than the controls between day 0 and day 7 post-coitum. This variation was not considered to represent an adverse effect since the differences from controls were not statistically significant, were only observed for the 0-7 interval, and were of minor amplitude. No other treatment-related effects on body weight were noted.
- Food consumption and compound intake (if feeding study):
- effects observed, non-treatment-related
- Description (incidence and severity):
- Males:
The food consumption of treated males was similar to that of the controls during the study.
Females:
There was no effect of treatment on group mean food consumption during the premating or lactation periods. Between day 7 and day 10 post-coitum, all groups given Lauryl MA consumed less food than the controls, with no dose-relationship trend, achieving statistical significance at 100 and 1000 mg/kg bw/day (-17%, p<0.05 and -25%, p<0.001, respectively). Due to the lack of dose response and lack of consistency with other time periods in the study, these differences in food consumption were not considered of toxicological importance. - Behaviour (functional findings):
- no effects observed
- Description (incidence and severity):
- Motor activity:
There were no differences in the measured motor activity (horizontal and rearing movements) which could be attributed to treatment with the test item.
Detailed clinical observations and reactivity to manipulation or different stimuli (FOB):
There was no evidence of disturbance of either autonomal or physiological functions at any dose-level - Organ weight findings including organ / body weight ratios:
- no effects observed
- Description (incidence and severity):
- There were no treatment-related effects on absolute or relative organ weights in any dose groups.
- Gross pathological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- No treatment-related findings were observed at necropsy. The palpable mass in one female given 100 mg/kg bw/day was found to be a ductular carcinoma. Taking into consideration the length of the present study (12 weeks) and as this neoplastic finding can be found in the young, untreated rat of this strain and age (Attia et. al., 1994; Oishi Y et al. 1995) as well as the single occurrence in the low dose group, the carcinoma was considered to be unrelated to test article treatment.
- Histopathological findings: non-neoplastic:
- no effects observed
- Description (incidence and severity):
- Microscopic examination of the testes:
No treatment-related abnormalities were found in the treated animals. The tailed and round spermatids were unaffected and the different stages of spermatogenic cycle were undisturbed by the treatment with the test item. Sloughing of spermatogenic cells into tubular lumen and vacuoles in seminiferous tubules were noted with minimal severity and equal incidence in control and test item treated animals. These findings are commonly recorded as spontaneous changes in the rat and were considered to be of no toxicological importance. Moreover, minimal degeneration of seminiferous tubules was noted in one male given 1000 mg/kg bw/day. As this finding can be found in the untreated rat with similar incidence and severity, it was considered of no toxicological importance.
Microscopic examination of the ovaries and uterus:
The microscopic examination of the ovaries and uterus did not reveal any treatment-related effects on these organs. The microscopic changes noted in both control and test item-treated animals correlated well with their status (post-partum).
Other organs and tissues:
No treatment-related microscopic findings were noted at the end of treatment in the organs which were examined microscopically. All microscopic findings reported were those which commonly occur in the rat of this strain and age and were considered to be of no toxicological importance. - Dead fetuses:
- no effects observed
- Other effects:
- no effects observed
- Description (incidence and severity):
- There was no effect of treatment on mating at any dose-level.
The male and female fertility indices were unaffected by treatment; all mated females, except one given 1000 mg/kg bw/day, were pregnant with live fetuses.The duration of gestation was similar between the control and test item-treated groups. There was no effect of treatment on the mean number of liveborn pups or on pup death after birth.There were no gross external abnormalities in the control or test item-treated groups. - Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- other: highest dose tested
- Abnormalities:
- not specified
- Fetal body weight changes:
- no effects observed
- Description (incidence and severity):
- There was no effect of treatment on mean pup body weight or body weight gain for males or females.
- Changes in sex ratio:
- no effects observed
- Description (incidence and severity):
- The sex ratios on days 1 and 5 post-partum were similar in the control and test item-treated groups, and close to a theoretical value of 50%.
- Other effects:
- no effects observed
- Description (incidence and severity):
- No relevant findings were observed in the pups sacrificed on day 6 post-partum or in the pups found dead.
- Details on embryotoxic / teratogenic effects:
- CLINICAL SIGNS (OFFSPRING)
Coldness to the touch was noted in seven pups (one litter) in the control group and four pups (three litters) at 1000 mg/kg bw/day. This sign was considered not to be related to treatment since it was observed at a greater incidence in the control group.
