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EC number: 231-403-1 | CAS number: 7534-94-3
Toxicological information
Developmental toxicity / teratogenicity
Currently viewing:
Administrative data
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study
Data source
Reference
- Reference Type:
- publication
- Title:
- Unnamed
- Year:
- 1 999
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Version / remarks:
- before 27th June 2018
- Deviations:
- no
- GLP compliance:
- not specified
- Limit test:
- no
Test material
- Reference substance name:
- Methacrylic acid
- EC Number:
- 201-204-4
- EC Name:
- Methacrylic acid
- Cas Number:
- 79-41-4
- Molecular formula:
- C4H6O2
- IUPAC Name:
- 2-methylprop-2-enoic acid
- Test material form:
- liquid
Constituent 1
- Specific details on test material used for the study:
- TEST MATERIAL:
- Name of test material: Methacrylic acid
- CAS: 79-41-4
Obtained from Fluka Chemie AG
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Details on test animals or test system and environmental conditions:
- Nulliparous female Sprague-Dawley rats, weighing 180-200 grams obtained from IFFA Credo Breeding Labs.
Age at Start of Test: sexually mature females; age not specified. Mated females were housed inclear polycarbonate cages with stainless steel wire lids and hardwood shavings for bedding.
Food and water available adlibitum except during exposures.
12 hours light-dark photocycle
Acclimatization of test animals: 2 weeks
Administration / exposure
- 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 chamber. Chamber temperature was 23 °C +/- 2 °C, and the relative humidity was 50% +/- 5%. Food and water were withheld during exposure. Dynamic and adjustable laminar air flow (6 - 20 m³/h). 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 determined 3 times at regular intervals during each 6 hr exposure by collecting the material and analyzing against a standard using GC.
Target concentrations [ppm] Analytical concentrations [ppm]
mean +/- SD
--------------------------------------------------------------------------------
50 55.3 +/- 8.1
100 101.5 +/-16.9
200 207.3 +/- 24.7
300 316.0 +/- 36.7
-------------------------------------------------------------------------------- - Details on mating procedure:
- 2-3 females were caged with one male rat for mating. 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 were turned 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.
Doses / concentrationsopen allclose all
- Dose / conc.:
- 50 ppm
- Remarks:
- corresponds to 179 mg/m3
- Dose / conc.:
- 100 ppm
- Remarks:
- corresponds to 358 mg/m3
- Dose / conc.:
- 200 ppm
- Remarks:
- corresponds to 716 mg/m3
- Dose / conc.:
- 300 ppm
- Remarks:
- corresponds to 1076 mg/m3
- No. of animals per sex per dose:
- 23 to 27 female rats were bred resulting in 22 to 23 pregnant rats used for experiment.
- Control animals:
- yes, concurrent no treatment
Examinations
- Maternal examinations:
- BODY WEIGHT: Yes
- Time schedule for examinations: GDs 0, 6, 13 and 21
FOOD CONSUMPTION: Yes
- Time schedule for examinations: GDs 6-13 and 13-21 - Ovaries and uterine content:
- Uterine content was examined after termination: Yes
Examinations included:
- uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: No data
- Number of viable and dead fetuses: Yes
At necropsy, the uterine horns and ovaries were exposed to count the C.L., implantation sites, resorption sites, and viable and dead fetuses. FERTILITY AND REPRODUCTIVE PERFORMANCE: The following data were recorded for each group of numbers of CL, and implantation sites o number of resorptions and viable and dead fetuses. O mean fetal body weights o fetuses examined for gross malformations and skeletal abnormalities of sex and of fetuses. - Fetal examinations:
- - External examinations: Yes
- Soft tissue examinations: Yes
- Skeletal examinations: Yes
- Head examinations: No data
Live fetuses were weighed, sexed, and examined for external anomalies. 50% of the live fetuses from each litter were preserved in Bouin's solution and examined for internal soft-tissue changes. The remaining fetuses (50%) were fixed in ethanol (70%), eviscerated and then processed for skeletal staining with alizarin red S. - Statistics:
- The number of corpora lutea, implantation sites, and live fetuses, maternal food consumption and various body weights were analyzed by ANOVA, followed by Dunnett's
test. The percentage of non-live implant, resorptions, and males and the proportion of fetuses with alterations in each 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 analyzed using Fisher's test. Where appropriate, least squares analysis was performed. The level of significance was p < 0.05. The litter was used as the basis of analysis of fetal variables. - Indices:
- Pre- and postimplantation loss; live birth index
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- not specified
- Dermal irritation (if dermal study):
- not specified
- Mortality:
- no mortality observed
- Description (incidence):
- All animals survied the exposure.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Absolute weight gain was significantly reduced at 300 ppm.
