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EC number: 230-813-8 | CAS number: 7328-22-5
- 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
Endpoint summary
Administrative data
Key value for chemical safety assessment
Effects on fertility
Description of key information
OECD 422, GLP, rat, oral: NOAEL parental 1,000 mg/kg bw/day (no effects observed); NOAEL developmental 1,000 mg/kg bw/day (no effects)
Link to relevant study records
- Endpoint:
- screening for reproductive / developmental toxicity
- Remarks:
- based on test type (migrated information)
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 27 August to 22 October 2013
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Remarks:
- GLP, coherence between data, results and conclusions
- 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
A total of 90 Sprague Dawley [Crl:CD(SD)BR] rats (45 males and 45 virgin females), 6 to 7 weeks old and weighing 190 - 217 g for males and 175 - 189 g for females, were received from Charles River Italia S.p.A., Italy.
After arrival the weight range for each sex was determined and the animals were temporarily identified within the cage by means of a coloured mark on the tail. A health check was then performed by a veterinarian.
An acclimatisation period of 13 days was allowed before the start of treatment, during which time the health status of the animals was assessed by thorough observations.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22°C +/- 2°C
- Humidity (%): 55% +/- 15%
- Air changes (per hr): 15 to 20 air changes per hour
- Photoperiod (hrs dark / hrs light): artificial light for 12 hours each day
No relevant deviations from these ranges were recorded during the study.
In-life phase: August 2013 to 22 October 2013 - Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on exposure:
- The test item was administered orally by gavage at a dose volume of 5 mL/kg body weight. Control animals received the vehicle alone at the
same dose volume.
The required amount of Butyl diglycol methacrylate was suspended in the vehicle (corn oil) and brought to the final volume appropriate for each
concentration (concentrations of 20, 60 and 200 mg/mL) and kept under magnetic stirrer at room temperature prior to use and until the time of dosing of the last animal.
The formulations were prepared daily and the concentrations were calculated and expressed in terms of test item as supplied. - Details on mating procedure:
- Mating was monogamous (one male to one female). A vaginal smear was taken from the day after the start of pairing until positive identification of
copulation (sperm identification, vaginal plug in situ or copulation plugs found in the cage tray).
The female was paired with the same male until positive identification occurred or 14 days had elapsed. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Prior to commencement of treatment, analysis was performed to confirm that the proposed formulation procedure was acceptable (concentration
and homogeneity). Results of the analyses were within the limits of acceptance.
The stability was found to be 24 hours at room temperature in the concentration range of 20 to 200 mg/mL.
Samples of the formulations prepared on Week 1 and last Week were also analysed to check the concentration and homogeneity. Results of the analyses were within the limits of acceptance.
Chemical analysis was carried out by the Analytical Chemistry Department at RTC according to a validated method (RTC Study No. 96370), in the range from 5 to 200 mg/mL. - Duration of treatment / exposure:
- Males
Animals were dosed once a day, 7 days a week, for a minimum of 2 consecutive weeks prior to pairing and thereafter through the day before necropsy
(Day 29 - 30 of treatment).
Dose volumes were adjusted once per week for each animal according to the last recorded body weight.
Females
Animals were dosed once a day, 7 days a week, for a minimum of 2 consecutive weeks prior to pairing and thereafter during pairing, post coitum and
post partum periods until Day 3 post partum (the day before sacrifice).
Dose volumes were adjusted once per week for each animal according to the last recorded body weight.
During the gestation period, dose volumes were calculated according to individual body weight on Days 0, 7, 14 and 20 post coitum and on Day 1
post partum. Thereafter individual dose volumes remained constant. - Frequency of treatment:
- once daily
- Remarks:
- Doses / Concentrations:
100, 300 and 1000 mg/kg/day
Basis:
nominal conc. - No. of animals per sex per dose:
- The test item was administered orally, by gavage. The oral route was selected as it is a possible route of exposure of the test item in man.
3 groups comprised 10 males and 10 females rats received the test item at the dose levels of 100, 300 and 1000 mg/kg/day.
Each group comprised 10 male and 10 female rats. - Control animals:
- yes
- Details on study design:
- Dose levels of 100, 300 and 1000 mg/kg/day were selected by the Sponsor based on information from a previous non GLP compliant study (2 week preliminary study) (RTC Study no.: 96020EXT).
- Parental animals: Observations and examinations:
- Mortality
Throughout the study, all animals were checked early in each working day in the morning and in the afternoon. At weekends and Public Holidays a
similar procedure was followed except that the final check was carried out at approximately mid-day.
Clinical signs
Once before commencement of treatment and at least once daily during the study, each animal was observed and any clinical signs were recorded.
Observations were performed at the same time interval each day, the interval was selected taking into consideration the presence of post-dose reactions.
Clinical observations (Functional Observation Battery Tests)
Once before commencement of treatment and once a week thereafter, each animal was given a detailed clinical examination.
Each animal was removed from the home cage and observed in an open arena.
The tests included observation of changes in gait and posture, reactivity to handling, presence of clonic or tonic movements, stereotypies or bizarre
behaviour and effects on the autonomic nervous system (e.g. lachrymation, piloerection, pupil size, unusual respiratory pattern).
All observations were recorded for individual animals.
All observed parameters are reported in a group incidence table.
Grip strength and sensory reactivity to stimuli
Once during the study, towards the end of treatment, 5 males and 5 females were randomly selected from each group for evaluation of sensory reactivity to stimuli of different modalities (e.g. auditory, visual and proprioceptive stimuli); an assessment of grip strength was also performed. Measurements were performed using a computer generated random order. For males the tests were performed on day before necropsy of the study and for females on Day 3 post partum.
Motor activity assessment (MA)
Once during the study, towards the end of treatment, 5 males and 5 females were randomly selected from each group and the motor activity was measured (for approximately 5 minutes) by an automated activity recording device. Measurements were performed using a computer generated random order. For males the tests were performed the day before necropsy and for females on Day 3 post partum.
