Bicyclo[2.2.1]heptanebis(methylamine)

Endpoint summary

Description of key information

Oral

LD50 1000 -1400 mg/kg bw (males); LD50 961 mg/kg bw (females) (rat), OECD 401, Chida, T. (1992).

Inhalation

Data requirement waived - substance is corrosive to skin.

Dermal

Data requirement waived - substance is corrosive to skin.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

9 July 1991 - 12 August 1992

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Remarks:

.

Qualifier:

according to guideline

Guideline:

other: Guidelines for Toxicity Studies of Drugs (Notification No. 2. of the First Evaluation and Registration Division, 1989

Deviations:

not specified

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Japan, Inc.
- Age at study initiation: 5 weeks
- Weight at study initiation: 121 - 135g for males, 96 - 111g for females
- Fasting period before study: Yes (overnight before dosing and for ca. 3 hours after dosing)
- Housing: polycarbonate cage with bedding for experimantal animals
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 8 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-25
- Humidity (%): 40-70
- Air changes (per hr): 12
- Photoperiod (hrs dark / hrs light): 12 hours light / 12 hours dark

Route of administration:

oral: gavage

Vehicle:

other: 0.5% CMC-Na solution

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 50 mg/mL to 200 mg/mL

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg

Doses:

500 mg/kg (5 males)
700 mg/kg (5 males)
1000 mg/kg (5 males)
1400 mg/kg (5 males)
2000 mg/kg (5 males)
700 mg/kg (5 females)
1000 mg/kg (5 females)
1400 mg/kg (5 females)
2000 mg/kg (5 females)

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 and weighing: at 30 min, 1, 3, 6 and 8 hours after dosing and afterwards, once daily for 14 days. The body weights were measured just before dosing and on Days 3, 7 and 14.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, macropathology.

Statistics:

95 % of confidence limit for LD50 was calculated

Sex:

male

Dose descriptor:

LD50

Effect level:

> 1 000 - < 1 400 mg/kg bw

Based on:

test mat.

Sex:

female

Dose descriptor:

LD50

Effect level:

961 mg/kg bw

Based on:

test mat.

95% CL:

> 883 - < 1 046

Mortality:

Male: 500 mg/kg bw; Number of animals: 5; Number of deaths: 0
Male: 700 mg/kg bw; Number of animals: 5; Number of deaths: 0
Male: 1000 mg/kg bw; Number of animals: 5; Number of deaths: 0
Male: 1400 mg/kg bw; Number of animals: 5; Number of deaths: 5
Male: 2000 mg/kg bw; Number of animals: 5; Number of deaths: 5

Female: 700 mg/kg bw; Number of animals: 5; Number of deaths: 0
Female: 1000 mg/kg bw; Number of animals: 5; Number of deaths: 3
Female: 1400 mg/kg bw; Number of animals: 5; Number of deaths: 5
Female: 2000 mg/kg bw; Number of animals: 5; Number of deaths: 5

Clinical signs:

other: A decrease in locomotor activity was observed in 1 male in the 1000 mg/kg group from 1 hour after dosing; however, it recovered for once. After that; however, decreases in locomotor activity and/or tiptoe gait were observed from Day 2. Emaciation was obse

Gross pathology:

Abnormal contents like tar in the stomach and/or small intestine, hemorrhage of the glandular stomach and/or small intestine were frequently noted among the dead animals. Congestion of the adrenal, dark reddish change of the lung, dilatation of the urinary bladder, and slight bloody ascites were observed sporadically in some dead animals.

Interpretation of results:

harmful

Conclusions:

The acute median lethal oral dose (LD50) to rats of test material was demonstrated to be between 1000 and 1400 mg/kg bw in males and 961 mg/kg bw in females (883 - 1046 mg/kg bw, 95% of confidence limit).

Executive summary:

The acute toxicity of the test material was investigated in a study which was conducted under GLP conditions and in accordance with the Guidelines for Toxicity Studies of Drugs (Notification No. 2. of the First Evaluation and Registration Division, 1989.

During the study the test material was administered once orally to male and female SD rats, and its acute toxicity was assessed. In addition, its lethal dose was calculated.

The dose levels were set at 500, 700, 1000, 1400, and 2000 mg/kg for 5 males/group, and 700, 1000, 1400, and 2000 mg/kg for 5 females/group. The dosing volume was set at 10 mL/kg.

