2-tert-butylaminoethyl methacrylate

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

Remarks:

combined repeated dose and reproduction / developmental screening

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Guideline study without detailed documentation. Peer-reviewed database.

Data source

Reference

Reference 1

Reference Type:

other: summary report

Title:

Unnamed

Year:

1998

Reference 2

Reference Type:

secondary source

Title:

MHW, Japan (1998) Ministry of Health and Welfare, Toxicity Testing Reports of Environmental Chemicals vol. 6, p 539-568

Author:

Ministry of Health and Welfare, Japan

Year:

2003

Bibliographic source:

cited in: OECD SIDS, 2-Dimethylaminoethylmethacrylate, CAS No: 2867-47-2, 07/2003

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)

GLP compliance:

yes

Test material

Test material information

Constituent 1

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

Details on test material:

- Purity: 99.9%
- Supplier: Sanyo-Kasei Co.

Specific details on test material used for the study:

Test substance 99.9% purity, Sanyo-Kasei. Co

Test animals

Species:

rat

Strain:

Crj: CD(SD)

Details on species / strain selection:

Rats supplied by Charles River Japan

Sex:

male/female

Details on test animals or test system and environmental conditions:

Rats were purchased at 7 weeks of age. After quarantine and acclimatisation for 7 days

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

Males: 43 days
Females: from 14 days before mating to day 3 of lactation (41 -52 days)

Frequency of treatment:

once daily

Doses / concentrations

Remarks:

Doses / Concentrations:
0 (Vehicle), 40, 200, 1000 mg/kg/day
Basis:
actual ingested

No. of animals per sex per dose:

12

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: As the LD50 value of > 2000 mg/kg was known, a preliminary test to decide the highest dose level at 30, 100, 300, and 1000 mg/kg/day for 14 days was conducted. At 1000 mg/kg/day, decrease of body weight in males and suppression of body weight increase in females were observed. Then the highest dose level for the test was set at 1000 mg/kg/day.
- Post-exposure period: 1 day

Results and discussion

Results of examinations

Details on results:

MALES:
At 1000 mg/kg/day, no deaths occured. Clinical observations revealed late onset of twitching, chronic convulsion and suppression of body weight gain. The histopathological examinations revealed a degeneration of nerve fibers in the brain and spinal cord, hyperplasia of the mucosa, edema and inflammatory cell infiltration in the forestomach and increased kidney and liver weights without histopathological correlates. Hematological and blood chemical examinations revealed a slight increase in BUN and slight anemic changes such as decreases in erythrocyte counts, hemoglobin concentration and hematocrit value, associated with a significant increase in reticulocyte ratio.

At 200 mg/kg/day, no adverse effects except for slight anemic changes such as decrease in hemoglobin concentration and hematocrit value with
increase in reticulocyte ratio were observed. However, the severities of these slight anemic changes were considered toxicologically insignificant.

At 40 mg/kg/day, no effects were observed.

FEMALES:
At 1000 mg/kg/day, 3 females out of 12 died. By clinical observations, late onset of twitching, chronic convulsion, suppression of body weight gain and a decrease in food consumption during lactation period were observed. Histopathological examinations revealed a degeneration of nerve fibers in
the brain and the spinal cord, a hyperplasia of the mucosa in the gastric tract, edema and inflammatory cell infiltrations in the forestomach, and an atrophy of the thymus. Also the increases in the weight of the kidney and the adrenals without histopathological changes were observed.

At 200 mg/kg/day no effects were observed.

At 40 mg/kg/day no effects were observed.