Change in weight during gestation in Sprague-Dawley rats inhaling Methacrylic acid on days 6 to 20 of gestation and euthanized on day 21:
-------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Concentrations No of dams Mean Body weight [g] +/- SD Mean body weight gain on GD [g] Mean absolute weight gain [g]
[ppm], 6 h/day on GD 6 6 - 13 13 - 21 6 - 21
---------------------------------------------------------------------------------------------------------------------------------------------------------------------------
0 23 276 +/- 19 32 +/- 9 109 +/- 32 141 +/- 36 36 +/- 13
50 22 278 +/- 18 32 +/- 8 115 +/- 13 147 +/- 15 35 +/- 11
100 22 283 +/- 19 34 +/- 7 110 +/- 19 144 +/- 23 36 +/- 14
200 22 284 +/- 22 29 +/- 8 107 +/- 20 136 +/- 24 32 +/- 13
300 23 276 +/- 16 20 +/- 7** 91 +/- 26* 111 +/- 29** 12 +/- 14**
-------------------------------------------------------------------------------------------------------------------------------------------------------------------------
*, ** Denote significant differences from the control (0 ppm), p < 0.05 and p < 0.01, respectively.
Mean absolute weight gain: Mean body weight gain corrected by gravid uterine weight - Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- Food consumption was reduced at 300 ppm.
Food consumption of Sprague-Dawley rats inhaling Methacrylic acid on days 6 to 20 of gestation and euthanized on day 21:
-------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Concentrations No of dams Mean food consumption [g/dam/day] on GD
[ppm], 6 h/day 6 - 13 13 - 21 6 - 21
------------------------------------------------------------------------------------------------------------------------------------------------------------------------
0 23 23 +/- 2 27 +/- 3 25 +/- 2
50 22 24 +/- 1 28 +/- 2 26 +/- 2
100 22 24 +/- 3 28 +/- 3 26 +/- 3
200 22 22 +/- 2 27 +/- 2 25 +/- 2
300 23 20 +/- 2** 24 +/- 2** 22 +/- 26*
------------------------------------------------------------------------------------------------------------------------------------------------------------------------
*, ** Denote significant differences from the control (0 ppm), p < 0.05 and p < 0.01, respectively. - Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- not specified
- Haematological findings:
- not specified
- Clinical biochemistry findings:
- not specified
- Urinalysis findings:
- not specified
- Behaviour (functional findings):
- not specified
- Immunological findings:
- not specified
- Organ weight findings including organ / body weight ratios:
- not specified
- Gross pathological findings:
- not specified
- Neuropathological findings:
- not specified
- Histopathological findings: non-neoplastic:
- not specified
- Histopathological findings: neoplastic:
- not specified
Maternal developmental toxicity
- Number of abortions:
- no effects observed
- Description (incidence and severity):
- There were no abortions reported.
- Pre- and post-implantation loss:
- no effects observed
- Description (incidence and severity):
- There were no significant changes in number of implantations across control and exposed groups.
- Total litter losses by resorption:
- no effects observed
- Description (incidence and severity):
- Total litter loss by resoprtion was not reported.
- Early or late resorptions:
- no effects observed
- Description (incidence and severity):
- The number of early and late resorptions was unaffected by treatment.
- Dead fetuses:
- no effects observed
- Description (incidence and severity):
- The number of dead fetuses was not reported.
- Changes in pregnancy duration:
- not specified
- Description (incidence and severity):
- In the OECD 414, a Caesarian section on GD 21 is performed.
- Changes in number of pregnant:
- no effects observed
- Description (incidence and severity):
- The number of pregnant females is comparable to the control.
- Details on maternal toxic effects:
- Maternal toxic effects: yes
Details on maternal toxic effects:
All animals survived the exposure. Exposure to 300 ppm led to significant decreases in maternal weight gain and food consumption throughout exposure. Absolute weight gain was significantly reduced at 300 ppm.
Effect levels (maternal animals)
- Dose descriptor:
- NOAEL
- Effect level:
- 200 ppm
- Based on:
- test mat.
- Basis for effect level:
- body weight and weight gain
- Remarks on result:
- other: corresponds to 716 mg/m³
Maternal abnormalities
- Abnormalities:
- no effects observed
Results (fetuses)
- Fetal body weight changes:
- no effects observed
- Description (incidence and severity):
- The fetal body weight was unaffected by treatment.
