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Acute Toxicity: oral

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Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
June 7, 2001 - November 8, 2001
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: The study was conducted in accordance with US EPA OPPTS 870.1100 (comparable to OECD Guideline 401) and in compliance with GLP.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2001
Report date:
2001

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.1100 (Acute Oral Toxicity)
Deviations:
no
GLP compliance:
yes
Test type:
standard acute method
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
4,4'-methylenebis(N-sec-butylcyclohexamine)
EC Number:
679-514-8
Cas Number:
154279-60-4
Molecular formula:
C21H42N2
IUPAC Name:
4,4'-methylenebis(N-sec-butylcyclohexamine)
Details on test material:
- Name of test material (as cited in study report): Clearlink 1000 Polymer Additive.
- Physical state: Clear colurless liquid.
- Lot: 811176191
- Storage condition of test material: Room temperature

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Texas Animal Specialities, Humble, TX
- Age at study initiation: 8 weeks
- Weight at study initiation: 204-282 g (males) and 156-184 g (females)
- Fasting period before study: Approximately 16 hours before dosing.
- Housing: Suspended, wire bottom, stainless steel cages individually.
- Diet (e.g. ad libitum): PMI Feeds Inc. Formulab #.5008 ad libitum.
- Water (e.g. ad libitum): Tap water from automatic water system ad libitum.
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ±3 °C
- Humidity (%): 30-70%
- Air changes (per hr): 10-12 air changes/hour
- Photoperiod (hrs dark / hrs light): 12-hour light/dark cycle

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
An individual dose was calculated for each animal based on its fasted body weight and administered by gavage at a volume ranging from 0.122 ml/kg at the 100 mg/kg level to 6.17 ml/kg at the 5050 mg/kg level. Each dose was administered using an appropriately sized syringe and stainless steel ball-tipped intubation needle.
Doses:
Males: 100, 250, 500 and 5050 mg/kg bw
Females: 250, 500 and 5050 mg/kg bw
No. of animals per sex per dose:
5 males per dose at dosages 100, 250, 500 and 5050 mg/kg bw and 5 females per dose at dosages 250, 500 and 5050 mg/kg bw.
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Observations for mortality and clinical/behavioural signs of toxicity were made at least three times on the day of dosing (Day 0) and at least once daily thereafter for 14 days. Individual bodyweights were recorded just prior to dosing on Days 7 and 14, or at the time of discovery after death.
- Necropsy of survivors performed: yes. At the end of the study each surviving animal was euthanized by an overdose of CO2. All study animals, whether dying during the study of euthanized, were subjected to gross necropsy and all abnormalities were recorded.
Statistics:
The LD50 value was calculated by a computer program utilizing probit analysis.

Results and discussion

Effect levelsopen allclose all
Sex:
male
Dose descriptor:
LD50
Effect level:
227 mg/kg bw
Based on:
test mat.
95% CL:
204 - 252
Sex:
female
Dose descriptor:
LD50
Effect level:
427 mg/kg bw
Based on:
test mat.
95% CL:
377 - 490
Sex:
male/female
Dose descriptor:
LD50
Effect level:
306 mg/kg bw
Based on:
test mat.
95% CL:
271 - 342
Mortality:
Individual mortality data, including time of death, are presented in Table 1, which is attached as background material. A summary of the incidences:
Dosage (mg/kg), Males, Females, Combined (number dead/number treated)
100, 0/5, none, not applicable
250, 3/5, 0/5, 3/10
500, 5/5, 4/5, 9/10
5050, 5/5, 5/5, 10/10
Clinical signs:
Clinical signs in surviving animals included activity decrease, ataxia, body tremors, crusted/stained fur, diarrhoea, decreased/no defecation, emaciation, hunched posture, loss of limb coordination, piloecretion, polyuria and withdrawn testes, which were clear in all except one male by Day 10. Cyanosis, ocular discharge, recumbency, ptosis, salivation, swollen penis and walking on tiptoe were observed only in animals that died on test. Clinical signs are presented in Table 2, which is attached as background material.
Body weight:
Bodyweight gain in surviving animals was unaffected by administration on the test substance, with the exception of one male and two females that lost 9-66 g between Days 0 and 7. Individual body weights are presented in Table 1, which is attached as background material.
Gross pathology:
The gross necropsy on animals that died on test revealed crusted/stained/matted/wet fur; withdrawn testes; discoloured lungs; liver, spleen and content of the gastrointestinal tract; empty intestines and gas in the gastrointestinal tract. The gross necropsy on animals surviving to termination of the study revealed abdominal staining and emaciation in one male; remaining animals had no observable abnormalities. Individual necropsy findings are presented in Table 1, which is attached as background material.

Applicant's summary and conclusion

Interpretation of results:
toxic
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The test substance (trade name Clearlink 1000) was evaluated for its acute oral toxicity potential by administering it as a single dose to albino rats using standard acute method and dose levels of 100, 250, 500, and 5050 mg/kg bw to males and 250, 500 and 5050 mg/kg bw to females.

No mortality occurred in males at the 100 mg/kg level or in females at the 250 mg/kg level. 3/5 males died at dose level 250 mg/kg and 4/5 females died at dose level 500 mg/kg. All the animals, both male and female died at the 5050 dose level. Clinical signs in surviving animals included activity decrease, ataxia, body tremors, crusted/stained fur, diarrhea, decreased/no defecation, emaciation, hunched posture, recumbency, ptosis, salivation, polyuria and withdrawn testes. Cyanosis, ocular posture, recumbency, ptosis, salivation, swollen penis and walking on tiptoe were observed only in animals that died on test. There was no effect on body weight gain in animals surviving to termination, with the exception of one male and two females that lost weight between Days 0 and 7. Most abnormal necropsy findings occurred in the animals dying on test and pertained to fur, testes, lungs, liver, spleen and contents of the gastrointestinal tract. The calculated LD50 value for acute oral toxicity for rats is 227 mg/kg (males), 427 mg/kg (females) and 306 mg/kg (combined).

The results of this study would lead to the classification of acute oral toxicity (Xn; R22) in accordance with the criteria set in Directive 67/548/EEC. According to EU Regulation No. 1272/2008 (CLP), the classification would be acute tox cat 3; Toxic if swallowed.

The study is classified as acceptable and satisfies the guideline requirements for the acute oral toxicity study. The result of this study is used as a key value in hazard assessment.