Registration Dossier

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Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

A combination study of OECD 422/ 408 is ongoing. The results will be reported as soon as they will become available. 


The current NOAEL is based on read-across data with the metabolites and will be updated  as soon as the new data will become available. 

Link to relevant study records
Reference
Endpoint:
screening for reproductive / developmental toxicity
Remarks:
A combination study of OECD 422/ 408 is ongoing
Data waiving:
other justification
Justification for data waiving:
other:
Justification for type of information:
The performance of the OECD 422/408 is in delay and is currently being conducted. The results will be available presumably in Q3/2023. The results will be included in the assessment in the next dossier update.

Principles of method if other than guideline:
OECD 422/ 408
GLP compliance:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Route of administration:
oral: gavage
Reproductive effects observed:
not specified
Effect on fertility: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
400 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
In summary the database is reliable for the assessment of the endpoint. NOAEL derived from BASF; read across with the analogous substance MMA
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available

Effects on developmental toxicity

Description of key information

A combination study of OECD 422/ 408 is ongoing. The results will be reported as soon as they will become available. 


The current NOAEL is based on read-across data with the metabolites and will be updated  as soon as the new data will become available. 


Depending on the results of the OECD 422, we will decide whether the OECD 414, 1st species has to be conducted or the current read-across strategy is still valid. 

Link to relevant study records

Referenceopen allclose all

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Method and result sufficient described, similar to OECD-guideline 414, GLP.
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
other: Crl:CDBR
Details on test animals or test system and environmental conditions:
Nulliparous female rats, weighing 183-240 grams upon arrival.
AGE AT TIME OF MATING: 88-95 days. 
ACCLIMATION PRIOR TO MATING: 7 days 
SOURCE: Charles River Breeding Laboratories Inc., Kingston, NY.
Animals were housed individually, except during mating, in suspended stainless-steel cages (7" x 8" x 13.5"). During exposures, females were housed individually in suspended stainless-steel, wire mesh cages (6" x 7" x 11"). Temperature range was 23 ± 2°C and the relative humidity ranged from 40-60% during cohabitation and 63-80% during the exposure and post-exposure periods. Food (Certified Purina Rodent Chow #5002) and filtered tap water were available ad libitum except during exposures. A photoperiod of 12 hrs dark/ 12 hrs light was maintained.
Route of administration:
inhalation
Type of inhalation exposure (if applicable):
whole body
Vehicle:
unchanged (no vehicle)
Details on exposure:
The test material exposure concentrations were generated by metering the test material with calibrated Fluid Metering Pumps (Fluid Matering Inc., Oyster Bay, NY) into 500 mL three-necked round bottom flasks (Lab Glass Inc., Vineland, NJ).
Exposures were whole body and were conducted in 2000 L stainless steel, glass and Plexiglas® chambers. Cage positions within the chamber were rotated daily. The temperature and relative humidity within the chambers during exposure were 22-24°C and 55-67%, respective.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The concentration of the test substance in the chambers was determined by the use of a Miran gas analyzer attached to a strip chart recorder. A probe was placed into the center of the chamber and the chamber atmosphere was drawn into the Miran A1 gas analyzer at a rate of 9.5 L/min. Each chamber was analyzed initially within 40 min. of the end of the t99 to insure that each chamber was within the accepted target range. Subsequently, each chamber was sampled every 120 min. A range of  plus or minus 10% of the target chamber concentration was maintained by making minor adjustments on the generator pump delivery rates whenever necessary.
Details on mating procedure:
Females were mated with males overnight (one male:one female) and the presence of sperm in the vaginal smear was considered  gestation day 0. Mated females were exposed via inhalation to the test material for 6 hrs/day on gestation days 6 through 15 and then sacrificed on day 20.  
Duration of treatment / exposure:
6 - 15 day of gestation
Frequency of treatment:
6 hours/day
Duration of test:
20 d (dams were euthanized on gestation day 20)
No. of animals per sex per dose:
27 animals per group exposed; 22-25 pregnant  females per exposure group.
Control animals:
yes, sham-exposed
Details on study design:
- Other: The strain was selected because background development toxicity data exists as Rohm and Haas Company on this rat strain. The test material was given by inhalation since the respiratory route is a potential route of human exposure.
Maternal examinations:
Maternal body weights were recorded on GD 0, 6, 8, 10, 13, 16 and 20. Food consumption was measured for GD intervals 0-6, 6-10, 10-16 and 16-20. Animals were observed daily for behavioral changes.
Ovaries and uterine content:
On GD 20, all dams were asphyxiated with carbon dioxide, the thoracic and abdominal cavities were examined and the uterus was removed and weighed, and corpora lutea, implantation sites and resorptions were counted. The number of fetuses per litter was counted and position inside the uterus recorded. The uteri of apparently non pregnant rats were stained with a 10% ammonium sulfide solution to detect very early resorptions. All fetuses were weighed, examined for external alterations and the sex of each fetus was determined. 
Fetal examinations:
One half of the fetuses from each litter were examined for visceral alterations using the Staples' technique. Head alterations were recorded for these fetuses examined for soft tissue alterations using the technique of Barrow and Taylor (1969, J. Morphol., 127: 291-306). The carcasses of all fetuses  were stained with alizarin red S and examined for skeletal alterations. 
Statistics:
For the purpose of statistical evaluation, the litter was considered the experimental unit for fetal parameters. Pregnancy rate, clinical signs, maternal deaths, gross necropsy findings  and liters with total resorptions were statistically analyzed using the  Fisher's exact test. Maternal body weight data and feed consumption values were statistically analyzed using Dunnett's test when the one-way ANOVA was significant. The number of implantations, live fetuses, resorptions, corpora lutea, mean fetal body weight/litter, and incidence of fetal alterations were statistically analyzed using the Mann-Whitney U test. When more than 75% ties occurred, then Fisher's exact test was used in place of the Mann-Whitney U test to detect significant differences between groups.
Details on maternal toxic effects:
Details on maternal toxic effects:
No animals died and no treatment-related clinical signs were noted for the dams in the 99, 304 or 1178 ppm groups. Scant feces was noted in the 2028 ppm group throughout the exposure period (GD 6-15). Treatment-related decreases on maternal body weight and feed consumption were noted at all exposure levels. The decreases in maternal body weight at 99 and 304 ppm were minimal and transient since they occurred only during the first 2 days of exposure and returned to control values by the  next weighing period. The body weight and feed consumption values returned to control values for all groups during the post exposure period  (GD 16-20). At 1178 and 2028 ppm, treatment-related effects included losses in maternal body and/or decreased body weight gain throughout the exposure period (GD 6 - 16) and decreased corrected maternal body weight gain. The gross necropsy evaluations did not indicate any treatment-related effects and there were no treatment-related differences between the control and treated groups in any reproductive parameter.  
Dose descriptor:
LOEC
Effect level:
ca. 0.41 mg/L air (analytical)
Basis for effect level:
other: maternal toxicity
Details on embryotoxic / teratogenic effects:
Details on embryotoxic / teratogenic effects:
 Fetal body weight was not affected by exposure to MMA vapors. The fetal external, visceral and skeletal examinations did not show any treatment related effects.
Dose descriptor:
NOAEC
Effect level:
>= 8.3 mg/L air (analytical)
Basis for effect level:
other: fetotoxicity
Dose descriptor:
NOAEC
Effect level:
>= 8.3 mg/L air (analytical)
Basis for effect level:
other: teratogenicity
Abnormalities:
not specified
Developmental effects observed:
not specified