The other clinical signs (anouria in one pup from the control group, necrosed forelimb in one pup from the 300 mg/kg bw/day group) were considered not to be treatment-related as they were isolated findings. - Key result
- Dose descriptor:
- NOEL
- Remarks:
- developmental toxicity
- Effect level:
- >= 1 000 mg/kg bw/day (nominal)
- Sex:
- male/female
- Basis for effect level:
- other: highest dose tested
- Abnormalities:
- not specified
- Developmental effects observed:
- no
Referenceopen allclose all
Table 1: Reproductive parameters in Sprague-Dawley Rats Inhaling Methacrylic acid on Days 6 to 20 of Gestation and Euthanized on Day 21
Concentration ppm/6h/day |
% of females pregnant at euthanization |
No. of litters |
No. of corpora lutea per dam |
No. of implantation sides per litter |
% of nonlive implants per litter(a) |
% of resorption sites per litter |
No. of live fetuses per litter |
% of males per litter |
0 |
92 |
23 |
17.05 ± 1.7(b) |
14.91 ± 5.06
|
8.96 ± 20.73
|
8.96 ± 20.73
|
14.73 ± 3.92
|
56.37 ± 17.76
|
50 |
88 |
22 |
16.10 ± 1.76 |
15.36 ± 1.97
|
3.22 ± 3.34
|
3.22 ± 3.34
|
14.86 ± 1.93
|
49.70 ± 14.90
|
100 |
84.6 |
22 |
16.23 ± 1.74 |
15.00 ± 2.93
|
6.76 ± 8.14
|
6.76 ± 8.14
|
14.05 ± 3.17
|
58.70 ± 13.10 |
200 |
88 |
22 |
16.32 ± 2.12 |
14.36 ± 3.74 |
5.67 ± 12.77
|
5.67 ± 12.77
|
13.77 ± 3.99
|
53.91 ± 17.15 |
300 |
88.5 |
23 |
16.00 ± 2.73 |
14.43 ± 4.63 |
10.61 ± 21.45
|
10.61 ± 21.45
|
14.05 ± 3.76
|
50.40 ± 16.30
|
Concentration ppm/6h/day |
Average fetal body weight (g) all |
Average fetal body weight (g) males |
Average fetal body weight (g) females |
0 |
5.71± 0.56
|
5.86± 0.57
|
5.42± 0.37 |
50 |
5.66± 0.27
|
5.82± 0.32
|
5.49± 0.27 |
100 |
5.79± 0.30
|
5.92± 0.32
|
5.62± 0.32 |
200 |
5.76± 0.47
|
5.92± 0.47
|
5.54± 0.45 |
300 |
5.67± 0.49
|
5.71± 0.34
|
5.54± 0.52 |
(a) resorptions plus dead fetuses
(b) values are expressed as means ± SD
Table 1: Mean Reproductive parameters of rabbits treated with Behenyl alcohol
Dose (mg behenyl alcohol/kg bw/day) |
||||
| 0 | 125 | 500 | 2000 | |
| Number of pregnant animals | 20 | 19 | 19 | 20 |
| Corpora lutea count | 12.8 (3.1) | 12.9 (2.2) | 12.6 (3.0) | 12.2 (3.9) |
| Implantations | 11.4 (3.9) | 11.1 (2.6) | 11.0 (3.3) | 10.6 (4.3) |
| viable young male | 4.6 (2.6) | 4.8 (1.5) | 3.8 (1.5) | 4.7 (2.2) |
| viable young female | 5.5 (2.4) | 4.9 (1.7) | 5.5 (2.1) | 4.3 (2.5) |
| viable young total | 10.1 (3.7) | 9.8 (2.1) | 9.3a(2.6) | 9.0 (3.8) |
| early resorptions | 0.4 (0.6) | 0.3 (0.5) | 0.4 (0.6) | 0.7 (0.8) |
| late resorptions | 1.0 (1.0) | 1.1 (1.0) | 1.2 (1.1) | 0.9 (0.9) |
| total resorptions | 1.4 (1.2) | 1.3 (1.2) | 1.7 (1.3) | 1.6 (1.2) |
| Pre-Implantation loss (%) | 10.4 | 14.2 | 13.9 | 13.5 |
| Post-Implantations loss (%) | 12.1 | 12.1 | 15.2 | 14.7 |
| Premature delivery and total litter loss (%) | 10.0 | 5.3 | 5.3 | 0 |
a Includes one fetus not sexed at necropsy
Numbers in parentheses represent standard deviations.