Body weight
Males were weighed weekly from allocation to termination.
Females were weighed weekly from allocation to positive identification of mating and on Days 0, 7, 14 and 20 post coitum. Dams were also weighed on Days 1 and 4 post partum.
Food consumption
The weight of food consumed by each cage of males and females was recorded weekly during the pre-mating period starting from allocation.
Individual food consumption for the females was measured on gestation Days 7, 14 and 20 post coitum starting from Day 0 post coitum and on Day 4 post partum starting from Day 1 post partum. - Oestrous cyclicity (parental animals):
- Vaginal smears were taken daily in the morning starting two weeks before pairing until a positive identification of copulation was made.
The vaginal smear data were examined to determine the following:
a) anomalies of the oestrous cycle;
b) pre-coital interval (i.e., the number of nights paired prior to the detection of mating). - Sperm parameters (parental animals):
- Parameters examined in [all/P/F1/F2] male parental generations:
Testis weight, epididymis weight. The testes and epididymides were cut at 2-3 micrometer thickness and stained with Periodic Acid Schiff (PAS).
The morphological evaluation of the seminiferous epithelium (staging of spermatogenic cycle) was performed. - Litter observations:
- A parturition check was performed from Day 20 to Day 25 post coitum. Females which did not give birth after 25 days of post coitum period were sacrificed shortly after. Gestation length was calculated as the time between the day of successful mating (Day 0 post coitum) and the day of commencement of birth (i.e. first detected presence of offspring in the cage). The day that offspring were first detected in the cage was considered Day 0 post partum.
As soon as possible, after parturition was considered complete (Days 0 or 1 post partum), all pups (live and dead) were counted, sexed and live pups were identified. Live pups were individually weighed on Days 1 and 4 post partum.
Pups killed or dying during the lactation period were weighed before the despatch to necropsy.
Observation was performed once daily for all litters. - Postmortem examinations (parental animals):
- Parental animals were killed by exsanguination under isofluorane anaesthesia.
Pups were euthanised by intraperitoneal injection of Thiopenthal
Parental males:
The males were killed after the mating of all females (after 29-30 days of treatment).
Parental females:
The females with live pups were killed on Day 4 post partum.
The females which did not give birth 25 days after positive identification of mating were killed shortly after.
Necropsy
The clinical history of the males and females of the parental generation was studied and a detailed post mortem examination was conducted
(including examination of the external surface and orifices). Changes were noted, the requisite organs weighed and the required tissue samples
preserved in fixative and processed for histopathological examination.
Females:
All females were examined also for the following:
- number of visible implantation sites (pregnant animals);
- number of corpora lutea (pregnant animals).
Uteri of female with no visible implantations were immersed in a 10-20% solution of ammonium sulphide to reveal evidence of implantation.
Organ weights
From all animals completing the scheduled test period, the organs were dissected free of fat and weighed.
The ratios of organ weight to body weight were calculated for each animal.
Tissues fixed and preserved
Samples of all the tissues listed were fixed and preserved in 10% neutral buffered formalin (except eyes, optic nerves and Harderian glands, testes and epididymides which were fixed in modified Davidson's fluid and preserved in 70% ethyl alcohol).
Histopathological examination
The tissues required for histopathological examination are listed in Annex 1. After dehydration and embedding in paraffin wax, sections of the
tissues were cut at 5 micrometer thickness and stained with haematoxylin and eosin.
In addition, the testes and epididymides were cut at 2-3 micrometer thickness and stained with Periodic Acid Schiff (PAS). The morphological
evaluation of the seminiferous epithelium (staging of spermatogenic cycle) was performed.
The examination was restricted as detailed below:
a) Tissues specified in Annex 1 from 5 males and 5 females randomly selected (animals evaluated for clinical pathology) in the control and
high dose groups killed at term.
b) All abnormalities in all groups. - Postmortem examinations (offspring):
- Pups
All pups found dead in the cage were examined for external and internal abnormalities.
All live pups sacrificed at termination were examined for external abnormalities and sex confirmation by gonadal inspection. All pups with
abnormalities were retained in an appropriate fixative. - Statistics:
- Standard deviations were calculated as appropriate. For continuous variables the significance of the differences amongst group means was assessed by Dunnett’s test or a modified t test, depending on the homogeneity of data.
Statistical analysis of histopathological findings was carried out by means of the non-parametric Kolmogorov-Smirnov test if n was more than 5. The
non-parametric Kruskal-Wallis analysis of variance was used for the other parameters. Intergroup differences between the control and treated
groups were assessed by the non-parametric version of the Williams test. The criterion for statistical significance was p<0.05. The mean values,
standard deviations and statistical analysis were calculated from actual values in the computer without rounding off. - Reproductive indices:
- Group mean values were calculated for all parameters. Data from non-pregnant females were excluded from group mean calculations.
The following reproductive indices were calculated:
Males
Copulatory Index (%) = no. of animals mated/no. of animals paired x 100
Fertility Index (%) = no. of males which induced pregnancy/no. of animals paired x 100
Females
Copulatory Index (%) = no. of animals mated/no. of animals paired x 100
Fertility Index (%) = no. of pregnant females/no. of females paired x 100
Males and Females
Pre-coital Interval = Mean number of days between pairing and mating
Sex ratios were calculated at birth and on Day 4 post partum and were presented as the percentage of males per litter.