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.

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study. Although the study was only reported in 2009 it was already commisioned before the establishment of ECHA and therefore no test proposal could be submitted.
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
yes (incl. QA statement)
Limit test:
no
Species:
rabbit
Strain:
Himalayan
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services, Germany GmbH
- Age at study initiation: 16-21 weeks
- Weight at study initiation: 2187-2917 g
- Fasting period before study: no
- Housing: the rabbits were housed singly in type 12.2395.C stainless steel wire mesh cages supplied by Draht-Bremer GmbH, Marktheidenfeld, Germany (floor area about 3,000 cm²)
- Diet: pelleted “Kliba maintenance diet for rabbits & guinea pigs, GLP”, supplied by Provimi Kliba SA, Kaiseraugst, Switzerland, ad libitum
- Water: tap water ad libitum
- Acclimation period: at least 5 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 30-70
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12 / 12 (6.00 p.m. to 6.00 a.m. dark, 6.00 a.m. to 6.00 p.m. light)
Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
The aqueous test substance preparations were prepared at the beginning of the administration period and thereafter at maximum intervals of 7 days, which took into account the analytical results of the stability verification. For the test substance preparation, an specific amount of test substance was weighed depending on the dose group, into a graduated flask (conical Erlenmeyer flasks with groundin stopper), topped up (shortly under the marking) with 1% Carboxymethylcellulose solution in drinking water and a few drops Cremophor EL and one drop of 32% hydrochloric acid. Afterwards the preparation was filled up with 1% Carboxymethylcellulose suspension in drinking water. The flask was sealed and the preparation was intensely mixed with a magnetic stirrer. During administration, the preparations were kept homogeneous with a magnetic stirrer and the vessels were kept closed between the withdrawals of the preparations.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Samples of the test substance preparations were sent to the analytical laboratory twice during the study period (at the beginning and towards the end) for verification of the concentrations. Samples were analyzed by GC with external calibration.
Details on mating procedure:
After an acclimatization period of at least 5 days, the female rabbits were fertilized by means of artificial insemination. This implied that 0.2 mL of a synthetic hormone which releases LH and FSH from the anterior pituitary lobe (Receptal) were injected intramuscularly to the female rabbits about 1 hour before insemination. The ejaculate samples used for the artificial insemination were derived from male Himalayan rabbits of the same breed as the females. Each female was inseminated with the sperm of a defined male donor. The male donors were kept under conditions (air conditioning, diet, water) comparable to those of the females participating in this study. The day of insemination was designated as gestation day (GD) 0 and the following day as GD 1.
Duration of treatment / exposure:
from implantation to one day prior to the expected day of parturition (GD 6-28)
Frequency of treatment:
daily
Duration of test:
until GD 29
No. of animals per sex per dose:
25 inseminated females per dose
Control animals:
yes, concurrent vehicle
Details on study design:
The dose volume was 10 mL/kg body weight. The calculation of the volume administered was based on the most recent individual body weight.
Maternal examinations:
CLINICAL EXAMINATIONS
- Mortality: Mortality was checked in the females twice a day on working days or once a day on Saturdays, Sundays or on public holidays (GD 0-29).
- Clinical symptoms: A clinical examination was conducted at least once daily for any signs of morbidity, pertinent behavioral changes and signs of overt toxicity. If such signs occurred, the animals were examined several times daily (GD 0-29).
- Food consumption: The food consumption was determined daily on GD 1–29.
- Body weight data: All animals were weighed on GD 0, 2, 4, 6, 9, 11, 14, 16, 19, 21, 23, 25, 28 and 29. The body weight change of the animals was calculated.
- Corrected (net) body weight gain: The corrected body weight gain was calculated after terminal sacrifice (terminal body weight on GD 29 minus weight of the unopened uterus minus body weight on GD 6).