Effect on developmental toxicity: via oral route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 2 000 mg/kg bw/day
- Study duration:
- subacute
- Species:
- rabbit
- Quality of whole database:
- GLP study according ICH Harmonised Tripartite Guidelines for Detection of Toxicity to Reproduction for Medicinal Products
Effect on developmental toxicity: via inhalation route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEC
- 1 076 mg/m³
- Study duration:
- subacute
- Species:
- rat
- Quality of whole database:
- study similar OECD TG 414
Effect on developmental toxicity: via dermal route
- Endpoint conclusion:
- no study available
Additional information
There is no study available on developmental toxicity for the target substance docosyl methacrylate. Methacrylate esters are rapidly hydrolyzed resulting in methacrylic acid and the corresponding alcohol (Jones,2002). Therefore, read-across from studies performed with the primary metabolites Docosan-1-ol (Behenyl alcohol, CAS 661-19-8) and Methacrylic acid (CAS 79-41-4) were utilized.
In a study comparable to OECD TG 414, groups of 19-25 pregnant female rats were given whole-body inhalation exposures to Methacrylic acid (CAS 79-41-4) at target concentrations of 0, 50, 100, 200 or 300 ppm (0, 179, 358, 716 and 1076 mg/m3) for 6 hours/day, during days 6 to 20 of gestation. Maternal toxicity in the form of significant decreases in maternal food consumption and weight gain was observed at 300 ppm. There were no significant changes in number of implantations and live fetuses, in the incidence of non-live implants and absorptions, or in fetal weights across groups. There was no consistent pattern of changes to suggest any treatment-related effects. The difference of fetuses with external, visceral, and skeletal variations did not differ between the control and the treated groups. No significant increase in embryo/fetal lethality or fetal malformations was observed after exposure. While maternal toxicity was observed, methacrylic acid caused no evidence of developmental toxicity up to 300 ppm. The NOAEC for developmental toxicity and teratogenicity was 300 ppm (1076 mg/m3) (Saillenfait et al. 1999).
In a further embryonic developmental study, pregnant rabbits were administered orally by gavage to Behenyl alcohol using doses of 125, 500 or 2000 mg/kg bw/day from day 6 to day 19 of gestation. No maternal toxicity was observed up to the highest dose tested. No intergroup differences suggestive of statistical significance were observed in the number of corpora lutea, pre- and postimplantation sites, early and late resorptions, and viable fetuses. Fetal and placental weights were not affected by treatment up to 2000 mg/kg bw/day. No external, visceral, and skeletal malformations between the control and the treated groups were observed. The NOAEL for developmental toxicity and teratogenicity was 2000 mg/kg bw/day, which was the highest dose tested (Iglesias et al, 2001).
In a study according OECD TG 422 Sprague-Dawley rats received the test item, Dodecyl methacrylate, by daily oral gavage at dose-levels of 100, 300 and 1000 mg/kg bw/day. The control group received the vehicle, corn oil, alone, under the same experimental conditions. There was no effect of treatment on the mean number of liveborn pups or on pup death after birth. There were no external pup abnormalities in the control or test item-treated groups. There was no effect of treatment on mean pup body weight or body weight gain for males or females. The sex ratios on days 1 and 5 post-partum were similar in the control and test item-treated groups. No relevant findings were observed in the pups sacrificed on day 6 post-partum. The NOEL for developmental toxicity was≥1000 mg/kg bw/day (SAM UNTER 05 -044).
In conclusion, based on studies in experimental animals, there is no evidence forreproductive/developmental toxicity of Docosyl methacrylate
Justification for classification or non-classification
Classification, Labelling, and Packaging Regulation (EC) No 1272/2008
The available experimental test data are reliable and suitable for classification purposes under Regulation (EC) No 1272/2008. Overall, in consideration of all data available for structurally analogous methacrylate esters and the primary metabolites of the target substance, there is no convincing evidence of reproductive or developmental toxicity. As a result the substance is not considered to be classified for developmental toxicity, as amended for the tenth time in Regulation (EU) No 2017/776.
Additional information
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