- Offspring viability indices:
- Females
Pre-birth loss was calculated as a percentage from the formula:
(No. of visible implantations-total litter size at birth)/No. of visible implantations x 100
Pup loss at birth was calculated as a percentage from the formula:
(Total litter size-live litter size)/Total litter size x 100
Cumulative pup loss on Day 4 post partum was calculated as a percentage from the formula:
(Total litter size at birth-live litter size at Day 4 post partum)/Total litter size at birth x 100
Pre- implantation loss was calculated as a percentage from the formula:
(no. of corpora lutea - no. of implantations)/no. of corpora lutea x 100 - Clinical signs:
- no effects observed
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
- Other effects:
- 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
- Effect level:
- 1 000 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: general toxicity
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: fertility
- Clinical signs:
- no effects observed
- Mortality / viability:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Gross pathological findings:
- no effects observed
- Key result
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- 1 000 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: no effects observed
- Reproductive effects observed:
- not specified
- Conclusions:
- On the basis of the results obtained in this study with Butyl diglycol methacrylate, the NOAEL (No Observed Adverse Effect Level) the NOAEL for
reproductive toxicity was found to be 1000 mg/kg/day for males and females. - Executive summary:
In a Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test according to OECD Guideline 422 (22 March 1996) Butyl diglycol methacrylate was administered to 10 Hsd: Sprague Dawley SD rats/sex/dose orally by gavage at dose levels of 0 (control), 100, 300 and 1000 mg/kg bw/d. The treatment schedule included 2 weeks before pairing for males and during pairing with females until the day before necropsy, for a total of 29/30 days. Females were treated for 2 weeks prior to pairing, during pairing and throughout the gestation and lactation periods until Day 3 post partum. The following investigations were performed in all groups: body weight, clinical signs (including neurotoxicity assessment, motor activity and sensory reaction to stimuli), food consumption, oestrous cycle, mating performance, clinical
pathology investigations (haematology and clinical chemistry), litter data, macroscopic observations, organ weights and histopathological examination. Clinical signs and macroscopic observations of pups were also performed. The histopathological examination was performed only on control and high dose groups (five animals/sex/group selected randomly). It included identification of the stages of the spermatogenic cycle in five males.
No animals died during the study. A total of 3 females were found not pregnant at necropsy: 2 in the mid-dose group and 1 in the high dose group. The number of females with live pups on Day 4 post partum was: 10 each in the control ad low dose groups, 8 in the mid-dose and 9 in the high dose groups.
No relevant clinical signs were seen throughout the whole study in treated animals of both sexes.
Clinical observations for neurotoxicity assessment (removal of animals from the home cage and open arena) did not reveal changes attributable to the test item.
Motor activity and sensory reaction to stimuli revealed in no relevant differences in all parameters investigated between
control and treated groups of both sexes.
No differences of toxicological significance in body weight and body weight gain were recorded in animals of both sexes compared to the control group, throughout the study.
Food consumption was unaffected by treatment in both sexes during the study.
Haematology: No changes of toxicological relevance were seen.
Clinical chemistry: No adverse findings were detected at any dose.
All females mated both in the control and treated groups. Oestrous cycle, precoital intervals, copulatory index and fertility index did not show intergroup differences.
Corpora lutea, implantations, pre-implantation and pre-birth loss percentages, total litter size and gestation length did not reveal any treatment-related effect. No differences in total and live litter size, litter weight, mean pup weight and
sex ratio were noted between groups at birth and on Day 4 post partum.
Clinical signs noted in pups throughout the study were considered unrelated to treatment.
Necropsy findings in decedent pups and in pups sacrificed on Day 4 post partum did not reveal any treatment-related effect.
Terminal body weight was unaffected by treatment in both sexes. Changes in organ weights were of slight severity and therefore considered of no toxicological significance.
Macroscopic observations: No remarkable changes were noted at post mortem examination in treated animals when compared to controls.
Microscopic observations: No treatment-related findings were observed in high dose males and females.
Conclusions:
This study is acceptable and satisfies the guideline requirement for a Screening reproductive study according to OECD 422 in rats.
On the basis of the results obtained in this study, the NOAEL (No Observed Adverse Effect Level) for general toxicity was considered to be 1000 mg/kg/day for males and females.
The NOAEL for reproductive toxicity was also found to be 1000 mg/kg/day for males and females.
Reference
No mortality occurred throughout the study. A total of 3 females were found not pregnant at necropsy: 2 in the mid-dose group and 1 in the high
dose group. The number of females with live pups on Day 4 post partum was: 10 each in the control and low dose groups (0 and 100 mg/kg bw/day), 8 in the mid-dose group (300 mg/kg bw/day) and 9 in the high dose group (1000 mg/kg bw/day).
Clinical signs and clinical observations (Functional Observation Battery Tests)
No relevant clinical signs were observed throughout the study in all treated animals of both sexes.
Observation of animals at removal from the cage and in an open arena (neurotoxicity assessment) did not reveal changes attributable to the test
item.
Motor activity and sensory reaction to stimuli
No relevant differences were noted in all parameters investigated between control and treated groups
Body weight and body weight gain
Means of body weight and body weight gain were comparable between control and treated groups both in males and females throughout the study.
The statistically significant decrease in body weight and/or body weight gain, detected in low dose group of males before pairing and during
mating, as well as the statistically significant increase in body weight gain of low dose group of females before pairing were considered of no
toxicological relevance since the changes were minimal and not dose-related.
In addition, decreases in body weight and body weight gain, noted during the post partum phase in control and treated females, were considered as a normal consequence of the parturition occurred in the females.
Food consumption
Food consumption was unaffected by treatment in both sexes during the study. The statistically decrease detected in the high dose group on Day 7
post coitum was minimal and not considered related to treatment.
Haematology
Reticulocytes were decreased in animals dosed with 1000 mg/kg/day (approximately 33%). Due to the absence of changes in the red cells
parameters, the above reticulopenia was considered toxicologically irrelevant. In addition, the statistically significant decrease of mean
corpuscular haemoglobin concentration, recorded in males dosed with 100 mg/kg/day and 1000 mg/kg/day (2%), was considered of no
toxicological importance due to its minimal severity. No changes were recorded in coagulation parameters.
Clinical chemistry
Statistically significant increase of glucose (50%) and potassium (14%) and decrease of cholesterol (27%), protein (9%), albumin (11%), calcium (3%)
and sodium (1%) were recorded in males dosed with 1000 mg/kg/day. No changes were recorded in treated females. Due to the slight severity of
the above changes, the recorded findings were not considered adverse.