TERMINAL EXAMINATIONS OF THE DOES
After the does had been sacrificed on GD 29, they were necropsied and assessed by gross pathology in randomized order.
Ovaries and uterine content:
On GD 29, the surviving does were sacrificed in randomized order by an intravenous injection of pentobarbital (Narcoren; dose: 2 mL/animal). After the does had been sacrificed, they were necropsied and assessed by gross pathology in randomized order. The uterus and the ovaries were removed and the following data were recorded:
- Weight of the unopened uterus
- Number of corpora lutea
- Number and distribution of implantation sites classified as:
1) live fetuses
2) dead implantations: a) early resorptions (only decidual or placental tissues visible or according to SALEWSKI (Salewski, 1964) from uteri from apparently non-pregnant animals and the empty uterus horn in the case of single-horn pregnancy); b) late resorptions (embryonic or fetal tissue in addition to placental tissue visible); c) dead fetuses (hypoxemic fetuses which did not breathe spontaneously after the uterus had been opened).
After the weight of the uterus had been determined, all subsequent evaluations of the does and the gestational parameters were conducted by technicians unaware of treatment group in order to minimize bias. For this purpose the animal numbers were encoded.
Furthermore, calculations of conception rate and pre- and postimplantation losses were carried out:
The conception rate (in %) was calculated according to the following formula: (number of pregnant animals)/(number of fertilized animals) x 100.
The preimplantation loss (in %) was calculated based on each individual pregnant animal with scheduled sacrifice according to the following formula: (number of corpora lutea – number of implantations)/(number of corpora lutea) x 100.
The postimplantation loss (in %) was calculated based on each individual pregnant animal with scheduled sacrifice from the following formula: (number of implantations – number of live fetuses)/(number of implantations) x 100.
Fetal examinations:
All fetal analyses were conducted by technicians unaware of the treatment group, in order to minimize bias.
- Examination of the fetuses after dissection from the uterus: Each fetus was weighed and examined macroscopically for any external findings.
Furthermore, the viability of the fetuses and the condition of the placentae, the umbilical cords, the fetal membranes, and fluids were examined. Individual placental weights were recorded. Thereafter, the fetuses were sacrificed by a subcutaneous injection of phenobarbital (Narcoren; 0.2 mL/fetus).
- Soft tissue examination of the fetuses: After the fetuses had been sacrificed, the abdomen and the thorax were opened in order to examine the organs in situ before they were removed. The heart and the kidneys were sectioned in order to evaluate the internal structure. The sex of the fetuses was determined by examination of the gonads in situ. After these examinations, the heads of approximately one half of the fetuses per litter and the heads of those fetuses, which revealed severe findings during the external examination (e.g. anophthalmia, microphthalmia or hydrocephalus) were severed from the trunk. These heads were fixed in BOUIN's solution and were, after fixation, processed and evaluated according to WILSON's method (Wilson and Warkany, 1965). About 10 transverse sections were prepared per head. After the examination these heads were discarded. All fetuses (partly without heads) were skinned and fixed in ethyl alcohol. After fixation for approx. 1-5 days, the fetuses were removed from the fixative for awhile. With a scalpel, a transversal incision was made into the frontal / parietal bone in the heads of the intact fetuses. The two halves of the calvarium were then cauteously bent outward and the brain was thoroughly examined. Subsequently, the fetuses were placed back into the fixative for further fixation.
- Skeletal examination of the fetuses: After fixation in ethyl alcohol the skeletons were stained according to a modified method of KIMMEL and TRAMMELL (Kimmel, C.A., and Trammell, C., 1981). Thereafter, the stained skeleton of each fetus was examined. After the examination the stained skeletons were retained individually.
Statistics:
- DUNNETT-test (two-sided) for food consumption, body weight, body weight change, corrected body weight gain (net maternal body weight change), carcass weight, weight of unopened uterus, number of corpora lutea, number of implantations, number of resorptions, number of live fetuses, proportions of preimplantation loss, proportions of postimplantation loss, proportions of resorptions, proportion of live fetuses in each litter, litter mean fetal body weight, litter mean placental weight.
- FISHER'S EXACT test (one-sided) for female mortality, females pregnant at terminal sacrifice, number of litters with fetal findings.
- WILCOXON-test (one-sided) for proportions of fetuses with malformations, variations and/or unclassified observations in each litter.
Details on maternal toxic effects:
Details on maternal toxic effects:
- Mortality: There were no test substance-related or spontaneous mortalities in any group.
- Clinical symptoms: No test substance-related clinical signs or any disturbances of the general behavior were observed in any rabbit during the entire study period.
- Food consumption: The food consumption in the high-dose females (450 mg/kg bw/d) was distinctly and statistically significantly reduced during a significant part of the treatment period (GD 15-23). During the entire treatment period (GD 6-28) the total average food consumption of the high dose rabbits was about 18% below controls. The food consumption of the mid dose females (150 mg/kg bw/d) was similarly affected in terms of magnitude and course of reduction, however the reduction of food consumption reached statistical significance only on GD 22-24. During the treatment period (GD 6-28) the total average food consumption of the mid-dose rabbits was about 13% below controls. Overall, the food consumption of the low-dose does (50 mg/kg bw/d) did not show test substance-related impairments. The reduced food consumption at the 150 and 450 mg/kg bw/d levels is considered to be related to the treatment.
- Body weight data: The mean body weights of the low-, mid- and high-dose rabbits (50; 150 and 450 mg/kg bw/d) were not significantly different from the concurrent control throughout the course of the study. The average body weight gain of the mid- and high-dose rabbits was statistically significantly reduced by about 27% and 31% during the treatment period. A significant reduction of mean body weight gain was also noted for the the high-dose rabbits on GD 19-21.
- Corrected (net) body weight gain: Mean carcass weights and the corrected body weight gain (terminal body weight on GD 29 minus weight of the unopened uterus minus body weight on GD 6) were comparable among all groups.
- Uterus weight: The mean gravid uterus weights of test groups 1, 2, and 3 (50; 150 or 450 mg/kg bw/d) did not show statistically significant differences in comparison to the control group.
- Necropsy findings: At necropsy, only spontaneous findings were seen in single females of every test group. No test substance-related findings were observed in the does.
- Reproduction data of does: The conception rate reached 96% in test groups 1 and 3 (50 and 450 mg/kg bw/d) and 100% in test groups 0 and 2 (0 and 150 mg/kg bw/d). Importantly, a sufficient number of pregnant females was available for the purpose of the study, as 24-25 pregnant rabbits per group had implantation sites in the uterus, at terminal sacrifice. There were no test substance-related and/or biologically relevant differences between the control and all dosed groups in conception rate, in the mean number of corpora lutea and implantation sites or in the values calculated for the pre- and the postimplantation losses, the number of resorptions and viable fetuses. Gestational parameters were within the normal range for animals of this strain and age.
Dose descriptor:
NOAEL
Effect level:
50 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
body weight and weight gain
food consumption and compound intake
Remarks on result:
other: maternal toxicity
Details on embryotoxic / teratogenic effects:
Details on embryotoxic / teratogenic effects:
- Sex distribution of fetuses: The sex distribution of the fetuses in test groups 1-3 (50; 150 and 450 mg/kg bw/d) was comparable to the control fetuses. Observable differences were without biological relevance.
- Weight of placentae: The mean placental weights in test groups 1, 2 and 3 (50; 150 and 450 mg/kg bw/d) were comparable to the controls.
- Weight of fetuses: The mean fetal weights of all treated groups were not influenced by the test substance. Neither female nor male weights showed statistically significant or biologically relevant differences between the test substance-treated groups and the controls.
- Fetal external malformations: One sole external malformation (unilateral microphthalmia) was recorded for two fetuses from 2 litters in the high-dose group (450 mg/kg bw/d). This malformation is present in the historical control data. Thus an association of these individual findings to the treatment is not assumed. The total incidences of external malformations were comparable to the historical control data.
- Fetal external variations: One external variation (paw hyperflexion) occurred in single fetuses of the low- and mid-dose groups and the control. The incidences did not demonstrate a dose-response relationship and were comparable to the historical control data. Thus an association of this finding to the treatment is not assumed.
- Fetal external unclassified observations: Unclassified external observations, such as necrobiotic placentae and discolored amniotic fluid, were recorded for single fetuses of test groups 1 and 2 (50 and 150 mg/kg bw/d). A relation to dosing is not present if normal biological variation is taken into account. Therefore, a test substance induced effect is not assumed.
- Fetal soft tissue malformations: The examination of the soft tissues revealed a variety of malformations in fetuses of all test groups including the controls (0; 50; 150 and 450 mg/kg bw/d). With the exception of a lateral pouch in the tongue of 2 fetuses all individual soft tissue malformations were present in the historical control data at comparable frequencies. No statistically significant differences between the test groups and the control were observed. The total incidences of external malformations were comparable to the historical control data. No malformation pattern was evident. Thus an association of these findings to the treatment is not assumed.
- Fetal soft tissue variations: A number of soft tissue variations, such as absent lung lobe (lobus inferior medialis) and malpositioned carotid branch, was detected in each test group including the controls. Incidences were without a relation to dosing. Neither statistically significant differences between the test groups nor differences to the historical control data were noted.
- Fetal soft tissue unclassified observations: Unclassified soft tissue observations, such as infarct of liver, hemorrhagic thymus or ovary and blood coagulum around urinary bladder, were recorded for some fetuses of test groups 0, 1, 2 and 3 (0; 50; 150 and 450 mg/kg bw/d). A relation to dosing is not present if normal biological variation is taken into account. Therefore, a test substance induced effect is not assumed.
- Fetal skeletal malformations: Malformations of the fetal skeletons were noted in fetuses of test groups 0, 2 and 3 (0; 150 and 450 mg/kg bw/d). Neither statistically significant differences between treated groups and the control were calculated nor a dose-response relationship was observed. All individual skeletal malformations were present in the historical control data at a comparable frequency.
- Fetal skeletal variations: For all test groups, variations in different skeletal structures were detected with or without effects on the corresponding cartilages. The observed skeletal variations were related to various parts of the fetal skeletons and were statistically significant higher in the low- and the
high-dose groups on a fetus per litter basis. Several specific skeletal variations were statistically significant higher than the concurrent control in the dosed groups (on a fetus per litter basis). These findings are delays or minor disturbances of ossification which are reversible or do not considerably affect the integrity of the underlying structures. Such slight changes of the ossification process occur very frequently in gestation day 29 rabbit fetuses of this strain and all observed incidences were within the historical control data. Thus an association of these findings to the treatment is not assumed.
- Fetal skeletal unclassified cartilage observations: Additionally, isolated cartilage findings without impact on the respective bony structures, which were designated as unclassified cartilage observations, occurred in all groups including the control. The observed unclassified cartilage findings did not show a relation to dosing and were comparable to historical control data and, therefore, regarded to be spontaneous in nature.
- Abstract of all classified fetal external, soft tissue and skeletal observations: Various external, soft tissue and skeletal malformations occurred throughout all test groups including the control. All individual malformations are present in the historical control data, with the exception of lateral pouches in the tongue of 2 fetuses. They did neither show a consistent pattern since a number of morphological structures of different ontogenic origin were affected nor a clear dose-response relationship. The overall incidence of malformations was comparable to the historical control data. One external (paw hyperflexion), two soft tissue (absent lobus inferior medialis and malpositioned carotid branch) and a broad range of skeletal variations occurred in all test groups including the controls. All fetal and litter incidences for these variations and the corresponding mean percentages of affected fetuses/litter were not significantly different from the concurrent control and their frequency is comparable to the historical control data. Therefore, they were not considered to be related to the treatment. A spontaneous origin is also assumed for external, soft tissue and unclassified skeletal cartilage observations which were observed in several fetuses of all test groups including controls (0, 50; 150 and 450 mg/kg bw/d). Distribution and type of these findings do not suggest relation to treatment.
Dose descriptor:
NOAEL
Effect level:
450 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other:
Remarks on result:
other: developmental toxicity
Abnormalities:
not specified
Developmental effects observed:
not specified

