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EC number: 201-150-1 | CAS number: 78-85-3
- 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
Developmental toxicity / teratogenicity
Administrative data
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 19 May 1993 to 17 February 1995
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: Guideline study (GLP)
Cross-reference
- Reason / purpose for cross-reference:
- reference to other study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 995
- Report date:
- 1995
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Qualifier:
- according to guideline
- Guideline:
- EPA OTS 798.4350 (Inhalation Developmental Toxicity Screen)
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- Methacrylaldehyde
- EC Number:
- 201-150-1
- EC Name:
- Methacrylaldehyde
- Cas Number:
- 78-85-3
- Molecular formula:
- C4H6O
- IUPAC Name:
- methacrylaldehyde
- Reference substance name:
- Methacrolein
- IUPAC Name:
- Methacrolein
- Details on test material:
- - Analytical purity: 94.6 %
- Purity test date: 19 June 1992
- Lot/batch No.: 52000726
- Expiration date of the lot/batch: not stated
- CAS: 78-85-3
Constituent 1
Constituent 2
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Remarks:
- Crl: CD (SD) BR VAF/Plus strain
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River U.K. Limited, Manston Road, Margate, Kent.
- Age at study initiation: 8 - 10 weeks.
- Weight at study initiation: 173 - 239 g
-Batches of animals: The animals were devided into 2 batches. The first batch (A) consisted of 63 animals followed by an second batch (B) of 42 animals mated one day later. Both batches were treated identically.
- Fasting period before study: No.
- Housing: Animals were housed five to a cage (except during exposure periods) in suspended stainless steel cages (North Kent Plastic Cages Ltd) equipped with solid sides and wire grid front, back and floor. Each group of rats was kept in a separate ventilated cabinet to prevent any possible cross-contamination between groups.
- Diet: ad libitum. SDS Laboratory Animal Diet No. 1.
- Water: ad libitum.
- Acclimation period: no data.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 plus/minus 4 °C.
- Humidity (%): 46 plus/minus 15 %.
- Air changes (per hr): no data.
- Photoperiod (hrs dark / hrs light): 12 hrs dark / 12 hrs light.
IN-LIFE DATES: From: 19 May 1993 To: 8 June 1993
Administration / exposure
- Route of administration:
- inhalation: vapour
- Type of inhalation exposure (if applicable):
- whole body
- Vehicle:
- unchanged (no vehicle)
- Details on exposure:
- GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: The exposure chambers were constructed from stainless steel and glass and were of approximately 5000 litres internal volume. The chambers were of square cross-section fitted with a pyramidal base and top. An extraction plenum was fitted in the base of each chamber.
The chamber atmosphere was extracted by mean of individual air handling units, each fitted with activated charcoal filters. Agate valve fitted in each extract line was used to adjust the pressure within each chamber to approx. 5 mm of water below that of the room.
- Method of holding animals in test chamber: The rats were held within individual compartments of stainless steel wire mesh cages during exposure.
- Source and rate of air: no data.
-Atmosphere generation: Each test atmosphere was produced by metering the liquid from a gas-tight syringe mounted on a Precidor type 5003 syringe pump to a sintered glass disc contained in a glass vessel. Air was passed through the glass sinter at a rate of 100 litres per minute. The air supply was heated prior to entering the vaporiser by passing it through a copper coil submerged in a water bath maintained at 80 °C. The vapour air mixture entered the exposure chamber via the inlet duct.
- System of generating particulates/aerosols: not relevant.
- Temperature, humidity, pressure in air chamber (means):
Group 1 (Air control, Batch A): 23.0 °C/52 %
Group 2 (Low dose, Batch A): 25.0 ° C/41 %
Group 3 (Intermediate dose, Batch A): 25.2 °C/37 %
Group 4 (High dose, Batch A): 24.4 °C/48 %
pressure in air chamber: approx. 5 mm of water below that of the room.
Group 1 (Air control, Batch B): 22.9 °C/53 %
Group 2 (Low dose, Batch B): 24.7 ° C/42 %
Group 3 (Intermediate dose, Batch B): 25.1 °C/36 %
Group 4 (High dose, Batch B): 24.2 °C/49 %
pressure in air chamber: approx. 5 mm of water below that of the room.
- Air flow rate: 100 L/min.
- Method of particle size determination: not relevant.
- Treatment of exhaust air: Each chamber was fitted with ports for withdrawal of chamber air samples for analytical purposes. Routinely a port in the upper centre of the chamber side wall was used.
TEST ATMOSPHERE
- Brief description of analytical method used: gas chromatography.