Oestrus cycle, reproductive parameters, pairing combination and mating performance
Oestrous cycle and reproductive parameters (pre-coital intervals, copulatory and fertility indices) did not show relevant differences between treated and control groups.
Implantation, pre-birth loss data and gestation length of females
Corpora lutea, implantations, pre-implantation loss and total litter size were similar between treated and control groups. The slight increase in
pre-birth loss percentage detected in mid- and high dose groups when compared to controls was not statistically significant and not dose-related. Gestation periods were similar in treated groups and controls.
Terminal body weight and organ weights
Terminal body weight was unaffected by treatment in both sexes. Some statistically significant differences were noted in the absolute and/or
relative organ weight of treated animals when compared to controls, such as:
– Higher absolute heart weight in low dose females (+11%).
– Lower absolute spleen weight in high dose females (-19%).
– Higher absolute and relative thymus weight in mid-dose females (+35% and +37% respectively).
– Higher relative kidneys weight in low dose males (+ 9%) and high dose females (13%).
All the above differences were of low magnitude and occurred without dosedependency. Therefore, they were considered unrelated to treatment.
Macroscopic observations
Detailed macroscopic observations have been reported for male and female animals from all groups. No remarkable changes were noted at post
mortem examination in treated animals when compared to controls.
Microscopic observations
Histopathological evaluation was performed on five randomly selected control and high dose males and females, as well as on all abnormalities
detected during post mortem observation. In addition, a detailed qualitative examination of the testes was performed in five randomly selected
control and high dose group males. No treatment-related findings were observed in high dose males and females. Seminiferous tubules were
evaluated with respect to their stage in the spermatogenic cycle and to the integrity of the various cell types within the different stages; regular
layering in the germinal epithelium was noted. The lesions reported in control and treated animals were considered to be an expression of
spontaneous and/or incidental pathology, commonly seen in this species and age under our experimental conditions.
No differences in total and live litter size, litter weight, mean pup weight and sex ratio were noted between groups at birth and on Day 4 post partum.
Clinical signs of pups
Apparently no food intake (milk), small appearance and pallor were the clinical signs noted in pups of the control and treated groups. A
malformation (acaudia) was detected in one foetus (female no. 96380039) of the low dose group. These clinical signs noted in pups were
considered unrelated to treatment.
Necropsy findings in decedent pups and in pups sacrificed on Day 4 post partum
Necropsy findings in decedent pups and in pups sacrificed on Day 4 post partum did not reveal any treatment-related effect.
Oestrus cycle – Before pairing - Group summary data
-----------------------------------------------------------------------------------------------------------------------------------
Group 1 Group 2 Group 3 Group 4
Animal Oestrus Animal Oestrus Animal Oestrus Animal Oestrus
Number Cycles Number Cycles Number Cycles Number Cycles
-----------------------------------------------------------------------------------------------------------------------------------
96380001 2 96380021 1 96380041 3 96380061 3
96380003 4 96380023 2 96380043 3 96380063 3
96380005 2 96380025 2 96380045 2 96380065 3
96380007 4 96380027 0 96380047 2 96380067 2
96380009 2 96380029 3 96380049 2 96380069 2
96380011 3 96380031 3 96380051 2 96380071 2
96380013 2 96380033 3 96380053 2 96380073 2
96380015 3 96380035 2 96380055 4 96380075 2
96380017 2 96380037 4 96380057 3 96380077 4
96380019 1 96380039 2 96380059 1 96380079 2
Means 2.5 2.2 2.4 2.5
-----------------------------------------------------------------------------------------------------------------------------------
Note: The number of oestrus cycles is based on the number of non sequential days the dams were in oestrus.
Reproductive parameters of males - Summary
-----------------------------------------------------------------------------------------------------------------------------------
Group 1 2 3 4
-----------------------------------------------------------------------------------------------------------------------------------
Copulatory Index% 100.0 100.0 100.0 100.0
-----------------------------------------------------------------------------------------------------------------------------------
Fertility Index% 100.0 100.0 80.0 90.0
-----------------------------------------------------------------------------------------------------------------------------------
Reproductive parameters of females – Summary
-----------------------------------------------------------------------------------------------------------------------------------
Group 1 2 3 4
-----------------------------------------------------------------------------------------------------------------------------------
Copulatory Index% 100.0 100.0 100.0 100.0
-----------------------------------------------------------------------------------------------------------------------------------
Fertility Index% 100.0 100.0 80.0 90.0
-----------------------------------------------------------------------------------------------------------------------------------
Effect on fertility: via oral route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 1 000 mg/kg bw/day
- Study duration:
- subacute
- Species:
- rat
- Quality of whole database:
- Neither the methacrylate moiety nor the higher glycol ethers and particularly butyldiglycol appear to affect fertility. Furthermore Butyldiglycol methacrylate showed no impact on fertility when tested in rats in an OECD 422 combined repeat dose and reproductive/developmental toxicity screening test (HRTF, 2014).
Effect on fertility: via inhalation route
- Endpoint conclusion:
- no study available
Effect on fertility: via dermal route
- Endpoint conclusion:
- no study available
Additional information
Butyldiglycol methacrylate (BDGMA) was studied in an OECD 422 combined repeat dose and reproductive/developmental toxicity screening test (HRTF, 2014). Groups of 10 male and 10 female rats were administered by gavage at dose levels of 0, 100, 300, or 1000 mg/kg/day. Male rats were dosed for 29 days and female rats were dosed from 14 days prior to mating through Day 3 of lactation. On the basis of the results obtained in this study, there were no significant signs of general systemic toxicity and fertility up to 1000 mg/kg/day for males and females. The NOAEL for effects on fertility was found to be 1000 mg/kg/day males and females.
In conclusion there is no indication for Butyldiglycol methacrylate to produce reprotoxic effects. The generated NOAEL for BDGMA in an OECD 422 repeated dose and reproductive toxicity screening study was determined to be 1000 mg/kg bw/day.