Table: Occurence of statistically significantly increased fetal skeletal variation (expressed as mean percentage of affected fetuses/litter)

Finding

Group 0

0 mg/kg/d

Group 1

50 mg/kg/d

Group 2

150 mg/kg/d

Group 3

450 mg/kg/d

HCD

(range)

Incomplete ossification of parietal; unchanged cartilage

0.0

0.0

1.9*

2.1*

0.4

(0.0 – 2.6)

Incomplete ossification of hyoid; cartilage present

11.2

11.4

19.1

20.4*

9.8

(0.0 – 21.6)

Splitting of skull bone

0.4

3.3*

3.3

2.3

2.9

(0.0 – 7.7)

Incomplete ossification of cervical centrum; unchanged cartilage

2.5

2.2

3.6

7.3*

2.5

(0.0 – 9.3)

Supemumerary 13th rib; cartilage not present

2.5

9.8

6.1

9.9*

6.6

(0.0 – 17.5)

Total fetal skeletal variations

46.3

63.7*

59.3

71.6**

63.5

(46.3 – 81.9)

HCD = Historical control data; * = p ≤ 0.05, ** = p ≤ 0.01 (Wilcoxon-Test [one-sided])

 

 

Table: Total fetal malformations

 

 

Group 0

0 mg/kg/d

Group 1

100 mg/kg/d

Group 2

300 mg/kg/d

Group 3

1000 mg/kg/d

Litter

Fetuses

N

N

25

171

24

154

25

157

24

158

Fetal incidence

N (%)

4 (2.3%)

2 (1.3%)

6 (3.8%)

9 (5.7%)

Litter incidence

N (%)

4 (16%)

1 (4.2%)

4 (16%)

7 (29%)

Affected fetuses/litter

Mean%

2.3

1.2

3.6

6.2

 

 

Table: Total fetal variations

 

 

Group 0

0 mg/kg/d

Group 1

100 mg/kg/d

Group 2

300 mg/kg/d

Group 3

1000 mg/kg/d

Litter

Fetuses

N

N

25

171

24

154

25

157

24

158

Fetal incidence

N (%)

106 (62%)

106 (69%)

106 (68%)

122 (77%)

Litter incidence

N (%)

21 (84%)

24 (100%)

24 (96%)

23 (96%)

Affected fetuses/litter

Mean%

59.9

69.8

64.3

74.2

 

Conclusions:
In conclusion, the no observed adverse effect level (NOAEL) for maternal toxicity is 50 mg/kg bw/d. 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:

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 50 mg/kg bw/d. The NOAEL for prenatal developmental toxicity is 450 mg/kg bw/d. No adverse fetal findings of toxicological relevance were evident at any dose.

