Methyl 1,3,3-trimethyl-2-methylidene-2,3-dihydro-1H-indole-5-carboxylate

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: well-documented GLP guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1989

Report date:

1989

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Test guideline 2

Qualifier:

according to guideline

Guideline:

other: directive 84/449/EEC

GLP compliance:

yes

Test type:

standard acute method

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

methyl 1,3,3-trimethyl-2-methylidene-2,3-dihydro-1H-indole-5-carboxylate

EC Number:

700-424-2

Cas Number:

6872-10-2

Molecular formula:

C14 H17 N O2

IUPAC Name:

methyl 1,3,3-trimethyl-2-methylidene-2,3-dihydro-1H-indole-5-carboxylate

Details on test material:

- Name of test material (as cited in study report): Carboxytrimethylbase, roh, feucht
- Lot/batch No.: Pt. 1 H
- Appearance: black powder (solid)

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Winkelmann Borchen, Germany
- Strain: Bor: WISW (SPF Cpb)
- Age at study initiation: males approx. 8 and females approx. 10 weeks
- Weight at study initiation: mean weight for males 177 g, mean weight for females 171 g
- Fasting period before study: approx. 16 hours
- Housing: in groups (5 animals per Makrolon type III cage)
- Diet and water: ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 2 °C
- Humidity (%): 50 +/- 10%
- Air changes (per hr): 10 times
- Photoperiod (hrs dark / hrs light): 12 hrs light/ 12 hrs dark

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

polyethylene glycol

Details on oral exposure:

VEHICLE: polyethylene glycol 400
- Application volume:10 ml/kg bw
- test substance formulation was prepared immediately before administration

Doses:

for males: 1000, 2000, 3100, 5000 mg/kg bw
for females: 1000, 2000 mg/kg bw

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations: On day of administration several times, thereafter 2 times per day (exception: on week-end once per day)
- Frequncy of weighing: Before administration and after 7 and 14 days
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight

Statistics:

LD50 was determined computer-assisted according to the method of Rosiello (J. Tox. Environ. Health, 3, 1977, 797), modified by Pauluhn (report no. 11835, Bayer AG, 1983). This procedure is based on the Maximum-Likelihood-Method according to Bliss (J. Pharm. Pharmacol., 11, 1938, 192).

Results and discussion

Effect levels

Effect levels 1

Sex:

male

Dose descriptor:

LD50

Effect level:

3 168 mg/kg bw

95% CL:

2 549 - 3 940

Effect levels 2

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Mortality:

Number of deaths at each dose/number of animals in dose group (time of deaths)
Male rats: 1000 mg/kg 0/5; 2000 mg/kg 1/5 (day 1); 3100 mg/kg 1/5 (day 1); 4000 mg/kg 4/5 (day 1); 5000 mg/kg 5/5 (day 1).
Female rats: 1000 mg/kg 0/5; 2000 mg/kg (0/5)

Clinical signs:

other: Clinical signs occurred approx. 1 hour after administration and were low to medium pronounced. All symptoms were resolved at least on Day 3 after administration. Male rats: - dose groups 2000 to 5000 mg/kg: poor general condition and sedation; dose group

Gross pathology:

Gross pathology of the male rats found dead: flattening of gastric mucosa, gastro-intestinal tract partially bloated and reddened or discoloured (violet-orange or violet), lungs strongly reddened, caecum hardened. For one animal of dose group 3100 mg/kg parts of the liver showed pale regions.
All animals sacrificed after the end of the study were found unobtrusive at necropsy.

Applicant's summary and conclusion

Executive summary:

A rat study according to directive 84/449/EEC (fulfilling OECD TG 401) was conducted under GLP with 5 animals per dose and with dose groups 1000, 2000, 3100 and 5000 mg/kg for males and 1000 and 2000 mg/kg for females.

Clinical signs (poor general condition, sedation, piloerection; for male rats also: increased diuresis, tremor, abdominal position, bloody snouts and eye surroundings; for one male clonical cramps) occurred approx. 1 hour after administration and were low to medium pronounced. All symptoms were resolved at least on Day 3 after administration. No clinical signs were observed for males or females of dose group 1000 mg/kg. Body weight gain was marginally reduced in the 1st and 2nd week post administration for females of dose group 2000 mg/kg. At necropsy the most prominent effects for rats found dead (only males) were observed in the gastro-intestinal tract (flattening of gastric mucosa, gastro-intestinal tract partially bloated and reddened or discoloured, caecum hardened). Also effects on lungs and for one animal on the liver were observed. Gross pathology was unobtrusive for all animals sacrificed at the end of the postobservation period.

The LC50 was 3168 mg/kg for male rats and > 2000 mg/kg for female rats.