Short description of key information:
OECD 422 reproductive toxicity screening study with Butyldiglycol methacrylate: Reproductive NOAEL 1000 mg/kg, no apparent systemic toxicity up to 1000 mg/kg (Klimisch score: 1, guideline study, GLP) (HRTF, 2014).
Justification for selection of Effect on fertility via oral route:
In a reproductive toxicity screening study according to OECD 422 with Butyldiglycol methacrylate in rats, no impact on fertility was observed (reliability 1, guideline study, GLP).
Effects on developmental toxicity
Description of key information
Developmental toxicity studies with primary metabolites:
MAA:
Saillenfait et al. (1999); Developmental study in rats; No effects on development up to 300 ppm (1232 mg/m³), equivalent to a body burden of 409 mg/kg/d.
MMA:
OECD 414 developmental toxicity study in rabbits; No effects on development up to 450 mg/kg bw/d. (Klimisch score: 1, guideline study, GLP) (HMRTF, 2009).
OECD 414 developmental toxicity study in rats; No effects on development up to 2028 ppm. (Klimisch score: 1, guideline study, GLP) (Rohm and Haas, 1991).
BDGE:
Ema et al. (1988); OECD 414-like developmental toxicity study in rats; No effects on development up to 1%.
Nolen et al. (1985); OECD 414-like developmental toxicity study in rabbits; No effects on development up to 1000 mg/kg bw/d.
Link to relevant study records
- Endpoint:
- developmental toxicity
- Type of information:
- read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Justification for type of information:
- Read across to the methacrylic metabolite:
According to RAAF 2019, the analogue read-across approach, Scenario 1: “read-across based on (bio)transformation to common compound(s)” has been identified as appropriate in order to fulfill the data gap.
Thus, the information requirement (according to REACH Regulation Annex IX) is covered with read across to the methacrylic metabolites.
For detailed information and justification please refer to the attached Read across Justification Document: “Read across assessment according to ECHA’s Read Across Assessment Framework (RAAF)”. - Reason / purpose for cross-reference:
- read-across source
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Version / remarks:
- before 27th June 2018
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EPA OTS 798.4350 (Inhalation Developmental Toxicity Screen)
- Deviations:
- no
- GLP compliance:
- yes
- Species:
- rat
- Strain:
- other: Crl:CDBR
- Key result
- Dose descriptor:
- NOAEC
- Remarks:
- maternal toxicity
- Effect level:
- 8.44 mg/L air (analytical)
- Based on:
- test mat.
- Basis for effect level:
- other: no adverse effects observed
- Remarks on result:
- other: no adverse effects observed
- Dose descriptor:
- LOEC
- Remarks:
- maternal toxicity
- Effect level:
- ca. 0.41 mg/L air (analytical)
- Based on:
- test mat.
- Basis for effect level:
- other: maternal toxicity
- Key result
- Abnormalities:
- no effects observed
- Key result
- Dose descriptor:
- NOAEC
- Remarks:
- prenatal developmental toxicity
- Effect level:
- 8.44 mg/L air (analytical)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: no adverse effects observed
- Remarks on result:
- other: no substance related effects observed
- Dose descriptor:
- NOAEC
- Remarks:
- fetotoxicity
- Effect level:
- 8.44 mg/L air (analytical)
- Based on:
- test mat.
- Sex:
- male/female
- Remarks on result:
- other: corresponding to 2028 ppm; no substance related effects observed
- Key result
- Abnormalities:
- no effects observed
- Key result
- Developmental effects observed:
- no
- Conclusions:
- For BDGMA, Methyl methacrylate (MMA) CAS: 80-62-6 serves as metabolite donor substance of the methacrylate moiety of BDGMA (see Read Across Document). From this study the adverse effect levels and potential developmental toxicity of BDGMA can be concluded. For read across purposes according to ECHA's RAAF (2019), this study is applicable with a high level of confidence.
Exposure by inhalation to methyl methacrylate concentrations up to 8.44 mg/L (2028 ppm) resulted in no embryo or fetal toxicity or malformations even at exposure levels that resulted in maternal toxicity. - Executive summary:
For BDGMA, Methyl methacrylate (MMA) CAS: 80-62-6 serves as metabolite donor substance of the methacrylate moiety of BDGMA (see Read Across Document). From this study the adverse effect levels and potential developmental toxicity of BDGMA can be concluded. For read across purposes according to ECHA's RAAF (2019), this study is applicable with a high level of confidence.
In a developmental toxicity study (1991) acc. OECD 414 by inhalation on CRl: CD Br rats pregnant rats were exposed to methyl methacrylate at concentrations of 0 (control), 99, 304, 1178 and 2028 ppm on days 6-15 of gestation. A maternal no observed level was not demonstrated since losses in maternal body weight or decreases in maternal body weight gain and decreases in maternal feed consumption were noted at all exposure levels tested. No embryo or fetal toxicity was evodent and no increase in the incidence of malformations or variations was noted at exposure levels up to and including 2028 ppm. Therefore toxicity to the conceptus was not evident even at expsoure levels that resulted in overt maternal toxicity.
- Endpoint:
- developmental toxicity
- Type of information:
- read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Justification for type of information:
- Read across to the methacrylic metabolite:
According to RAAF 2019, the analogue read-across approach, Scenario 1: “read-across based on (bio)transformation to common compound(s)” has been identified as appropriate in order to fulfill the data gap.
Thus, the information requirement (according to REACH Regulation Annex IX) is covered with read across to the methacrylic metabolites.
For detailed information and justification please refer to the attached Read across Justification Document: “Read across assessment according to ECHA’s Read Across Assessment Framework (RAAF)”. - Reason / purpose for cross-reference:
- read-across source
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Version / remarks:
- adopted 22nd January 2001
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)
- Version / remarks:
- August 1998
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- other: ECC Directive 2004/73/EC, Part B: Method for the determination of Toxicity: Prenatal Developmental Toxicity Study; Official Journa of the European Communities; L 216, pp.227-235.