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Reason / purpose for cross-reference:
reference to same study
Principles of method if other than guideline:
Teratology study as part of a 5 generation study; F2A animals were used as parental animals
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
Wistar
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: FDRL-stock
- Age at study initiation: (P) 14-15 wks
- Housing: individually
- Diet: semipurified diet, ad libitum
- Water: tap water, ad libitum
ENVIRONMENTAL CONDITIONS
controlled
- Temperature (°C): 22+-2
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: feed
Details on exposure:
In the diet, test substance was substituted for equal ammounts by weight of corn starch and dextrose.
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
- M/F ratio per cage: 1/1
- Length of cohabitation: 7 d
- Proof of pregnancy: vaginal plug referred to as day 0 of pregnancy
- After 7 days of unsuccessful pairing replacement of first male by another male
- Further matings after two unsuccessful attempts: no
- After successful mating each pregnant female was caged:individually
Duration of treatment / exposure:
F0 rats were treated 4 weeks before the mating period. Female rats of the F0 were fed diets containing 1,3-butanediol throughout the mating, gestation and lactating period. After 11 weeks of feeding, 25 males and 25 females from each dosage group of F1A animals were randomly selected and paired to produce the F2 generation (no further information).
Frequency of treatment:
daily
Duration of test:
At day 19 of pregnancy, three-quarters of the F2A dams were killed.
Dose / conc.:
5 other: %
Remarks:
nominal in the diet
Dose / conc.:
10 other: %
Remarks:
nominal in the diet
Dose / conc.:
24 other: %
Remarks:
nominal in the diet
No. of animals per sex per dose:
14-15 animals/ group
Control animals:
yes, plain diet
Details on study design:
Previous chronic studies have been conducted by feeding 1,3-butanediol at levels up to 10% of the diet for rats and 3% for dogs, without obvious deleterious test effects. The present study was conducted to evaluate the effects of 1,3-butanediol on the reproductive performance of rats through five generations fed levels up to 24% of the diet by weight including a developmental study.
Maternal examinations:
Maternal toxicity parameters were not explicitely reported for the developmental toxicity portion of the study. After 4 weeks of feeding of the F0 the respective diets, blood samples were collected from ten rats per sex per group for determination of alkaline phosphatase, glucose, hematocrit, hemoglobin and to tal and differential leucocyte counts. Urine analysis of the same animals provided measurements of albumin, glucose, ketones, occult blood, pH, specific gravity and microscopic examination. For F1A rats which survived at least 66 weeks, the gonads and pituitary glands were examined microscopically. During the eleventh week of feeding of F1A animals blood and urine samples were collected from ten rats per sex per group and evaluated as mentioned above.

Ovaries and uterine content:
Numbers of implantations, resorptions, and viable and nonviable fetuses were determined. Data on gross abnormalities, weight and sex of fetuses were also recorded.
Fetal examinations:
One-third of these F3B fetuses were examined
for soft tissue abnormalities and the remaining fetuses were used for skeletal examinations. For soft tissue examinations, fetuses of each group were fixed in Bouin's solution, sectioned according to the method of Wilson and examined in detail for abnormalities. For skeletal examinations, fetuses were fixed in ethyl alcohol and stained with alizarin red and examined for defects.
Clinical signs:
no effects observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Reduced weight gain in males of the highest dose group of the F1A, F1B, F2A and F3A generation (except F0)
Food efficiency:
no effects observed
Description (incidence and severity):
The efficiency of food utilization through 10 weeks of post-weaning remained constant for all generations of both sexes and was not affected by the level of 1,3-butanediol in the diet.
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Description (incidence and severity):
Urinalyis showed no trends associated with treatment for the F0, F1, F2 and F3 generation animals.
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Histopathological findings: non-neoplastic:
not specified
Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
no effects observed
Details on maternal toxic effects:
The viability of the pups, the number of implantation and resorption sites were unaffected by feeding diets with 1,3-butanediol at levels up to 24%.
Dose descriptor:
NOAEL
Effect level:
10 other: %
Based on:
test mat.
Basis for effect level:
body weight and weight gain
other: reproductive performance: only females: no pregnant females to produce the F2E generation; reduced number of females in former litters of the F2 generation
Abnormalities:
no effects observed
Fetal body weight changes:
no effects observed
Details on embryotoxic / teratogenic effects:
Skeletal tissue examination revealed a statistically significant increase of incomplete ossification of sternebrae for the middle and high level fetuses (40 and 63%, respectively), as compared with the control fetuses (25%). Also, a statistically significant increase of missing sternebrae was noted for high-dose fetuses as compared with the controls: 36% and 8%, respectively. The numbers of other abnormalities seen either in skeletal or soft tissue of the fetuses were not significantly different between test and control groups nor were there any dose response effects.
Dose descriptor:
NOAEL
Effect level:
5 other: %
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: fetotoxicity (delayed growth of fetal skeletal tissue)
Dose descriptor:
NOAEL
Effect level:
24 other: %
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: teratogenicity (no effects observed)
Abnormalities:
effects observed, treatment-related
Localisation:
skeletal: sternum
Description (incidence and severity):
delayed growth of fetal skeletat tissue/ incomplete ossification of sternebrae
Developmental effects observed:
yes
Lowest effective dose / conc.:
10 mg/kg bw/day (nominal)
Treatment related:
yes
Relation to maternal toxicity:
developmental effects in the absence of maternal toxicity effects
Dose response relationship:
yes
Relevant for humans:
not specified

For the teratogenic study, incomplete sternebral ossification (at mid- and high-dose levels) and missing sternebrae (at high-dose level) were noted, probably indicating slight delayed development of fetal skeletal tissue. The respective NOAEL and LOAEL for this effect of 5 and 10% substance in diet corresponds to approx. 2500 and 5000 mg/kg/d based on ECHA guidance table R.8 -17 for female rats.

In the publication it is discussed that physiological stress may be associated with increased ingestion of 1,3-butanediol.

