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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
16-03-2014 - 12-05-2014
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2014

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Version / remarks:
adopted 22 January 2001
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
2-dimethylaminoethyl methacrylate
EC Number:
220-688-8
EC Name:
2-dimethylaminoethyl methacrylate
Cas Number:
2867-47-2
Molecular formula:
C8H15NO2
IUPAC Name:
2-(dimethylamino)ethyl methacrylate
Test material form:
liquid
Specific details on test material used for the study:
- Name of test material (as cited in study report): Dimethyl aminoethyl methacrylate
- Supplier: Evonik Röhm GmbH, D-64293 Darmstadt, Germany
- Substance type: organic
- Physical state at room temperature: liquid
- Storage condition of test material: 4°C, light protected

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Italy S.p.A., Calco (Lecco), Italy
- Age at study initiation: 9 weeks old (females), 11 weeks old (males)
- Weight at study initiation:females 197 to 236 g, males at least 322 g)
- Fasting period before study: no data
- Housing: during pre-pairing period and after mating animals were housed no more than 5 of one sex to a cage in polisulphone cages (59.5 x 38 x 20 cm); during mating period, the rats were housed 1 male to 1 female in clear polycarbonate cages (42.5 x 26.6 x 18.5 cm)
- Diet (e.g. ad libitum): ad libitum (4 RF 21, Mucedola S.r.1., Via G. Galilei, 4, 20019, Settimo Milanese (MI), Italy
- Water (e.g. ad libitum): ad libitum
- Acclimation period: approximately 4 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ±2°C
- Relative humidity: 55 ± 15%
- Air changes (per hr): 15 to 20 cycles/hour
- Photoperiod (hrs dark / hrs light): artificial light 12 h/12 h

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:

DIET PREPARATION
- Rate of preparation of diet (frequency): The required amount of Dimethylaminoethyl methacrylate was dissolved in the vehicle
(corn oil). The formulations were prepared daily (concentrations of 20, 60 and 120 mg/mL) and the concentrations were calculated and
expressed in terms of test item as supplied.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Final results for all levels were within the acceptability limits stated in RTC SOPs for concentration (85-115%) and homogeneity (CV < 10 %).
In this study a 24 hour stability at room temperature was verified in the range from 20 to 100 mg/mL.
According to RTC SOPs, suspensions are considered to be stable if concentration after the defined period of storage is still acceptable (85-115% for concentration and CV < 10%) for homogeneity).
Samples of the formulations perpared on week 1 and last week, were analysed to check the homogeneity and concentration. The received results of the analyses were within the above mentioned acceptability limits stated in RTC SOP's for suspensions.
Details on mating procedure:
Females were paired one to one in the home cage of the male and left overnight. Vaginal smears were taken daily in the morning from the day after pairing until a positive identification of mating was made. The presence of sperm in the vaginal smear or by the presence of a copulation plug, was considered as Day0 of gestation.
Duration of treatment / exposure:
6 - 19 day post coitum inclusive
Frequency of treatment:
once a day
Duration of test:
14 d (dams were euthanized on gestation day 20)
Doses / concentrationsopen allclose all
Dose / conc.:
100 mg/kg bw/day (actual dose received)
Dose / conc.:
300 mg/kg bw/day (actual dose received)
Dose / conc.:
600 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
24 mated female rats per group exposed.
Control animals:
yes, concurrent vehicle

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: No data
- Time schedule:

DETAILED CLINICAL OBSERVATIONS: Yes (starting from allocation until sacrifice)
- Time schedule: once a day; Morbidity and mortality: at least twice a day including weekends and public holidays

BODY WEIGHT: Yes
- Time schedule for examinations: All animals were weighted on GD0, 3, 6, 9, 12, 15, 18 and 20 p.c.starting from Day0 post coitum.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Food consumption: The quantity of food consumed by each female was measured on Days 3, 6, 9, 12, 15, 18 and 20 p.c.starting from Day 0 post coitum. 
- Food consumtion was not reported for cage no. 3 on Day 20 post coitum, since its value was unreliable.