- Samples taken from breathing zone: yes
PROCEDURE
-The rats were placed within the exposure cages, the cages loaded into the exposure chambers and the chamber doors sealed.
The air supply to the vaporisers was switched on and the flow rate set to 100 litres per minute. Chamber pressure was checked and adjusted if necessary to 5 mm of water below ambient.
Exposure commenced when the syringe pumps were switched on. The concentration of methacrolein within each chamber was cotrolled by the rate at which the test substance was supplied to each vaporiser. The feed rates required to achieve the target concentrations were determinded during preliminary investigations.
Following 6 hours of exposure the syringe pumps were switched off. After approx. 20 minutes the rats were unloaded from the chambers and returned to their holding cages.
Group 1 (Air control) rats were treated in similar fashion except that no methacrolein was introduced into the chamber.
VEHICLE (if applicable)
-air
- Justification for use and choice of vehicle: no data.
- Composition of vehicle: no data. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- - Gas chromatography.
- For further details see Appendix A1. - Details on mating procedure:
- - Cohoused:
- M/F ratio per cage: no data.
- Length of cohabitation: no data.
- Verification of same strain and source of both sexes: yes.
- Proof of pregnancy: vaginal plug or sperm in vaginal smear referred to as day 0 of pregnancy.
- Any other deviations from standard protocol: no. - Duration of treatment / exposure:
- 6 hours per day, gestation day 6-15 of pregnancy. A total of 10 exposures.
- Frequency of treatment:
- daily
- Duration of test:
- 20 Days.
Doses / concentrations
- Remarks:
- Doses / Concentrations:
0, 5, 10, 20 ppm nominal (= 0, 0.014, 0.028 and 0.056 mg/L)
Basis:
nominal conc.
- No. of animals per sex per dose:
- Batch A: 15 female animals per sex and dose.
Batch B: 10 female animals per sex and dose. - Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale:
The exposure levels employed were agreed between HRC and the Sponsor and based on the results of a preliminary study in pregnant rats (HRC Report No. BGH 42/921663) performed at these laboratories in which levels of 10, 20 and 30 ppm produced clear evidence of a dose-related maternal response, principally manifested as reduced bodyweight gain and food intake, although embryofoetal development appeared unaffected at all exposure levels. In a previous two-week study in male and non-pregnant female rats (HRC Report No. BGH 40/920648) performed at these laboratories, 5 ppm was identified as a "No Adverse Effect Level".
Group 1 (control, Batch A and B): 0 ppm.
Group 2 (low dose, Batch A and B): 5 ppm.
Group 3 (intermediate dose, Batch A and B): 10 ppm.
Group 4 (high dose, Batch A and B): 20 ppm.
- Rationale for animal assignment: Random.
-Other:
The rat is a universally accepted species in reproductive studies; in addition, Huntingdon Research Centre Ltd has background control data on reproductive performance in pre-natal toxicity studies for rats of the strain employed.
The route of administration (inhalation exposure) was selected by the Sponsor as this was a potential route of exposure to man.
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: at least twice daily (during exposure in 30-minute intervals).
- Cage side observations checked in table [No.1] were included.
DETAILED CLINICAL OBSERVATIONS: No
BODY WEIGHT: Yes
- Time schedule for examinations:
at arrival and on Days 3, 6, 8, 10, 12, 14, 16, 18 and 20 of gestation.
FOOD CONSUMPTION: Yes
Time schedule for examinations:
- group mean values (g/rat/day) on Days: 3-5, 6-7, 8-9, 10-11, 12-13, 14-15, 16-17, 18-19 of gestation.
WATER CONSUMPTION: Yes
- Time schedule for examinations:
- group mean values (g/rat/day): daily (Day 3 to Day 19 of gestation).
POST-MORTEM EXAMINATIONS: Yes
from all adult animals:
- Sacrifice on gestation day 20
- Organs examined: No data. - 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
- Other:
Number and distribution of live young
Number and distribution of embryofoetal deaths
Individual foetal weight from which the litter weight was calculated
Foetal abnormalities - Fetal examinations:
- - External examinations: Yes: all per litter.
- Soft tissue examinations: Yes: half per litter.
- Skeletal examinations: Yes: half per litter.
- Head examinations: No. - Statistics:
- Group mean values for maternal bodyweights and litter parameters have been calculated using all animals with live young at terminal sacrifice. All values expressed as a percentage were first calculated within the litter and the group values derived as a mean of individual litter percentages.
Group values for food and water were calculated from cage values and include all animals.