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Principles of method if other than guideline:
limited available data comparable to OECD 414 with low number of animals per group
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
Long-Evans
Route of administration:
oral: gavage
Duration of treatment / exposure:
gestation day 6 to 15
Frequency of treatment:
daily
Dose / conc.:
706 mg/kg bw/day (nominal)
Dose / conc.:
4 236 mg/kg bw/day (nominal)
Dose / conc.:
7 060 mg/kg bw/day (nominal)
No. of animals per sex per dose:
10
Control animals:
yes
Maternal examinations:
All animals were observed daily for mortality or for signs of intoxication (lethargy, ataxia, activity in response to a light cage tap). Food consumption was monitored by daily visual inspection of ground dietremaining in calibrated metal feed cups. All dams were overdosed with ether on day 20 of gestation, and their fetuses were delivered by caesarean section.
Ovaries and uterine content:
At necropsy on gestation day 20, total uterine weight, total litter weight were recorded for each pregnancy.
Fetal examinations:
At necropsy on gestation day 20, individual pup weights, crown-rump length, number of live pups, stillbirths and resorptions, implantation sites, sex distribution, and number of corpora lutea were recorded for each pregnancy. All live pups were examined for gross malformations at birth. Soft tissue (internal) defects were evaluated by free-hand slicing, and skeletal and cartilaginous variations were detected by alizarin red-S and alcian blue staining.
Dose descriptor:
NOAEL
Effect level:
7 060 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: no relevant adverse effects found
Dose descriptor:
NOEL
Effect level:
706 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: Maternal sedation was observed at 7060 and 4236 mg/kg bw/d, feed consumptions and maternal body weights were unaffected.
Dose descriptor:
NOAEL
Remarks:
teratogenicity
Effect level:
7 060 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no adverse teratogenic effects found
Dose descriptor:
NOAEL
Remarks:
fetotoxicity
Effect level:
4 236 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
fetal/pup body weight changes
Dose descriptor:
NOAEL
Remarks:
fetotoxicity
Effect level:
7 060 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: no adverse fetotoxic effects found
Developmental effects observed:
no

Butanediol caused a significant, dose-dependent decrease in offspring birthweights. At the highest butanediol dose, birthweights were preferentially and significantly decreased in male pups not contiguous in utero to female siblings. Other group's offspring were not affected and did not differ significantly from controls. As butanediol was given prior to the period of greatest fetal growth and fetal sex steroidogenests, it is concluded that intra-uterine levels of female sex steroids (estradiol) enhance fetal repair of cellular damage (restitution ad integrum), whereas testosterone inhibits fetal repair or exacerbates previous embryonic damage by some unknown mechanism. Such interaction furthers the concept that intrauterine position affects the endpoints of developmental toxicity, as expressed at partuition.

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
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
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
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
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.
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
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
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
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.
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
Abnormalities:
no effects observed
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.
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
Abnormalities:
no effects observed
Developmental effects observed:
no

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))
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).

NOTE: Any of data in this dataset are disseminated by the European Union on a right-to-know basis and this is not a publication in the same sense as a book or an article in a journal. The right of ownership in any part of this information is reserved by the data owner(s). The use of this information for any other, e.g. commercial purpose is strictly reserved to the data owners and those persons or legal entities having paid the respective access fee for the intended purpose.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
405 mg/kg bw/day
Study duration:
subacute
Species:
rabbit
Quality of whole database:
In summary the database is reliable for the assessment of the endpoint. Value derived from BASF 2009; read across from the metabolite donor substance methyl methacrylate.
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
1 076 mg/m³
Study duration:
subacute
Species:
rat
Quality of whole database:
In summary the database is reliable for the assessment of the endpoint. Value derived from Saillenfait 1999, read across from the metabolite methacrylic acid.
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

A combination study of OECD 422/ 408 with 1,3-BDDMA is ongoing. The results will be reported as soon as they will become available. 


Reliable data are available for the alcohol metabolite 1,3-Butanediol and the methacrylic metabolite methacrylic acid or its respective donor substance, namely methyl methacrylate. Supportive evidence can be derived from a reliable screening study conducted with the structurally closely related isomer 1,4-BDDMA and a developmental study with the analogous alcohol metabolite ethylene glycol. 1,3-BDDMAwill rapidly be hydrolyzed by unspecific carboxylesterases in the liver into methacrylic acid (MAA) and 1,3-butanediol (see chapter Toxikokinetics and the Category document, respectively). Therefore corresponding to the requirements of Annex IX higher studies were covered in a read across approach with the hydrolyses products methacrylic acid plus its metabolite donor substance methyl methacrylate. Animal testing with Methyl methacrylate as metabolite donor substance for MAA avoids the local high toxicity of MMA due to its acidity.


 


Methacrylic acid


Methacrylic acid (MAA), the common metabolite for all the esters, also was tested in groups of 19-25 pregnant female rats (whole-body inhalation exposure for 6 hr/day, during days 6 to 20 of gestation), at 0, 50, 100, 200, and 300 ppm (0, 179, 358, 716 and 1076 mg/m3) and produced no embryo- or fetal lethality, nor fetal malformations after exposure with MAA at any concentration, despite overt maternal toxicity (decreased body weight and feed consumption) at 300 ppm (1076 mg/m3). The NOAEL for developmental toxicity was considered 300 ppm (1076 mg/m3) MAA (Saillenfait et al., 1999).


 


Methyl methacrylate


In a developmental toxicity study according to OECD 414 with Crl:CDBR rats, MMA was administered by inhalation exposure to 99, 304, 1178, and 2028 ppm (412, 1285, 4900, 8436 mg/m³; Rohm and Haas, 1991).Treatment related maternal effects on body weight and food consumption were noted at all exposure levels, consequently the LOEC for maternal toxicity is 99 ppm. No embryo of foetal toxicity was evident and no increase in the incidence in the malformations or variations was noted at exposure levels up to and including 2028 ppm. In this study the NOAEC for developmental toxicity was 2028 ppm (8436 mg/m³).


In addition, another study with MMA has been performed, an oral OECD 414 study in rabbits at 50, 150 , and 405 mg/kg/d. The no observed adverse effect level (NOAEL) for prenatal developmental toxicity is 450 mg/kg bw/d. No adverse foetal findings of toxicological relevance were evident at any dose, even in the presence of maternal toxicity (body weight and food consumption effects at 150 and 405 mg/kg/d; BASF, 2009). MMA is not a selective teratogen.