- Version / remarks:
- 29th April 2004
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
- Species:
- rabbit
- Strain:
- Himalayan
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- general toxicity
- Effect level:
- 450 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Remarks on result:
- not determinable due to absence of adverse toxic effects
- Dose descriptor:
- NOEL
- Effect level:
- 50 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Basis for effect level:
- food consumption and compound intake
- Remarks on result:
- other:
- Remarks:
- actual dose: 41 mg/kg bw/d
- Key result
- Abnormalities:
- no effects observed
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- prenatal developmental toxicity
- Effect level:
- 450 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Remarks on result:
- not determinable due to absence of adverse toxic effects
- Key result
- Abnormalities:
- no effects observed
- Key result
- Developmental effects observed:
- no
- Conclusions:
- For BDGMA, Methyl methacrylate (MMA) CAS: 80-62-6 serves as metabolite donor substance of the methacrylate moiety of BDGMA (see Read Across Document). From this study the adverse effect levels and potential developmental toxicity of BDGMA can be concluded. For read across purposes according to ECHA's RAAF (2019), this study is applicable with a high level of confidence.
In conclusion, the no observed adverse effect level (NOAEL) for maternal toxicity is 450 mg/kg bw/d and the no observed effect level (NOEL) for maternal toxicity is 50 mg/kg bw/d based on effects on food consumption. The NOAEL for prenatal developmental toxicity is 450 mg/kg bw/d. No adverse fetal findings of toxicological relevance were evident at any dose. - Executive summary:
For BDGMA, Methyl methacrylate (MMA) CAS: 80-62-6 serves as metabolite donor substance of the methacrylate moiety of BDGMA (see Read Across Document). From this study the adverse effect levels and potential developmental toxicity of BDGMA can be concluded. For read across purposes according to ECHA's RAAF (2019), this study is applicable with a high level of confidence.
The study was performed according to OECD TG 414 in compliance with GLP.
Methyl Methacrylate was tested for its prenatal developmental toxicity in Himalayan rabbits. The test substance was administered as an aqueous preparation to 25 inseminated female Himalayan rabbits by stomach tube at doses of 50; 150 and 450 mg/kg body weight/day on gestation days (GD) 6 through GD 28. The control group, consisting of 25 females, was dosed with the vehicle (1% Carboxymethylcellulose CB 30.000 in drinking water and a few drops Cremophor EL and one drop hydrochloric acid [1% CMC]) in parallel. A standard dose volume of 10 mL/kg body weight was used for each test group. At terminal sacrifice on GD 29, 24-25 females per group had implantation sites.
The following test substance-related adverse effects/findings were noted:
Test group 3 (450 mg/kg body weight/day):
- Reduced food consumption (-18%) and body weight gain (-31%)
- No test substance-related adverse effects on gestational parameters or fetuses
Test group 2 (150 mg/kg body weight/day):
- Reduced food consumption (-13%) and body weight gain (-27%)
- No test substance-related adverse effects on gestational parameters or fetuses
Test group 1 (50 mg/kg body weight/day):
- No test substance-related adverse effects on does, gestational parameters or fetuses
In conclusion, the no observed adverse effect level (NOAEL) for maternal toxicity is nominal 450 mg/kg bw/d (actual 406 mg/kg bw/d), the highest dose tested. The no observed effect level (NOEL) for maternal toxicity is nominal 50 mg/kg bw/d (effective 41 mg/kg bw/d) based on effects on food consumption being a consequence of reduced appetite observed at the LOEL (Lowest Observed Effect Level) of 150 mg/kg bw/d (actual 132 mg/kg bw/d).
The no observed adverse effect level (NOAEL) for prenatal developmental toxicity is nominal 450 mg/kg bw/d (actual 406 mg/kg bw/d). No adverse fetal findings of toxicological relevance were evident at any dose.
- Endpoint:
- developmental toxicity
- Type of information:
- read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study
- Justification for type of information:
- Read across to the methacrylic metabolite:
According to RAAF 2019, the analogue read-across approach, Scenario 1: “read-across based on (bio)transformation to common compound(s)” has been identified as appropriate in order to fulfill the data gap.
Thus, the information requirement (according to REACH Regulation Annex IX) is covered with read across to the methacrylic metabolites.
For detailed information and justification please refer to the attached Read across Justification Document: “Read across assessment according to ECHA’s Read Across Assessment Framework (RAAF)”. - Reason / purpose for cross-reference:
- read-across source
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Version / remarks:
- before 27th June 2018
- Deviations:
- no
- Species:
- rat
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- general toxicity
- Effect level:
- ca. 200 ppm
- Based on:
- test mat.
- Basis for effect level:
- body weight and weight gain
- Key result
- Abnormalities:
- no effects observed
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- prenatal devolpmental toxicity
- Effect level:
- > 300 ppm
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: no adverse effects observed
- Remarks on result:
- other: no adverse effects observed
- Key result
- Abnormalities:
- no effects observed
- Key result
- Developmental effects observed:
- no
- Conclusions:
- Using a valid scientific method, no significant increase in embryo/fetal lethality or fetal malformations were observed after exposure to methacrylic acid. While maternal toxicity was observed, methacrylic acid caused no evidence of developmental toxicity up to 300 ppm.
For BDGMA, MAA is the primary methacrylic metabolite of BDGMA (see Read Across Document). From this study the adverse effect levels for parental and developmental toxicity of MAA in rats can be concluded. For read across purposes according to ECHA's RAAF (2019), this study is applicable with a high level of confidence. - Executive summary:
For BDGMA, MAA is the primary methacrylic metabolite of BDGMA (see Read Across Document). From this study the adverse effect levels for parental and developmental toxicity of MAA in rats can be concluded. For read across purposes according to ECHA's RAAF (2019), this study is applicable with a high level of confidence.
In an OECD 414 prenatal developmental toxicity study using whole body inhalation methacrylic acid produced no embryo - or foetal lethality, nor fetal malformations after exposure with methacrylic acid, despite overt maternal toxicity (decreased body weight and feed consumption). The NOEC (teratogenicity) was considerd to be 300 ppm (1076 mg/m³).