- Reduction in number of live offspring:
- no effects observed
- Description (incidence and severity):
- Reproductive parameters in Sprague-Dawley rats inhaling Methacrylic acid on days 6 to 20 of gestation and euthanized on day 21:
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Concentrations No of litters No. of live fetuses per litter
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
0 22 14.73 +/- 3.92
50 22 14.86 +/- 1.93
100 22 14.05 +/- 3.17
200 22 13.77 +/- 3.99
300 22 14.05 +/- 3.76
----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- - Changes in sex ratio:
- no effects observed
- Description (incidence and severity):
- Reproductive parameters in Sprague-Dawley rats inhaling Methacrylic acid on days 6 to 20 of gestation and euthanized on day 21:
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Concentrations No of litters Average fetal body weight [g/per litter]
[ppm], 6 h/day All Males Females
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
0 22 5.71 +/- 0.56 5.86 +/- 0.57 5.42 +/- 0.37
50 22 5.66 +/- 0.27 5.82 +/- 0.32 5.49 +/- 0.27
100 22 5.79 +/- 0.30 5.92 +/- 0.32 5.62 +/- 0.32
200 22 5.76 +/- 0.47 5.92 +/- 0.47 5.54 +/- 0.45
300 22 5.67 +/- 0.49 5.71 +/- 0.34 5.54 +/- 0.52
----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- - Changes in litter size and weights:
- not specified
- Description (incidence and severity):
- Litter size and weights were not reported.
- Changes in postnatal survival:
- not specified
- Description (incidence and severity):
- The pups were euthanised before birth.
- External malformations:
- no effects observed
- Description (incidence and severity):
- No significant increase of external fetal malformations was observed after exposure to methacrylic acid. There was no difference between the control and exposed groups.
Description please see attached document (Incidence of malformations and variations in fetuses of Spraque-Dawley rats inhaling Methacrylic acid on days 6 to 20 of gestation). - Skeletal malformations:
- no effects observed
- Description (incidence and severity):
- No significant increase of skeletal fetal malformations was observed after exposure to methacrylic acid. There was no difference between the control and exposed groups.
Description please see attached document (Incidence of malformations and variations in fetuses of Spraque-Dawley rats inhaling Methacrylic acid on days 6 to 20 of gestation). - Visceral malformations:
- no effects observed
- Description (incidence and severity):
- No significant increase of visceral fetal malformations was observed after exposure to methacrylic acid. There was no difference between the control and exposed groups.
Description please see attached document (Incidence of malformations and variations in fetuses of Spraque-Dawley rats inhaling Methacrylic acid on days 6 to 20 of gestation). - Other effects:
- not specified
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects: no effects
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 malfomations. 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 were observed after exposure to methacrylic acid. While maternal toxicity was observed, methacrylic acid caused no evidence of developmental toxicity up to 300 ppm.
Effect levels (fetuses)
- Dose descriptor:
- NOAEL
- Remarks:
- prenatal developmental toxicity
- Effect level:
- > 300 ppm
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: no adverse effects observed
Fetal abnormalities
- Abnormalities:
- no effects observed
Overall developmental toxicity
- Developmental effects observed:
- no
Any other information on results incl. tables
| Methacylic acid (Saillenfait 1999, OECD 414 rat inhalativ 6 h/day) | |||||
| control | 50 ppm (corresponding 179 mg/m³) |
100 ppm (corresponding 358 mg/m³) |
200 ppm (corresponding 716 mg/m³) |
300 ppm (corresponding 1076 mg/m³) |
|
| number of pregnant/ non pregnant dams | 25 (total) / 23 (= 92%) pregnant / 2 non pregnant |
25 (total) / 22 (= 88%) pregnant / 3 non pregnant |
26 (total) / 23 (= 84.6%) pregnant / 3 non pregnant |
25 (total) / 22 (= 88%) pregnant / 3 non pregnant |
26 (total) / 23 (= 88.5%) pregnant / 3 non pregnant |
| number of dams with abortions/ early deliveries/ stillbirths/ resorptions and/or dead fetuses |