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data
- Time schedule for examinations:

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20 post coitum
Ovaries and uterine content:
The ovaries and uterus of the females were examined to determine:
gravid uterine weight (will not be obtained from animals found dead or killed during the study), number of corpora lutea, number of implantation sites, number, sex and weight of all live foetuses, number and sex of dead fetuses (foetuses at term without spontaneous movements and breathing), number of intra-uterine deaths and gross evaluation of placentae.
A gross evaluation of placentae was also undertaken.
Fetal examinations:
- External examinations: Yes: all live foetuses
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: in all groups
- Head examinations: No data
Statistics:
Continuous data (for instance body weight, food consumption, …) amongst group means were assessed by Dunnett's test or a modified t test, depending on the homogeneity of data.
Statistical analysis of non-continous data are carried out by means of the Kruskal-Wallis test and intergroup differences between the control and treated groups assessed by a non-parametric version of the Williams test. The mean values, standard deviations and statistical analysis were calculated from actual values in the computer without rounding off.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:no effects

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
600 mg/kg bw/day (actual dose received)
Based on:
test mat.
Remarks on result:
not determinable due to absence of adverse toxic effects

Maternal abnormalities

Abnormalities:
no effects observed

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
600 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Remarks on result:
not determinable due to absence of adverse toxic effects

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
no

Any other information on results incl. tables

Mortality and fate of females

 

One high dose female (animal no. 97130185) died during the study, on gestation Day 10. A total of 4 females were found not pregnant at necropsy: 1 each in the control, low, mid- and high dose groups. One mid-dose female had unilateral implantation and another mid-dose female had unilateral total resorption.

The number of females with live foetuses on gestation Day 20 was 23 in each of the control, low and mid-dose groups and 22 in the high dose group.

 

Clinical signs

 

Scabs and hairloss were the most frequent signs recorded in control and treated females. These signs were not considered of toxicological significance.

 

Body weight and body weight gain

 

No differences in body weight were noted between control and treated groups.

At body weight gain, a statistically significant decrease of approximately 27% was noted on Day 6 post coitum in females receiving 100 mg/kg/day and a statistically significant increase of approximately 33 % was noted in the same group on Day 18 post coitum, when compared to controls. These changes were considered of no toxicological relevance.

 

Food consumption

 

No differences in food consumption were detected between control and treated groups.

Terminal body weight, uterus weight and absolute weight gain

 

No significant differences in terminal body weight, gravid uterus weight and absolute weight gain were observed in treated groups, when compared to the control group.

Litter data and sex ratios

 

Litter data and sex ratios were not affected by treatment.

 

Macroscopic examination of females

                                                                

No cause of death was identified in the animal which died during the study, due to the significant presence of organs and tissues cannibalized. No treatment-related changes were noted at macroscopic observation performed at the final sacrifice. The minor changes observed are suggested to be incidental, having a comparable incidence in control and treated groups, and/or characteristically seen in untreated Sprague Dawley SD rats of the same age.

 

External examination of foetuses

 

Multiple malformations (such as cor bilocular and ectopic cordis of the heart; malpositioned lungs with lobes agenesia; thymus agenesia) and anomalies were detected in one foetus of the low dose group examined externally and internally. One foetus was found dead in the high dose group. A total of 8 small foetuses ( <2.7 g) were detected in control and treated groups, without dose-relationship. All these findings were considered incidental and not dose-related.

 

Skeletal examination of foetuses

 

Malformations were detected in two foetuses of the low dose group (no ossification of pubis and ischium in one foetus and cleaved sternum in the other) and in one foetus of the mid-dose group (no ossification of pubis). No malformations were observed in the control and high dose groups. In addition, most of the anomalies and variants recorded at skeletal examination were noted both in control and treated groups, with a similar incidence. Considering the low incidence and the absence of dose-relation, all the findings were considered incidental.

 

Visceral examination of foetuses

 

No findings that could be considered treatment-related were noted at visceral examination of the foetuses in any group.

Applicant's summary and conclusion

Conclusions:
In a developmental toxicity study according to OECD 414 Dimethylaminoethyl methacrylate (purity: 99.79 %) was administered to female rats dosed dissolved in corn oil by gavage at dose levels of 0, 100, 300 and 600 mg/kg bw/day from days 6 through 19 of gestation. The NOAEL in this study was found to be 600 mg/kg bw/day for maternal and developmental toxicity.
Executive summary:

In a developmental toxicity study according to OECD 414 Dimethylaminoethyl methacrylate (purity: 99.79 %) was administered to female rats (Sprague-Dawley, (SD)) by oral gavage at dose levels of 0, 100, 300 and 600 mg/kg bw/day from days 6 through 19 of gestation.

Neither clinical signs nor signs of reaction to treatment were noted in treated females that could be related to treatment. No significant differences were noted in body weight, food consumption, gravid uterus weight, litter data and macroscopic observation of treated females, when compared to controls. Due to the absence of dose-relation, the findings detected at the external, visceral and skeletal examination of foetuses from all groups were considered incidental.

 

The maternal and developmental NOAEL was therefore 600 mg/kg bw/day.

Dimethylaminoethyl methacrylate formulation analyses were 85% to 115% of the nominal concentration (homogeneity (CV < 10%)) and were within the acceptable range.

The developmental toxicity study in the rat is classified acceptable and satisfies the guideline requirement for a developmental toxicity study (OPPTS 870.3700; OECD 414) in rats.

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