- Endpoint:
- developmental toxicity
- Type of information:
- read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Justification for type of information:
- Read across to the alcohol metabolite:
According to RAAF 2019, the analogue read-across approach, Scenario 1: “read-across based on (bio)transformation to common compound(s)” has been identified as appropriate in order to fulfill the data gap.
Thus, the information requirement (according to REACH Regulation Annex IX) is covered with read across to the alcohol metabolite.
For detailed information and justification please refer to the attached Read across Justification Document: “Read across assessment according to ECHA’s Read Across Assessment Framework (RAAF)”. - Reason / purpose for cross-reference:
- read-across source
- Key result
- Dose descriptor:
- NOEL
- Effect level:
- > 1 000 mg/kg bw/day
- Based on:
- test mat.
- Remarks on result:
- not determinable due to absence of adverse toxic effects
- Key result
- Abnormalities:
- no effects observed
- Key result
- Dose descriptor:
- NOEL
- Effect level:
- > 1 000 mg/kg bw/day
- Based on:
- test mat.
- Remarks on result:
- not determinable due to absence of adverse toxic effects
- Key result
- Abnormalities:
- no effects observed
- Key result
- Developmental effects observed:
- no
- Executive summary:
For BDGMA, Butylidiglycol (DGBE) CAS: 112-34-5 serves as metabolite donor substance of the butyldiglycol moiety of BDGMA (see Read Across Document). From this study the adverse effect levels and potential for reproductive toxicity of BDGMA can be concluded. For read across purposes according to ECHA's RAAF (2019), this study is applicable with a high level of confidence.
No significant differences were seen in any of the reproductive characteristics measured, indicating that the doses of DGBE given in this study were not embryotoxic. Furthermore, there were no significant differences in the incidences of malformed fetuses, indicating that these doses of DGBE were not teratogenic in the rabbit.
- Endpoint:
- developmental toxicity
- Type of information:
- read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Justification for type of information:
- Read across to the alcohol metabolite:
According to RAAF 2019, the analogue read-across approach, Scenario 1: “read-across based on (bio)transformation to common compound(s)” has been identified as appropriate in order to fulfill the data gap.
Thus, the information requirement (according to REACH Regulation Annex IX) is covered with read across to the alcohol metabolite.
For detailed information and justification please refer to the attached Read across Justification Document: “Read across assessment according to ECHA’s Read Across Assessment Framework (RAAF)”. - Reason / purpose for cross-reference:
- read-across source
- Key result
- Dose descriptor:
- LOAEL
- Effect level:
- ca. 0.04 other: %
- Based on:
- test mat.
- Basis for effect level:
- body weight and weight gain
- Key result
- Abnormalities:
- no effects observed
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- > 1 other: %
- Based on:
- test mat.
- Sex:
- male/female
- Remarks on result:
- not determinable due to absence of adverse toxic effects
- Key result
- Abnormalities:
- no effects observed
- Key result
- Developmental effects observed:
- no
- Conclusions:
- For BDGMA, Butylidiglycol (DGBE) CAS: 112-34-5 serves as metabolite donor substance of the butyldiglycol moiety of BDGMA (see Read Across Document). From this study the adverse effect levels and potential for reproductive toxicity of BDGMA can be concluded. For read across purposes according to ECHA's RAAF (2019), this study is applicable with a high level of confidence.
In conclusion, it is apparent that DEGMBE has no harmful effects on the pre- and postnatal development of the rat offspring at the oral doses employed in the present study. - Executive summary:
For BDGMA, Butylidiglycol (DGBE) CAS: 112-34-5 serves as metabolite donor substance of the butyldiglycol moiety of BDGMA (see Read Across Document). From this study the adverse effect levels and potential for reproductive toxicity of BDGMA can be concluded. For read across purposes according to ECHA's RAAF (2019), this study is applicable with a high level of confidence.
cited from the publication: Pregnant rats were given DEGMBE at a dosage of 0, 0.04., 0.2 or 1% in the diet during pregnancy. Food consumption during pregnancy was not significantly different among the groups, but the maternal body weight gaing during pregnancy in the DEGMBE-treated groups was significantly lower than that of the control group. These observations suggest that DEGMBE is toxic to the pregnant rat.
As for the prenatal development of the offspring, DEGMBE did not cause any significant change in the incidence of pre- or postimplanation loss or the fetal body weight of both sexes. These findings suggest that DEGMBE possesses no adverse effects on the prenatal growth of rat offspring.
External, skeletal and internal examinations of the fetuses revealed no evidence on teratogenesis. Although one fetus with fusion of sternebrae was observed in each of the 0.2 and 1% groups, this anomaly is considered to be spontaneous, because it is of a type seen in term fetuses of control rats. Several types of skeletal variations were detected in all the groups, but no consistent tendency was observed in the incidence of the fetuses with these variations. In addition, no significant differences between the DEGMBE-treated groups and the control group were found in the incidences of individual types of skeletal variation and delayed ossification of sternebrae. The degree of ossification in the 0.04% group was significantly lower than that of the control group, but no dose-related manner was observed, and the skeletal variations and delayed ossifications were frequently seen in term fetuses of rats. Therefore, it appears that DEGMBE has no teratogenicity in rats.
In postnatal development of the offspring, a high survival rate and good growth of the offspring were observed in all groups. These findings suggest that DEGMBE administered to pregnant rats induces no adverse effects on the postnatal growth of the offspring.
In conclusion, it is apparent that DEGMBE has no harmful effects on the pre- and postnatal development of the rat offspring at the oral doses employed in the present study.
Referenceopen allclose all
Mean measured concentrations (± SD) within the chambers for the 0, 100, 300, 1200 and 2000 ppm groups were 98.8 (±3.4), 304.4 (±9.1), 1178.1 (±69.1) and 2028.2 (±107.3) ppm, respectively.