Effect levels

1

Key result

Dose descriptor:

NOAEL

Effect level:

200 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

food consumption and compound intake

haematology

histopathology: non-neoplastic

mortality

neuropathology

2

Dose descriptor:

NOEL

Effect level:

40 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male

Basis for effect level:

body weight and weight gain

food consumption and compound intake

haematology

neuropathology

3

Dose descriptor:

NOEL

Effect level:

200 mg/kg bw/day (actual dose received)

Sex:

female

Basis for effect level:

body weight and weight gain

food consumption and compound intake

mortality

neuropathology

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

Hematological examination results in male rats (mean ± SD):

 

Dose mg/kg)	0	200	1000
No. of males	12	12	11
RBC (10000/µl)	881.7 ± 43.6	859.8 ± 36.7	821.6 ± 34.1**
Hematocrit (%)	46.73 ± 2.45	44.84 ± 1.26*	41.72 ± 1.97**
Hemoglobin (g/dL)	15.91 ± 0.69	15.28 ± 0.40*	14.24 ± 0.74**
Reticulocytes (‰)	17.81 ± 2.61	21.56 ± 3.57*	24.84 ± 3.75**

 

* = p<0.05, ** = p<0.01

_

Major histopathological findings in male rats:

 

Dose (mg/kg)	0	200	1000
No. of males	12	12	11
Findings in stomach:
Slight dilatation, gastric gland	0	0	0
Slight edema	0	0	7**
Slight hyperplasia, squamous, forestomach diffuse	0	0	11**
Slight inflammatory cell infiltration, forestomach	0	0	10**
Slight ulcer, forestomach	0	0	0
Slight ulcer, glandular stomach	0	0	0
Findings in brain:
Slight degeneration, nerve fiber	0	0	3
Findings in spinal cord:
Slight degeneration, nerve fiber	0	0	8**

 

** = p<0.01

_

Major histopathological findings in female rats:

 

Dose (mg/kg)	0		200	1000
	Surviving	Dead^a)		Surviving	Dead^b)
No. of females	11	1	12	9	3
Findings in stomach:
Slight dilatation, gastric gland	0	0	0	0	0/2
Slight edema	0	0	0	2	1/2
Slight hyperplasia, squamous, forestomach diffuse	0	0	0	9**	2/2
Slight inflammatory cell infiltration, forestomach	0	0	0	5**	1/2
Slight ulcer, forestomach	0	0	0	1	0/2
Slight ulcer, glandular stomach	0	0	0	0	1/2
Findings in brain:
Slight degeneration, nerve fiber	0	0	0	4	0
Findings in spinal cord:
Slight degeneration, nerve fiber	0	0	0	6**	0

a)     One female died of dystocia at gestation day 23

b)     Dead animals were observed at days 26 and 38 after administration

** = p<0.01

Applicant's summary and conclusion

Conclusions:

According to this study, the NOAEL for oral (gavage) repeated dose toxicity in rats is considered to be 200 mg/kg/day for both sexes. The NOELs for repeated dose toxicity are considered to be 40 mg/kg/day for males and 200 mg/kg/day for females.

Executive summary:

The test substance was studied for oral (gavage) toxicity in rats in an OECD combined repeated dose and reproductive/developmental toxicity screening test at doses of 0, 40, 200 and 1000 mg/kg/day. The study was conducted in compliance with GLP.

Three females died in the 1000 mg/kg group. Soiled tail, twitching, chronic convulsion and suppression of body weight gain in both sexes, and a decrease in food consumption in females were also observed in the late period of administration in this group. Histopathological examination revealed degeneration of nerve fibers in the brain and spinal cord, and hyperplasia of the mucosa, edema and inflammatory cell infiltration in the forestomach in both sexes, and atrophy of the thymus in females in the 1000 mg/kg group. Increases in organ weights without histopathological changes were observed for the kidneys of both sexes, the livers of males, and the

adrenals of females in this group. BUN was slightly increased in males in the same group. Slight anemic changes were observed in males of the 200 and 1000 mg/kg groups.

Conclusion: According to this study, the NOAEL for oral (gavage) repeated dose toxicity in rats is considered to be 200 mg/kg/day for both sexes. The NOELs for repeated dose toxicity are considered to be 40 mg/kg/day for males and 200 mg/kg/day for females.