 


1,3-Butanediol


The effect of 1,3-BD on reproductive performance as well as its teratogenic, dominant lethal and


cytogenetic effects were studied in a five generation of Wistar rats (Hess et al. 1981). The study is rated with a reliability of 2 (publication with some limitations in documentation and result evaluation). Animals of both sexes were fed either control diet or diet supplemented with 1,3-BD at dose levels of 5, 10 or 24% of the diet by weight. Animals of the F2A generation were used as parental animals and the F3B generation was used for evaluation of developmental toxicity. The viability of the pups, the number of implantation and resorption sites and the mean fetal weight were unaffected. Skeletal tissue examination revealed a statistically significant increase of incomplete ossification of sternebrae for the middle and high level fetuses (40 and 63%, respectively), as compared with the control fetuses (25%). Also, a statistically significant increase of missing sternebrae was noted for high-dose fetuses as compared with the controls: 36% and 8%, respectively. The numbers of other abnormalities seen either in skeletal or soft tissue of the fetuses were not significantly different between test and control groups nor were there any dose response effects. These two findings probably indicate slightly delayed growth of fetal skeletal tissue rather than a teratogenic test effect. Furthermore, since the sternebrae of 25% of the control group demonstrated partial ossification, possible dietary and/or environmental factors may be involved. A NOAEL of 5% for fetotoxic effects is derived. Based on ECHA guidance R.8 (table R8.17), assuming a daily food amount of 50 g/kg for female rats, this level corresponds to approx. 2500 mg/kg bw/d. Also, no teratogenic test effects were observed in the soft tissue examinations of F3B generation animals. Thus, a NOAEL of 24% for teratogenic effects is derived.


 


Comparable effects of 1,3-BD were found in Long-Evans rats in an oral gavage study comparable to OECD 414 with however low animal number (Mankes et al. 1986). The study is rated with a reliability of 2 (study well documented; acceptable for assessment). Females were administered 1,3-BD at dose levels of 0, 706, 4236 and 7060 mg/kg bw/d. Temporary sedative effects were observed at the mid and high dose group, but feed consumptions and maternal body weights remained unaffected. Thus, the parenteral NOAEL was found to be 7060 mg/kg bw/d and the parenteral NOEL for narcotic effects was 706 mg/kg bw/d in this study. Offspring birthweights were decreased significantly at the highest dose. There were no indications for a teratogenic effects. Sceletal changes observed were considered to reflect the birthweight reductions noted earlier and not to be indicative of a teratogenic effect of 1,3-BD.Thus, the fetotoxic NOAEL is 4236 mg/kg bw/d (i.e., above today’s guideline limit dose of 2000 mg/kg bw/d) and the teratogenic NOAEL is 7060 mg/kg bw/d in this study (Mankes et al., 1986).


 


1,4-BDDMA


1,4-BDDMA was studied in an OECD 422 combined repeat dose and reproductive/developmental toxicity screening test (RTC, 2013). 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 33 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 significant signs of toxicity in the 1000 mg/kg/day group for males and females with histopathological findings in the liver (females) and stomach (males and females). A reduction of the fertility index has been observed at 1000 mg/kg/day. The NOAEL for effects on fertility as well as for parental toxicity was found to be 300 mg/kg/day.


 


Ethylene glycol


The developmental toxicity of ethylene glycol in animals has been assessed by several animal studies. From those, oral studies are considered most relevant for the metabolite of EGDMA. In brief, developmental effects in animal studies have been shown to be species specific and, in addition are effected by the dosing regime. For REACh regulation reasons, a study with a non-rodent species is of most relevance for the alcohol metabolite pathway (Tyl 1993). As stated by NTP-CERHR (2004), “rabbits demonstrated no developmental toxicity following gavage exposure to doses as high as 2,000 mg/kg bw/day on gd 6–19, as noted by a lack of malformations, prenatal deaths, or decrease in fetal weights. Severe maternal toxicity was observed at 2,000 mg/kg bw/day as evidenced by maternal deaths, increased early delivery, and lesions as well as oxalate crystals in the kidneys. Maternal and fetal NOAELs were identified as 1,000 and 2,000 mg/kg bw/ day, respectively. Thus, the data were sufficient to demonstrate a lack of developmental toxicity in rabbits following oral gavage throughout organogenesis at doses ≤ 2,000 mg/kg bw/day.” More details are available in the category document.


 


In summary there is no evidence of prenatal developmental toxicity for the aforementioned metabolites, metabolite donor substances and analogous substances in rodents and non-rodents, and therefore no prenatal developmental toxicity is expected for 1,3-Butanediol dimethacrylate.


 


Compliance to REACh requirements


The screening study requirement is covered by a reliable screening study donewith the analogous substance 1,4-BDDMA. As alternative approach, available and valid reproduction/ developmental toxicity data from the metabolites could be used to waive this requirement. The reproduction toxicity requirements are covered with a reliable two generation study in rats with the methacrylic metabolite donor MMA and a reliable five generation study with rats with the alcohol metabolite 1,3-BD. The development toxicity requirements for two species are covered with reliable oral or inhalation studies with the methacrylic metabolite MAA, its donor MMA, or with the alcohol metabolite 1,3-BD and the metabolite analogue EG. The read across is done with a high level of confidence.


According to column 1 of Annex IX, section 8.7.3 of REACH regulation, a decision on the need to perform a second two generation study at this tonnage level should be based on the outcome of all other relevant available data. In the available data set on 1,4-Butanediol dimethacrylate itself, its metabolites/ metabolite donor substances and the analogous metabolites mentioned above, 1,4 -Butanediol dimethacrylate did not show reproductive effects in rats. The available data are sufficient for evaluation.


 

Toxicity to reproduction: other studies

Additional information

A combination study of OECD 422/ 408 with 1,3-BDDMA is ongoing. The results will be reported as soon as


they will become available. 


Reliable data are available for the alcohol metabolite 1,3-Butanediol and the methacrylic metabolite methacrylic acid or its respective donor substance, namely methyl methacrylate. Supportive evidence can be derived from a developmental study with the analogous alcohol metabolite ethylene glycol. 1,3-BDDMAwill rapidly be hydrolyzed by unspecific carboxylesterases in the liver into methacrylic acid (MAA) and 1,3-butanediol (see chapter Toxikokinetics and the Category document, respectively). Therefore, corresponding to the requirements of Annex IX higher studies were covered in a read across approach with the hydrolyses products methacrylic acid plus its metabolite donor substance methyl methacrylate. Animal testing with Methyl methacrylate as metabolite donor substance for MAA avoids the local high toxicity of MMA due to its acidity.


 


Methacrylic acid


Methacrylic acid (MAA), the common metabolite for all the esters, also was tested in groups of 19-25 pregnant female rats (whole-body inhalation exposure for 6 hr/day, during days 6 to 20 of gestation), at 0, 50, 100, 200, and 300 ppm (0, 179, 358, 716 and 1076 mg/m3) and produced no embryo- or fetal lethality, nor fetal malformations after exposure with MAA at any concentration, despite overt maternal toxicity (decreased body weight and feed consumption) at 300 ppm (1076 mg/m3). The NOAEL for developmental toxicity was considered 300 ppm (1076 mg/m3) MAA (Saillenfait et al., 1999).