Effect on developmental toxicity: via oral route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 1 000 mg/kg bw/day
- Study duration:
- subacute
- Species:
- rat
- Quality of whole database:
- Screening level data available from OECD 422 study, supported by developmental toxicity data from primary metabolites methacrylic acid and butyldiglycol, both indicating an absence of developmental toxicity.
Effect on developmental toxicity: via inhalation route
- Endpoint conclusion:
- no study available
Effect on developmental toxicity: via dermal route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 1 000 mg/kg bw/day
- Study duration:
- subacute
- Species:
- rat
- Quality of whole database:
- Publication on BDGE; well documented and in accordance to scientifically accepted principles
Additional information
a) Parental compound BDGMA:
In a Combined Repeated Dose Toxicity Study with the Reproduction/ Developmental Toxicity Screening Test according to OECD Guideline 422 (22 March 1996), BDGMA was administered to 10 Hsd: Sprague Dawley SD rats/sex/dose orally by gavage at dose levels of 0 (control), 100, 300 and 1,000 mg/kg bw/d. The treatment schedule included 2 weeks before pairing for males and during pairing with females until the day before necropsy, for a total of 29/30 days. Females were treated for 2 weeks prior to pairing, during pairing and throughout the gestation and lactation periods until Day 3 post-partum. The following investigations were performed in all groups: body weight, clinical signs (including neurotoxicity assessment, motor activity and sensory reaction to stimuli), food consumption, oestrous cycle, mating performance, clinical pathology investigations (haematology and clinical chemistry), litter data, macroscopic observations, organ weights and histopathological examination. Clinical signs and macroscopic observations of pups were also performed. The histopathological examination was performed only on control and high dose groups (five animals/sex/group selected randomly). It included identification of the stages of the spermatogenic cycle in five males.
Regarding the analysed endpoints (see above), the results were comparable between the control and treated animals. Based on these results, the NOAEL (No Observed Adverse Effect Level) for both general toxicity and reproduction/developmental toxicity was determined to 1,000 mg/kg/day for males and females (RTC, 2014).
b) Metabolites
MAA/ MMA
In an OECD 414 prenatal developmental toxicity study using whole body inhalation methacrylic acid at test concentrations of 50, 100, 200 and 300 ppm, corresponding to 179, 358, 716 and 1,076 mg/m³ MAA did not produce any embryo - or foetal lethality, nor fetal malformations, despite overt maternal toxicity (decreased body weight and feed consumption). The NOEC (teratogenicity) was considered to be 300 ppm (1,076 mg/m³) (Saillenfait, 1999).
MMA as metabolite donor substance for MAA has been tested in an oral OECD 414 study in rabbits at 0, 50, 150 and 450 mg/kg bw/d. The NOAEL for developmental toxicity was reported as 450 mg/kg bw/d. There were no adverse effects observed in the pups, even in the presence of maternal toxicity manifested in a reduced body weight due to reduced food consumption. The derived maternal NOEL was 50 mg/kg bw/d (BASF, 2009).
In a developmental toxicity study according to OECD 414 by inhalation, pregnant rats were exposed to MMA at concentrations of 0, 99, 304, 1178 and 2028 ppm on Gestation Day 6-15. A maternal NOEL was not demonstrated since transient losses in maternal body weight or transient decreases in maternal body weight gain and decreases in maternal feed consumption were noted at all exposure levels tested. The body weight No embryo or foetal toxicity was evident and no increase in the incidence of malformations or variations was noted at exposure levels up to and including 2028 ppm. Therefore, toxicity to the conceptus was not evident even at exposure levels that resulted in overt maternal toxicity (Solomon et al., 1991).
Based on the available results on MMA, it was concluded in the OECD SIDS of MAA that ”data on reproductive toxicity of MAA in animals or humans does not exist. From studies with MMA no concern in relation to reproductive toxicity of MAA has to be assumed” (OECD SIDS, 2002). This statement is supported by the results of an oral OECD 414 in rabbits showing no effects on the pups, even in the presence of maternal toxicity.
BDGE
Pregnant rats were given BDGE at a dosage of 0, 0.04., 0.2 or 1% in the diet during pregnancy. Although the food consumption was comparable in all treated groups, the body weight gain was significantly lower in the treated rats. The alcohol did not cause any significant change in the incidence of pre- or postimplanation loss or the fetal body weight of both sexes. There were no treatment-related external, skeletal and internal malformations observed. Furthermore, a high survival rate and good growth of the offspring were observed in all groups. The maternal LOAEL was considered to be 0.04%. The developmental NOAEL was considered to be 1% (Ema, 1988).
The alcohol BDGE was administered dermally to rabbits (20 does per group). The substance was applied dermally at doses of 0/100/300/1000 mg/kg from Gestation Day 7-18. No differences were seen in any of the reproductive/ developmental characteristics measured, indicating that the doses of DGBE given in this study were not embryotoxic. Furthermore, there were no significant differences in the incidences of malformed foetuses, indicating that these doses of DGBE were not teratogenic in the rabbit. The maternal and developmental NOAEL were considered to be 1,000 mg/kg bw/d (Nolen, 1985).
The alcohol BDGE was tested for toxicity to reproduction in a well conducted repeated dose study in rats (25 animals per sex and dose group). The substance was applied dermally at a dose of 2,000 mg/kg to males for 90 days pre-mating and until mating was successful. Females were exposed 90 for days pre-mating and during the gestation (20 days) and lactation period (21 days). Parental animals showed no substance induced effects on fertility, reproductive indices did not differ from controls. Litters delivered were allowed to grow until the end of lactation. They showed no signs of teratogenicity or fetotoxicity and no deviation to controls in offspring viability indices. There was no evidence for systemic toxicity by clinical and histopathological evaluations for all animals. Therefore, the NOAEL of the study can be determined to 2,000 mg/kg/d (Auletta, 1993).
Justification for classification or non-classification
Overall, in consideration of all data available for BDGMA and its metabolites, there is no evidence of reproductive toxicity and a general absence of developmental effects.
In summary, classification of Butyldiglycol methacrylate for reproductive toxicity is not required.
Additional information
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.