Registration Dossier

Toxicological information

Acute Toxicity: oral

Currently viewing:

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1985-05-31 (day of dosing)
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: comparable to guideline study

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
1985
Report Date:
1985
Reference Type:
other: addendum to study report
Title:
Unnamed
Report Date:
2006
Reference Type:
other: addendum to study report
Title:
Unnamed
Report Date:
2006

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Principles of method if other than guideline:
BASF test. In principle, the methods described in OECD guideline 401 were used.
GLP compliance:
no
Test type:
standard acute method
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Coffein (caffeine)
No further data.

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Dr. K. Thomae GmbH, D-7950 Biberach, Germany
- Weight at study initiation: mean weights: 179 - 199 g (males); 180 - 189 g (females)
- Fasting period before study: yes. The animals were given no food 16 hours before administration, but water was available ad libitum.
- Housing: 5 per cage, in stainless steel wire mesh cages
- Diet (ad libitum): Kliba Labordiät, Klingentalmühle, CH-4303 Kaiseraugst, Switzerland
- Water (ad libitum): tap water
- Acclimation period: at least one week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24 °C
- Humidity (%): 30 - 70 %
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: no data

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Details on oral exposure:
VEHICLE
0.5% aqueous carboxymethylcellulose
- Concentration in vehicle: 1.78 - 3.83 % (w/v), see table 1 below
- Amount of vehicle (if gavage): 10 ml/kg bw
- Justification for choice of vehicle: aqueous formulation corresponds to the physiological medium

MAXIMUM DOSE VOLUME APPLIED: 10 ml/kg bw
Doses:
178, 261, 383 mg/kg bw
No. of animals per sex per dose:
5 males and 5 females per dose group
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, gross pathology
Group-wise documentation of clinical signs was performed over the 14-day observation period. The clinical signs and findings are reported in summary form.
Body weight was determined before the start of the study as it was needed for determination of the dose.
Statistics:
On the basis of the observed lethality, the LD50 was estimated or determined using a graphical evaluation of the dose-response curve on probability paper.

Results and discussion

Effect levels
Sex:
male/female
Dose descriptor:
LD50
Effect level:
367.7 mg/kg bw
Mortality:
In the high dose group, 3/5 males and 5/5 females died within 1 day after dosing. No other deaths were reported. See table 2 below.
Clinical signs:
Signs of toxicity comprised dyspnea, apathy, staggering, piloerection , and poor general state. The symptoms persisted up to day 7 post dose and were observed in all groups, regardless of sex and dose level.
Body weight:
There was no adverse effect on body weight and body weight gain in the surviving animals. See table 3 below.
Gross pathology:
General congestion was observed in male and female decedents. No abnormalities of the organs were observed in survivors sacrificed at the end of the observation period.

Any other information on results incl. tables

Table 2: mortality rates

Dose [mg/kg bw]

178

261

383

males

Number of animals

5

5

5

Dead animals after

1 hour

1 day

2 days

7 days

14 days

0

0

0

0

0

0

0

0

0

0

0

3

3

3

3

females

Number of animals

5

5

5

Dead animals after

1 hour

1 day

2 days

7 days

14 days

0

0

0

0

0

0

0

0

0

0

0

5

5

5

5

Table 3: Body weight data, mean body weight in [g]

Dose [mg/kg bw]

178

261

383

males

Beginning of the test

181

179

199

after

3 days

7 days

14 days

194

222

259

179

217

260

208

243

287

females

Beginning of the test

180

180

189

after

3 days

7 days

14 days

182

204

220

181

201

221

all animals

died by

day 1

LD50 determination oral actue toxicity in rats (Probit Analysis)

LD50 derived from observations (1985):

LD50 (males and females: >261 <383 mg/kg

LD50 (males): ca. 383 mg/kg

LD50 (females): >261 <383 mg/kg

Statistical estimation of LD50 (2006):

Due to the GHS-classification for this test substance, a detailed determination of the LD50 was necessary, because the statement given in the original study report of 1985 ("the LD50 is greater than 261 mg/kg and lower than 383 mg/kg") is not sufficient; classification limits are 300 mg/kg and 2000 mg/kg. Therefore, the dose-response curve was fitted via the Probit model (according to Finney DJ Probit analysis, Cambridge Univ Press, 3rd ed. 1971). Statistical analyses were performed using the SAS system.

The LD50 of males and females is estimated as 367.7 mg/kg.

Applicant's summary and conclusion

Interpretation of results:
Category 4 based on GHS criteria
Remarks:
Migrated information
Executive summary:

LD50: 367.7 mg/kg bw (males and females)

Groups of 5 male and 5 Wistar rats were administered the test substance by gavage at doses of 178, 261, and 383 mg/kg bw and were observed for 14 days. Eight out of 10 rats given 383 mg/kg bw died within the first day after dosing; no other deaths were reported. Signs of toxicity were observed in all groups and comprised dyspnea, apathy, staggering, piloerection, and poor general state. Body weight gain was unaffected. Pathology revealed general congestion in decedents and no abnormalities in survivors.