Registration Dossier

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
22 Feb - 05 Mar 1994
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP-Guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1994
Report Date:
1994

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
EU Method B.1 (Acute Toxicity (Oral))
Version / remarks:
adopted 29 Dec 1992
Deviations:
no
Qualifier:
according to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Version / remarks:
adopted 24 Feb 1987
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPP 81-1 (Acute Oral Toxicity)
Version / remarks:
adopted 22 Sep 1988
Deviations:
no
Qualifier:
according to
Guideline:
other: Agricultural chemicals, Laws and Regulations Japan, HAFF (p. 19 - 20), 1985
Deviations:
no
GLP compliance:
yes
Test type:
standard acute method
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Animal strain as specified by the author: WISKf(SPF71)
- Source: Hoechst AG, Kastengrund, SPF breeding colony
- Age at study initiation: approx. 6 weeks (males), approx. 7 weeks (females)
- Weight at study initiation: 183 g (males), 173 g (females)
- Fasting period before study: from about 16 hours before to 3 - 4 hours after treatment
- Housing: Makrolon cages (Type 4) on soft wood granulate in groups of 5 animals
- Diet: Altromin 1324 rat diet (Altromin GmbH, Lage/Lippe), ad libitum
- Water: tap water, ad libitum
- Acclimation period: at least 1 day

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

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: sesame oil
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 6.25, 12.5, 20, 25 and 50 % (w/v)
- Amount of vehicle (if gavage): 10 mL/kg bw

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg bw

DOSAGE PREPARATION: The test substance was suspended in the above stated concentrations in sesame oil with mortar and pestle and distributed homogeneously by means of a magnetic stirrer.

Doses:
625, 1250, 2000, 2500 and 5000 mg/kg bw
No. of animals per sex per dose:
5 males (625 mg/kg bw dose group)
5 males and 5 females (all other dose groups)
Control animals:
yes
Details on study design:
- Duration of observation period following administration: 15 days (16 days for 1250 mg/kg bw dose group for technical reasons)
- Frequency of observations and weighing: animals were observed 10, 30, 60 min and 2, 4 and 6 h after dosing, twice daily from day 2 to 6 and daily thereafter until the end of the observation period, and individual body weights were determined weekly
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight
Statistics:
The LD50, the 95% limits of confidence and the equation of the probit lines were established on the basis of the mortality rates by probit analysis. The LD50 is estimated for each line with simultaneous limits of confidence according to FIELLER and SIDAK.

Results and discussion

Effect levels
Sex:
male/female
Dose descriptor:
LD50
Effect level:
1 740 mg/kg bw
Based on:
test mat.
95% CL:
>= 1 251 - <= 2 245
Mortality:
625 mg/kg bw: 0/5 males died
1250 mg/kg bw: 3/5 males (48 -72 h post-dose) and 1/5 females (6 days post-dose) died
2000 mg/kg bw: 2/5 males (48 h post-dose) and 2/5 females (48 h and 13 days post-dose) died
2500 mg/kg bw: 4/5 males (48 -72 h post-dose) and 4/5 females (48 - 96 h post-dose) died
5000 mg/kg bw: 5/5 males (48 h post-dose) and 5/5 females (48 - 96 h post-dose) died
Clinical signs:
The clinical signs of intoxication were largely the same for the males and females and dose-related in incidence and severity. They began to emerge 1 hour after administration and generally persisted up to Days 3 to 4 (males) and up to Days 14 (females) of the study. Clinical signs such as increased respiratory rate, irregular respiration, coat bristling, flanks drawn in, stilted gait, squatting posture and decreased spontaneous activity were observed in most animals. The other clinical signs (palpebral fissure narrow, lid margin blood-encrusted, contracted pupils (miosis), clear, colourless lacrimation, snout encrusted blood-coloured, reduced pawreflex to pinching, reduced placing reaction, hyperactivity, hypoactivity, straddling hind limbs, stupor, ataxic gait, uncoordinated gait, forward crawling, prone position, decreased spontaneous activity, trembling, twitching) occurred to a smaller extend.
Body weight:
625 mg/kg bw: body weight gains were within the normal ranges in males during the whole study period.
1250 mg/kg bw: body weight gains were within the normal ranges in surviving males and females during the whole study period.
2000 mg/kg bw: body weight gains were within the normal ranges in surviving males during the whole study period. Body weight gain was reduced in 3/4 females in the first week and returned to normal in all surviving females in the second observation in week
2500 mg/kg bw: body weight gains were within the normal ranges in the surviving male and female during the whole study period.
5000 mg/kg bw: all animals died on Day 2 or 3, post-mortem body weights were slightly below the initial body weight
Gross pathology:
625 mg/kg bw: Necropsy revealed no substance-related findings.
1250 mg/kg bw:
- animals found dead: general autolysis, small intestine full of a reddish-black mass, positive in the fecal occult blood test
- animals sacrificed at termination: Necropsy revealed no substance-related findings.
2000 mg/kg bw:
- animals found dead: general autolysis, liver with light discolouration, small intestine discoloured by test compound and full of test compound
- animals sacrificed at termination: necropsy revealed no substance-related findings.
2500 mg/kg bw:
- animals found dead: general autolysis, liver with light discolouration and lobular demarcation, lungs discoloured red, small intestine full of test compound, and reddish black mass
- animals sacrificed at termination: necropsy revealed no substance-related findings.
5000 mg/kg bw:
- animals found dead: general autolysis, liver with light discolouration and lobular demarcation, lungs discoloured orange, stomach full of test compound, small intestine full of test compound, and reddish black mass

Any other information on results incl. tables

Table 1. Table for acute oral toxicity.

Dose
[mg/kg bw]

Toxicological results*

Duration of clinical signs

Time of death

Mortality (%)

Males

625

0/5/5

1 h – Day 2

---

0

1250

3/5/5

2 h – Day 3

Day 2 + Day 3

60

2000

2/5/5

2 h – Day 2

Day 2

40

2500

4/5/5

2 h – Day 5

Day 2 + Day 3

80

5000

5/5/5

1 h - death

Day 2

100

Females

650

0/0/0

---

---

---

1250

1/4/5

4 h - Day 6

Day 6

20

2000

2/5/5

2 h - Day 14

Day 2 + Day 13

40

2500

4/5/5

2 h - Day 4

Day 2 + Day 4

80

5000

5/5/5

2 h - death

Day 2 - Day 4

100

LD50 = 1740 mg/kg bw

* number of dead animals/number of animals with clinical signs/number of animals used  

Applicant's summary and conclusion

Interpretation of results:
harmful
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
CLP: Acute Oral 4, H302
DSD: Xn, R22