Significance tests, employing analysis of variance followed by an intergroup comparison with the control, were performed on the following parameters and results are presented in relevant tables of this report:
- body weight change
- food consumption
- water consumption
- litter data
- foetal changes
Dependent on the heterogeneity of variance between treatment groups,
- parametric tests, analysis of variance (Snedecor and Cochran, 1967) followed by Williams' test (Williams, 1971/72) or
- non-parametric tests, Kruskal-Wallis (Hollander and Wolfe, 1968) followed by Shirley's test (Shirley, 1977)
were used to analyse these data, as most appropriate.
For litter data and skeletal variants the basic sample unit was the litter and, due to the preponderance of non-normal distributions, non-parametric analyses were routinely used.
Malformations and anomalies were analysed in terms of litters with affected foetuses, using a one-tailed permutation test (Edgington 1980).
Where 75 % or more of the value for a given variable are the same, a Fisher's exact test (Fisher, 1950) was used, when considered necessary. - Historical control data:
- See Appendix 3.
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Clinical signs observed at 10 and 20 ppm during the 6-hour exposure periods (as noted from outside die exposure chambers) were principally related to irritancy i.e. half-closed/closed eyelids, noted generally between 0.5 and 1.5 hours after exposure began from the first day of treatment (Day 6 post coitum) at 20 ppm and from the third day at 10 ppm. At 5 ppm, no treatment-related clinical signs were observed during exposure.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- At 20 ppm, bodyweight gain was reduced following the start of treatment (Day 6) through to termination at Day 20, attaining statistical significance (P<-0.01) throughout.
Bodyweight gain at 5 and 10 ppm was essentially similar to controls (P >0.05).
Maternal developmental toxicity
- Details on maternal toxic effects:
- Maternal toxic effects:yes
Details on maternal toxic effects:
Half-closed/closed eyes were seen at the 20 and 10 ppm treatment levels during the exposure periods, although this sign was considered to be due to an irritant effect of the vapour and was not of major toxicological importance.
There was clear evidence of a significant treatment-related toxic response in adult females at 20 ppm, principally manifested as reduced bodyweight gain, impaired food intake and increased water consumption. The only possible treatment-related maternal effect at 5 or 10 ppm was a marginal reduction in food intake after initiation of treatment.
Effect levels (maternal animals)
- Dose descriptor:
- NOAEL
- Effect level:
- 0.014 mg/L air (analytical)
- Basis for effect level:
- other: maternal toxicity
Results (fetuses)
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:yes
Details on embryotoxic / teratogenic effects:
Amongst litter parameters, litter and mean foetal weight were slightly lower at 20 ppm. It is therefore considered that the no adverse effect level for all litter parameters is 10 ppm. However, in utero survival and morphological development appeared unaffected at exposure levels up to and including 20 ppm and it can be concluded that methacrolein does not induce any specific or permanent alteration in embryofoetal development in the rat.
Effect levels (fetuses)
- Dose descriptor:
- NOAEC
- Effect level:
- 0.028 mg/L air (analytical)
- Basis for effect level:
- other: slight reduction of the mean fetal weight in the 20 ppm group
Fetal abnormalities
- Abnormalities:
- no effects observed
- Description (incidence and severity):
- no teratogenicity
Overall developmental toxicity
- Developmental effects observed:
- not specified
Applicant's summary and conclusion
- Executive summary:
In this assessment of the effect of methacrolein on pregnancy and in utero development of the rat, daily target doses of 0 (Control), 5, 10 and 20 ppm were administered to groups of 25 time-mated females by whole-body inhalation exposure for 6 hours each day from Day 6 to Day 15 post coitum inclusive. On Day 20, all animals were killed and subjected to post mortem examination; litter values were determnined and foetuses were subsequently examined for visceral and skeletal changes.
Clear evidence of maternal toxicity was observed at 20 ppm, principally manifested as reduced weight gain and food intake. In addition, microscopic changes to the nasal turbinates, larynx, trachea, lungs and liver were observed at this exposure level in the preliminary study (HRC Report No. BGH 42/921663). At 10 ppm, food intake was slightly reduced with microscopic changes to the nasal turbinates observed in the preliminary study. With the possible exeption of marginally lower food intake at 5 ppm, no clear maternal effects were seen at this exposure level and 5 ppm was considered to be the no adverse effect level for adult females.
Amongst litter parameters, litter and mean foetal weight were slightly lower at 20 ppm. It is therefore considered that the no adverse effect level for all litter parameters is 10 ppm. However, in utero survival and morphological development appeared unaffected at exposure levels up to and including 20 ppm and it can be concluded that methacrolein does not induce any specific or permanent alteration in embryofoetal development in rat.
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