number of abortions not explicitly specified early deliveries were not reported (assumed to be 0) number of stillbirth were not reported (assumed to be 0) number of resorptions: 8.96 +/- 20.73 | number of abortions not explicitly specified early deliveries were not reported (assumed to be 0) number of stillbirth were not reported (assumed to be 0) number of resorptions: 3.22 +/- 3.34 | number of abortions not explicitly specified early deliveries were not reported (assumed to be 0) number of stillbirth were not reported (assumed to be 0) number of resorptions: 6.76 +/- 8.14 | number of abortions not explicitly specified early deliveries were not reported (assumed to be 0) number of stillbirth were not reported (assumed to be 0) number of resorptions: 5.67+/- 12.77 | number of abortions not explicitly specified early deliveries were not reported (assumed to be 0) number of stillbirth were not reported (assumed to be 0) number of resorptions: 10.61 +/- 21.45 |
| pre-implantation loss (as no individual data is given in the publication, the pre-implantation loss is calculated based on the means of number of corpora lutea and number of implantation sites) | 12.55 mean | 4.6 mean | 7.58 mean | 12.01 mean | 9.81 mean |
| postimplantation loss (as no individual data is given in the publication, the postimplantation loss is calculated based on the means of number of implantation sites and number of live offspring) | 1.21 mean | 3.26 mean | 6.33 mean | 4.11 mean | 2.63 mean |
| Mean Body weight [g] on GD6 | 276 +/- 19 SD | 278 +/- 18 SD | 283 +/- 19 SD | 284 +/- 22 SD | 276 +/- 16 SD |
| Mean Body weight change [g] | 141 +/- 36 on GD 6-21 | 147 +/- 15 on GD 6-21 | 144 +/- 23 on GD 6-21 | 136 +/- 24 on GD 6-21 | 111 +/- 29** on GD 6-21 significant different from the control (0 ppm) |
| mean gravid uterine weight including optionally body weight change corrected for gravid uterine weight (difference between body weight gain from GD 6-21 and absolute body weight gain) |
105 g mean | 112 g mean | 108 g mean | 104 g mean | 99 g mean |
| mean number and percent of live offspring | 14.73 live pups/litter percentage not specified | 14.86 live pups/litter percentage not specified |
14.05 live pups/litter percentage not specified | 13.77 live pups/litter percentage not specified |
14.05 live pups/litter percentage not specified |
| mean foetal/ pup weight by sex and sexes combined | 5.71 mean (g/litter) 5.86 males (g/litter) 5.42 females (g/litter) |
5.66 mean (g/litter) 5.82 males (g/litter) 5.49 females (g/litter) |
5.79 mean (g/litter) 5.92 males (g/litter) 5.62 females (g/litter) |
5.76 mean (g/litter) 5.92 males (g/litter) 5.54 females (g/litter) |
5.67 mean (g/litter) 5.71 males (g/litter) 5.54 females (g/litter) |
| number and percent of foetuses and litters with malformations (including runts) and/ or variations |
number of malformations: - litter affected: - number of variations: 37/324 or 11.4% litter affected: 21/22 (95.4%) |
number of malformations: - litter affected: - number of variations: 35/327 or 10.7% litter affected: 20/22 (90.9%) |
number of malformations: - litter affected: - number of variations: 41/309 or 13.3% litter affected: 15/22 (68.2%) |
number of malformations: 1/303 or 0.3% litter affected: 1/22 or 4.5% number of variations: 29/303 or 9.6% litter affected: 16/22 (72.7%) |
number of malformations: 2/309 or 0.6% litter affected: 2/22 or 9.0% number of variations: 39/309 or 12.6% litter affected: 16/22 (72.7%) |
| description and incidences of malformations and main variations (and/or retardation) |
(detailed information see attached document to the IUCLID entry of this study (Incidence of malformations and variations in fetuses of Spraque-Dawley rats inhaling Methacrylic acid on days 6 to 20 of gestation)) |
(detailed information see attached document to the IUCLID entry of this study (Incidence of malformations and variations in fetuses of Spraque-Dawley rats inhaling Methacrylic acid on days 6 to 20 of gestation)) |
(detailed information see attached document to the IUCLID entry of this study (Incidence of malformations and variations in fetuses of Spraque-Dawley rats inhaling Methacrylic acid on days 6 to 20 of gestation)) |
(detailed information see attached document to the IUCLID entry of this study (Incidence of malformations and variations in fetuses of Spraque-Dawley rats inhaling Methacrylic acid on days 6 to 20 of gestation)) |
(detailed information see attached document to the IUCLID entry of this study (Incidence of malformations and variations in fetuses of Spraque-Dawley rats inhaling Methacrylic acid on days 6 to 20 of gestation)) |
Applicant's summary and conclusion
- 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.
- Executive summary:
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 1076 mg/m³ methacylic acid 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 considerd to be 300 ppm (1076 mg/m³).
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