 


Methyl methacrylate


In a developmental toxicity study according to OECD 414 with Crl:CDBR rats, MMA was administered by inhalation exposure to 99, 304, 1178, and 2028 ppm (412, 1285, 4900, 8436 mg/m³; Rohm and Haas, 1991).Treatment related maternal effects on body weight and food consumption were noted at all exposure levels, consequently the LOEC for maternal toxicity is 99 ppm. No embryo of foetal toxicity was evident and no increase in the incidence in the malformations or variations was noted at exposure levels up to and including 2028 ppm. In this study the NOAEC for developmental toxicity was 2028 ppm (8436 mg/m³).


In addition, another study with MMA has been performed, an oral OECD 414 study in rabbits at 50, 150 , and 405 mg/kg/d. The no observed adverse effect level (NOAEL) for prenatal developmental toxicity is 450 mg/kg bw/d. No adverse foetal findings of toxicological relevance were evident at any dose, even in the presence of maternal toxicity (body weight and food consumption effects at 150 and 405 mg/kg/d; BASF, 2009). MMA is not a selective teratogen.


 


1,3-Butanediol


The effect of 1,3-BD on reproductive performance as well as its teratogenic, dominant lethal and


cytogenetic effects were studied in a five generation of Wistar rats (Hess et al. 1981). The study is rated with a reliability of 2 (publication with some limitations in documentation and result evaluation). Animals of both sexes were fed either control diet or diet supplemented with 1,3-BD at dose levels of 5, 10 or 24% of the diet by weight. Animals of the F2A generation were used as parental animals and the F3B generation was used for evaluation of developmental toxicity. The viability of the pups, the number of implantation and resorption sites and the mean fetal weight were unaffected. Skeletal tissue examination revealed a statistically significant increase of incomplete ossification of sternebrae for the middle and high level fetuses (40 and 63%, respectively), as compared with the control fetuses (25%). Also, a statistically significant increase of missing sternebrae was noted for high-dose fetuses as compared with the controls: 36% and 8%, respectively. The numbers of other abnormalities seen either in skeletal or soft tissue of the fetuses were not significantly different between test and control groups nor were there any dose response effects. These two findings probably indicate slightly delayed growth of fetal skeletal tissue rather than a teratogenic test effect. Furthermore, since the sternebrae of 25% of the control group demonstrated partial ossification, possible dietary and/or environmental factors may be involved. A NOAEL of 5% for fetotoxic effects is derived. Based on ECHA guidance R.8 (table R8.17), assuming a daily food amount of 50 g/kg for female rats, this level corresponds to approx. 2500 mg/kg bw/d. Also, no teratogenic test effects were observed in the soft tissue examinations of F3B generation animals. Thus, a NOAEL of 24% for teratogenic effects is derived.


Comparable effects of 1,3-BD were found in Long-Evans rats in an oral gavage study comparable to OECD 414 with however low animal number (Mankes et al. 1986). The study is rated with a reliability of 2 (study well documented; acceptable for assessment). Females were administered 1,3-BD at dose levels of 0, 706, 4236 and 7060 mg/kg bw/d. Temporary sedative effects were observed at the mid and high dose group, but feed consumptions and maternal body weights remained unaffected. Thus, the parenteral NOAEL was found to be 7060 mg/kg bw/d and the parenteral NOEL for narcotic effects was 706 mg/kg bw/d in this study. Offspring birthweights were decreased significantly at the highest dose. There were no indications for a teratogenic effects. Sceletal changes observed were considered to reflect the birthweight reductions noted earlier and not to be indicative of a teratogenic effect of 1,3-BD.Thus, the fetotoxic NOAEL is 4236 mg/kg bw/d (i.e., above today’s guideline limit dose of 2000 mg/kg bw/d) and the teratogenic NOAEL is 7060 mg/kg bw/d in this study (Mankes et al., 1986).


 


Ethylene glycol


The developmental toxicity of ethylene glycol in animals has been assessed by several animal studies. From those, oral studies are considered most relevant for the metabolite of EGDMA. In brief, developmental effects in animal studies have been shown to be species specific and, in addition are effected by the dosing regime. For REACh regulation reasons, a study with a non-rodent species is of most relevance for the alcohol metabolite pathway (Tyl 1993). As stated by NTP-CERHR (2004), “rabbits demonstrated no developmental toxicity following gavage exposure to doses as high as 2,000 mg/kg bw/day on gd 6–19, as noted by a lack of malformations, prenatal deaths, or decrease in fetal weights. Severe maternal toxicity was observed at 2,000 mg/kg bw/day as evidenced by maternal deaths, increased early delivery, and lesions as well as oxalate crystals in the kidneys. Maternal and fetal NOAELs were identified as 1,000 and 2,000 mg/kg bw/ day, respectively. Thus, the data were sufficient to demonstrate a lack of developmental toxicity in rabbits following oral gavage throughout organogenesis at doses ≤ 2,000 mg/kg bw/day.” More details are available in the category document.


 


In summary there is no evidence of prenatal developmental toxicity for the aforementioned metabolites, metabolite donor substances and analogous substances in rodents and non-rodents, and therefore no prenatal developmental toxicity is expected for 1,3-Butanediol dimethacrylate.


Compliance to REACh requirements


The reproduction toxicity requirements will be covered by an ongoing screening study done with the substance. Meanwhile, available and valid reproduction/ developmental toxicity data from the metabolites could be used instead. The development toxicity requirements for two species are covered with reliable oral or inhalation studies with the methacrylic metabolite MAA, its donor MMA, or with the alcohol metabolite 1,3-BD and the metabolite analogue EG. The read across is done with a high level of confidence.


According to column 1 of Annex IX, section 8.7.3 of REACH regulation, a decision on the need to perform an EOGRTS at this tonnage level should be based on the outcome of all other relevant available data. The necessity to perform an EOGRTS will be assessed as soon as the data of the combination study will become available.  


 

Justification for classification or non-classification

Based on the available data, 1,3-BDDMA does not need to be classified for toxicity to reproduction, developmental toxicity and teratogenicity according to the criteria given in regulation (EC) 1272/2008 or the former European directive on classification and labelling 67/548/EEC. Thus, no labelling is required.

Additional information