All animals in the 1400 mg/kg or higher groups died by Day 2. Three females in the 1000 mg/kg group died on the day after dosing. From the mortality, LD50 values were between 1000 and 1400 mg/kg in males and 961 mg/kg in females (883 - 1046 mg/kg, 95% of confidence limit).

In clinical observation, decreases in locomotor activity, crouching position, lateral position, cyanosis, and/or ataxic gait were observed in both sexes. Moreover, gasping, tiptoe gait, anemia, emaciation, and/or loose stool were observed in males.

Although decreases in body weight were observed in 1 male in the 1000 mg/kg group until 7 days after dosing, it recovered thereafter. The body weights of the other animals were increased constantly during the observation period.

Necropsy findings of dead animals were as follows: abnormal contents like tar in the stomach and/or small intestine, hemorrhage of the glandular stomach and/or small intestine, congestion of the adrenal, dark reddish change of the lung, dilatation of the urinary bladder, and bloody ascites. In necropsy at the end of recovery period, no abnormalities were observed.

Under the conditions of the study the acute median lethal oral dose (LD50) of the test material to rats was demonstrated to be between 1000 and 1400 mg/kg bw in males and 961 mg/kg bw in females (883 - 1046 mg/kg bw, 95% of confidence limit).

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

961 mg/kg bw

Quality of whole database:

The key study was performed in accordance with standardised guidelines and under GLP conditions and was awarded a reliability score of 1 in accordance with the criteria set forth by Klimisch et al. (1997). The quality of the database is therefore considered to be good.

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

the study does not need to be conducted because the substance is classified as corrosive to the skin

Justification for type of information:

JUSTIFICATION FOR DATA WAIVING
In accordance with Column 2 of REACH Annex VIII, information requirement 8.5, this study does not need to be conducted because the substance is classified as skin corrosion.

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

the study does not need to be conducted because the substance is classified as corrosive to the skin

Justification for type of information:

JUSTIFICATION FOR DATA WAIVING
In accordance with Column 2 of REACH Annex VIII, information requirement 8.5, this study does not need to be conducted because the substance is classified as skin corrosion.

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Oral

The acute toxicity of the test material was investigated in a study which was conducted under GLP conditions and in accordance with the Guidelines for Toxicity Studies of Drugs (Notification No. 2. of the First Evaluation and Registration Division, 1989).

During the study the test material was administered once orally to male and female SD rats, and its acute toxicity was assessed. In addition, its lethal dose was calculated.

The dose levels were set at 500, 700, 1000, 1400, and 2000 mg/kg for 5 males/group, and 700, 1000, 1400, and 2000 mg/kg for 5 females/group. The dosing volume was set at 10 mL/kg.

All animals in the 1400 mg/kg or higher groups died by Day 2. Three females in the 1000 mg/kg group died on the day after dosing. From the mortality, LD50 values were between 1000 and 1400 mg/kg in males and 961 mgkg in females (883 - 1046 mg/kg, 95 % of confidence limit).

In clinical observation, decreases in locomotor activity, crouching position, lateral position, cyanosis, and/or ataxic gait were observed in both sexes. Moreover, gasping, tiptoe gait, anemia, emaciation, and/or loose stool were observed in males.

Although decreases in body weight were observed in 1 male in the 1000 mg/kg group until 7 days after dosing, it recovered thereafter. The body weights of the other animals were increased constantly during the observation period.

Necropsy findings of dead animals were as follows: abnormal contents like tar in the stomach and/or small intestine, hemorrhage of the glandular stomach and/or small intestine, congestion of the adrenal, dark reddish change of the lung, dilatation of the urinary bladder, and bloody ascites. In necropsy at the end of recovery period, no abnormalities were observed.

Under the conditions of the study the acute median lethal oral dose (LD50) of the test material to rats was demonstrated to be between 1000 and 1400 mg/kg bw in males and 961 mg/kg bw in females (883 - 1046 mg/kg bw, 95 % of confidence limit).

Inhalation

In accordance with Column 2 of REACH Annex VIII, information requirement 8.5, this study does not need to be conducted because the substance is classified for skin corrosion.

Dermal

In accordance with Column 2 of REACH Annex VIII, information requirement 8.5, this study does not need to be conducted because the substance is classified for skin corrosion.

Justification for classification or non-classification

In accordance with the criteria for classification as defined in Annex I, Regulation (EC) No 1272/2008, the substance meets the criteria for classification as Acute Category 4 with the hazard statement H302: Harmful if swallowed.