2-dimethylaminoethyl methacrylate

Endpoint summary

Description of key information

No mortality occurred in a well-conducted GLP guideline study (OECD TG 401) at the dose level of 2000 mg/kg. Therefore, the acute oral LD50 of this substance is

considered to be higher than 2000 mg/kg bw.
No mortality occurred in a well-conducted GLP guideline study (OECD TG 402) at the dose level of 2000 mg/kg. Therefore, the acute dermal LD50 of this substance is

considered to be higher than 2000 mg/kg bw.
According to a report on the acute 4-hour inhalation toxicity in rats the acute inhalation LC50 of this substance is considered to be 620 mg/m³. The reliability of this value

is not assignable since no sufficiently detailed data were available for assessment.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

GLP compliance:

yes

Test type:

standard acute method

Specific details on test material used for the study:

TEST MATERIAL:
Name of test material: 2-(dimethylamino)ethyl methacrylate

Species:

rat

Strain:

other: Crj:CD(SD)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Japan Charles River Co., Ltd.
- Age at study initiation:
- Weight at study initiation: 134-152 g (males); 108-125 g (females)
- Fasting period before study: not specified
- Housing: polycarbonate cage (265W x 426D x 200H mm, Tokiwa Scientific Instruments Co., Ltd.) for lab animal bedding (Beta Chip, Nippon Charles River Co., Ltd.)
- Historical data: not specified
- Diet (e.g. ad libitum): autoclave-sterilized lab animal solid feed (MF, Oriental Yeast Co., Ltd.), ad libitum
- Water (e.g. ad libitum): Uv-irraditated tap water filtered through 5 µm filter,ad libitum
- Acclimation period: 7 days
- Microbiological status when known: SPF animals
- Method of randomisation in assigning animals to test and control groups

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22+/-2°C
- Humidity (%): 55+/-15%
- Air changes (per hr): 12
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: To:

Route of administration:

oral: gavage

Vehicle:

corn oil

Doses:

0 (Vehicle), 500, 1000, 2000 mg/kg bw

No. of animals per sex per dose:

5

Control animals:

yes

Details on study design:

- Duration of observation period following administration: 14 days
- Necropsy of survivors performed: yes

Statistics:

The weight measurements were tested for homoscedasticity through the Bartlett method, one-way ANOVA for equal variances, and Kruskal-Wallis for unequal variances. If there was a significant difference between the groups, the Dunnet method or Dunnet-type multiple comparison test was performed.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

not determinable due to absence of adverse toxic effects

Mortality:

No deaths occurred in any of the treated groups.

Clinical signs:

other:

Body weight:

other body weight observations

Remarks:

Both males and females showed similar transitions compared to the control group.

Gross pathology:

Two males in the 2000 mg / kg group had a raised lesion in the anterior stomach. No other abnormalities were found.

Other findings:

Examination of the stomachs of two males in the 2000 mg / kg group, which were abnormal at autopsy, revealed mild papillary hyperplasia in the anterior gastric mucosa in one case. No other abnormalities were found.

Interpretation of results:

GHS criteria not met

Executive summary:

2- (Dimethylamino) ethyl methacrylate was orally administered to rats at a dose of 500, 1000 and 2000 mg / kg.

No deaths were observed in any of the groups, and no abnormalities were observed in the general condition or in body weight. Necropsy revealed a raised lesion in the anterior gastric region in males in the 2000 mg / kg group, and histopathologically papillary hyperplasia of the anterior gastric mucosa was observed as a related change. Acrylic acid esters containing this test substance are known to cause acute irritation to mucosa, and it has been reported that oral administration of ethyl acrylate causes hyperplasia of the anterior gastric mucosa in rats ²⁾. Since this change is considered to be the result of a local inflammatory response to the stimulant ²⁾, the change in the anterior stomach observed with this test substance is also considered to be the convergent with the inflammatory response to the stimulus.

The median lethal dose (LD₅₀ value) of a single oral dose of 2- (dimethylamino) ethyl methacrylate to rats was 2000 mg / kg or more for both males and females.

Reference 2

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Remarks:

Restrictions: purity of TS not specified

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

yes

Remarks:

observation period 4 weeks

GLP compliance:

no

Test type:

standard acute method

Specific details on test material used for the study:

TEST MATERIAL:
- Name of test material (as cited in study report): 2-(dimethylamino)ethyl methacrylate

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: S. IVANOVAS GmbH & Co., Med. Versuchstierzuchten K.G., Postfach 7, D-7964 Kißlegg/Allgäu)
- Age at study initiation: males 52 days, females 70 days
- Weight at study initiation: 170-180 g
- Fasting period before study: 15-16 hours
- Housing: single housing in Makrolon cages (Type II)
- Diet: ALTROMIN 1323 (Altromin GmbH, Postfach 285, D-4937 Lage/Lippe) ad libitum except during fasting period
- Water: tap water ad libitum


