N,N-Diethylacrylamide

Neurotoxicity

Administrative data

Endpoint:

neurotoxicity: 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

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Reference

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

Reason / purpose for cross-reference:

reference to same study

Qualifier:

no guideline followed

Limit test:

no

Species:

mouse

Strain:

other: ddY

Sex:

male

Details on test animals or test system and environmental conditions:

Male mice, 5-6 weeks of age and 29 ± 2.2 g body weight at the beginning of the experiments, were randomly placed in plastic cages (5-7 per cage) containing wooden flakes. They were fed laboratory chow and water ad libitum.

Route of administration:

oral: gavage

Vehicle:

olive oil

Doses:

for 10 weeks: 5.5 mmol/kg

No. of animals per sex per dose:

6

Control animals:

yes

Details on study design:

- Treatment of Animals: Dosed with a blunt tip metal intubation needle, twice weekly; Control animals received a comparable volume of the vehicle.

Statistics:

Intergroup comparison was conducted by the Student's t-test.

Sex:

male

Dose descriptor:

LD50

Effect level:

11 other: mmol/kg

Based on:

test mat.

95% CL:

> 7.4 - < 17

Gross pathology:

The seminiferous tubules show injuries in their epithelia in all cases. Lesions commonly seen in the epithelia are: degeneration of cells, especially of the spermatids and spermatocytes; reduction of the spermatozoa; and the presence of multinucleate giant cells. Sertoli cells and interstitial cells, however, appeared to be unaffected in all cases. Epididymis seemed histologically normal, although their relative weights were slightly reduced in some cases.

11 mmol/kg = 1399 mg/kg bw

Conclusions:

LD50 for the test item was 11 mmol/kg (1399 mg/kg) after dosed at 5.5 mmol/kg in olive oil for 10 weeks.

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

1981

Materials and methods

Test guideline

Qualifier:

no guideline followed

Test animals

Species:

mouse

Strain:

other: ddY

Sex:

male

Details on test animals or test system and environmental conditions:

Male mice, 5-6 weeks of age and 29 ± 2.2 g body weight at the beginning of the experiments, were randomly placed in plastic cages (5-7 per cage) containing wooden flakes. They were fed laboratory chow and water ad libitum.

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

olive oil

Duration of treatment / exposure:

10 weeks

Frequency of treatment:

Twice weekly

Doses / concentrations

Dose / conc.:

5.5 other: mmol/kg

Remarks:

in olive oil for 10 weeks

No. of animals per sex per dose:

6

Control animals:

yes, concurrent vehicle

Details on study design:

- Treatment of Animals: Dose levels were so chosen, by preliminary experiments, that they produce either the least acute general symptoms of poisoning or no such symptoms at all. To examine the effect of metabolic activation, sodium phenobarbital (PB), which was prepared from phenobarbital before use, was given intraperitoneally at 50 mg/kg for five successive days per week, from one week before, up until the last week of treatment with the test compounds.

Examinations

Neurobehavioural examinations performed and frequency:

For the test experiments, only those animals in which rotarod performance was able to be carried out were preliminarily selected. A modified apparatus, which consisted of a 5 cm diameter, roughly surfaced PVC rod, rotated at 3 revolutions per minute, was used. Arithmetic means of the longest performance periods, in five successive 30 s trials in each rat, were calculated for every test group. For the comparison of neurotoxic potencies among compounds, ID50, a half maximal inhibition dose of the walking performance, was estimated from a plot of time course vs. response as follows: days to half maximal inhibition x 2/7 x single oral dose (mmol/kg).

Sacrifice and (histo)pathology:

After treatment with the test compounds for 10 weeks, mice were killed under ether anesthesia for histology and blood examination. The testis was weighed and fixed in 10% neutral formalin, processed, and embedded in paraffin. Ten-micron sections were stained with hematoxylin and eosin. Blood was taken from the right atrium with a heparinized syringe. Measurements of red and white blood cell counts, hemoglobin concentration, and hematocrit value, and differentiation of white blood cells, were conducted by routine methods.

Statistics:

Intergroup comparison was conducted by the Student's t-test.

Results and discussion

Results of examinations

Body weight and weight changes:

no effects observed

Description (incidence and severity):

Body Weight together with testicular weights: No significant change was seen in any of the treated groups when compared to control.

Haematological findings:

no effects observed

Neuropathological findings:

no effects observed

Details on results:

- Effect of PB Treatment:
Group of mice, treated with the test item, were given PB (50 mg/kg, 5/week), which has been known to elevate the activity of drug metabolizing enzymes, from one week before, up until the last week of treatment with the test compounds. Neither weakness nor ataxia developed in the groups treated with test item within 10 weeks following treatment.

Applicant's summary and conclusion

Conclusions:

The test item was non-neurotoxic.