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 24±0.5
- Humidity (%): 60±3

Route of administration:

oral: gavage

Doses:

1.00, 1.26, 1.59, 2.00, 2.52, 3.18, 4.00, 5.04, 6.35 ml/kg
(933, 1176, 1483, 1866, 2351, 2967, 3732, 4702, 5925 mg/kg; calculated from original data using density of 0.933 g/cm³)

No. of animals per sex per dose:

10

Details on study design:

- Duration of observation period following administration: 4 weeks
- Observations: behaviour, food consumption, body weight gain
- Necropsy of survivors performed: yes

Statistics:

Calculation of LD50 according to LITCHFIELD and WILCOXON.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

2 659 mg/kg bw

Remarks on result:

other: calculated from original data using density of 0.933 g/cm³

Sex:

male

Dose descriptor:

LD50

Effect level:

2 706 mg/kg bw

95% CL:

> 2 333 - < 3 079

Remarks on result:

other: calculated from original data using density of 0.933 g/cm³

Sex:

female

Dose descriptor:

LD50

Effect level:

2 612 mg/kg bw

95% CL:

> 2 333 - < 2 986

Remarks on result:

other: calculated from original data using density of 0.933 g/cm³

Mortality:

Dead occured within 24 hours after administration of the TS (within 1-24 hours after tonoclonic spasms). The lowest dose that caused death was 2.00 ml/kg (1866 mg/kg).

Clinical signs:

other: Sedation, food consumption decreased, ataxia, dyspnoea, comatose condition, tonoclonic spasms. Surviving animals recovered within 2-4 days.

Gross pathology:

Hemorrhagic mucous membrane of the stomach in dead animals. Survivors showed no pathologic signs.

Acute oral toxicity in rats:

 

Dose* (mg/kg)	No. of males/females	Decrease in food consumption (%, group mean)			Decrease in body weight gain (%, group mean)			Mortality after
								24 h		14 d
		d 1	d 2	d 14	d 1	d 2	d 14	m	f	m	f
933	10/10	4	0	6	0	2	3	0	0	0	0
1176	10/10	36	6	0	4	6	2	0	0	0	0
1483	10/10	46	4	6	2	4	6	0	0	0	0
1866	10/10	38	6	2	4	2	6	3	3	3	3
2351	10/10	56	26	4	0	0	6	4	5	4	5
2967	10/10	58	20	8	4	8	10	6	6	6	6
3732	10/10	68	31	5	6	4	8	6	7	6	7
4702	10/10	86	48	6	2	8	8	8	8	8	8
5925	10/10	100	-	-	6	-	-	10	10	10	10

* calculated from original data using density of 0.933 g/cm³; m = males, f = females, d = day

Interpretation of results:

Category 5 based on GHS criteria

Executive summary:

The acute oral LD50 in rats was calculataed to be 2612 mg/kg bw based on the results obtained in female rats. The LD50 in female rats is slightly lower than in male rats.

Laut OECD SIDS: LD50 ist 2656 mg/kg bw (beide Geschlechter)

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Remarks:

GLP.

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

GLP compliance:

yes

Test type:

standard acute method

Specific details on test material used for the study:

TEST MATERIAL:
- Name of test material (as cited in study report): Dimethylaminoethyl methacrylate (MADAME)

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Strain: ICO: OFA-SD (IOPS Caw)
- Source: Iffa Crédo, 69210 L'Arbresle, France
- Age at study initiation: approx. 8 weeks
- Weight at study initiation: mean males 255±3 g, mean females 228±8 g
- Housing: in groups of 4 to 7 of the same sex per cage in sterilizable polycarbonate cages (48 x 27 x 20 cm) during the acclimatization period and individually in sterilizable polycarbonate cages (35.5 x 23.5 x 19.3 cm) during the study
- Diet: certified pellet diet "Rats - Mice sustenance ref. A04 C" (U.A.R., 91360 Villemoisson-sur-Orge, France) ad libitum
- Water: filtered tap water ad libitum
- Acclimation period: at least 5 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22±3
- Humidity (%): 50±20
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light): 12 / 12

Type of coverage:

semiocclusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

The day before treatment, the dorsal area of each animal was clipped with an electric clipper on an area of 6 x 8 cm. Only animals with healthy intact skin were used for the study. The TS in its original form was applied at a dose level of 2000 mg/kg at a volume taking into consideration that the specific gravity (SG) of the TS was 0.933 directly to an area of skin representing approximately 10% (5 x 6 cm for the females and 5 x 7 cm for the males) of the body surface of the animal. This was calculated according to Meeh's formula (AFNOR-TO3-23 Standard, August 1980, France). A hydrophilic gauze patch was then applied to the skin. The TS and the gauze patch were held in contact with the skin for 24 hours by means of an adhesive hypoallergic aerated semi-occlusive dressing attached to a restraining bandage. This dressing prevented the ingestion of the TS by the animal. No residual TS was observed at removal of the dressing.

Duration of exposure:

24 hours

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

5

Control animals:

other: The body weight gain of the treated animals was compared to a reference curve of the C.I.T. control animals with the same initial weight.

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Mortality was checked frequently just after application of the TS and then at least twice a day during the 14-day observation period. The animals were observed for clinical signs frequently after application of the TS and at least once a day during the observation period. The animals were individually weighed just before application of the TS and then on days 5, 8 and 15.
- Necropsy of survivors performed: yes

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Mortality:

No deaths occured at the dose level of 2000 mg/kg.

Clinical signs:

other: Within 72 hrs of application of the test substance, hypokinesia, sedation and dyspnea were observed and had reversed on day 5. Local signs of marked irritations were noted during the study.

Gross pathology:

The macroscopic examination revealed no abnormalities in the animals sacrificed at the end of the study. Signs of cutaneous irritation had eversed.

Interpretation of results:

GHS criteria not met

Conclusions:

The LD50 of the test substance administered by dermal route in rats is higher than 2000 mg/kg.

Executive summary:

The LD50 of the test substance administered by dermal route in rats is higher than 2000 mg/kg.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Additional information

There were various studies on the acute toxicity of the test substance by different administration routes. In total, eleven reports on the acute toxicity via oral, dermal, inhalation or intraperitoneal routes to rats, mice or rabbits were reviewed.

Oral exposure route:

As for oral toxicity, the study by the Ministry for Health and Welfare, Japan (MHW Japan, 1998) was considered to be the most reliable because it was well conducted according to OECD TG 401 in compliance with GLP and was therefore identified as the key study. In this study, SD rats (5/sex/dose) were administered doses of 0 (vehicle), 500, 1000, 2000 mg/kg bw by gavage. Although raised patches and papillomatous hyperplasia in die forestomach were observed, no death occurred in the 2000 mg/kg bw dose group. The LD50 after oral application is considered to be greater than 2000 mg/kg bw. This result is supported by an acute oral toxicity study in rats from Roehm, where an LD50 of 2659 mg/kg was determined (Roehm, 1978).

Two other acute oral LD50 values in rats were reported to be equal to 1550 mg/kg bw (Kirk-Othmer, 1978 -1984) or greater than 1751 mg/kg bw (Izmerov, 1982). The reliability of these two studies is not assignable.

Dermal exposure route:

As for dermal toxicity, the study on rats by Atochem was identified as the key study (Atochem, 1992). This study was conducted in accordance with OECD TG 402 in compliance with GLP. At 2000 mg/kg dose in rats, no mortality was observed although symptoms of hypokinesia, sedation, dyspnoea and skin irritation were observed. The dermal acute lethal dose is considered to be greater than 2000 mg/kg bw.

Inhalation exposure route:

Due to low vapour pressure (0.58 hPa at 20°C) and the exclusion of spray applications, inhalation is not a relevant pathway of exposure. Regarding acute toxicity by inhalation, a LC50 of 0.62 mg/L (620 mg/m³) after a 4-hour inhalation of the test substance in rats and a LC50 of 1.8 mg/L (1800 mg/m³) after a 2-hour inhalation of the test substance in mice were reported (Izmerov, 1982). However, the reliability of these values is not assignable since no sufficiently detailed data were available for assessment.

Other exposure routes (intraperitoneal):

As to the acute toxicity by intraperitoneal (i.p.) administration, LC50 values ranging from 25 mg/kg bw to 310 mg/kg bw were reported in three studies with rats or mice (Kirk-Othmer, 1978 -1984; Paulet, 1975; NTIS, 1986). The severest value for the intraperitoneal acute toxicity was 25 mg/kg bw for mice (NTIS, 1986).

Justification for classification or non-classification

In the key study for acute oral toxicity the LD50 of the test substance was determined to be higher than 2000 mg/kg (MHW Japan, 1998). Based on these data, no classification of the test substance is required. There are no reliable data considering acute inhalation toxicity. Based on the data from acute dermal toxicity studies no classification of the test substance is required. Accordingly, the following classification of the test substance concerning acute toxicity is proposed:

GHS classification according to Annex I 1272/2008 CLP (EU GHS):

- Oral route: No classification

- Dermal route: No classification.

- Inhalation route: No classification.

However, the test substance is listed in Annex I of the Directive 67/548/EEC and in Annex VI of CLP regulation 1272/2008 (EU-GHS). Accordingly, in spite of the contradictory database, the test substance has to be classified as follows:

GHS classification according to Annex VI 1272/2008 CLP (EU GHS):

- Oral route: Acute toxicity - Cat. 4*

- Dermal route: Acute toxicity - Cat. 4*

- Inhalation route: No classification.