Methyl 4(or 1)-isopropyl-1(or 4)-methylbicyclo[2.2.2]oct-5-ene-2-carboxylate

Endpoint summary

Description of key information

In an acute oral study, Sprague-Dawley rats were exposed to a single dose of the test item (1429, 2000, 2800 and 3920 mg/kg bw) via oral gavage. Acute toxicological symptoms attributed to the test item were observed, however, no macroscopic organ changes were detected in pathological examinations post-mortem. Fifty percent mortality was not observed at any tested dose level, however, due to the unexpectedly low mortality at the high dose, the LD50 value was not statistically quantifiable. The authors suggest a projected LD50 value of >2000 mg/kg bw. 

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:

28 April 1994 - 27 October 1994

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Justification for type of information:

Fully adequate for assessment. Conducted according to OECD TG 401 Acute Oral Toxicity, which was removed from the OECD Test Guidelines Programme in 2001, the GLP compliant study is considered reliable according to OECD 420, EU B.1bis (Commission directive 2004/73/EC).

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Version / remarks:

Adopted February 24, 1987

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

fixed dose procedure

Limit test:

yes

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Sprague-Dawley Albino rats breeded by commericial supplier
- Age at study initiation: not stated. OECD TG 401 required use healthy young adult animals
- Veterinary preliminary examination: without morbid signs; females were nulliparous and non-pregnant
- Body Weight (bw) at study initiation: female bw 203g (range: 194-211g); male bw 206g (range: 188-237g).
- Body Weight (bw) variation: females 95-103% the mean bw; males 91-115% the mean bw (< ±20% bw variation)
- Fasting period before study: overnight before the day of administration
- Housing: Housed individually in Macrolon cages (area 800 cm2, height 17 cm)
- Diet: commerical diet, twice 8g daily
- Water: ad libitum
- Acclimation period: 5 days prior to the administration

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 – 23 ºC
- Humidity (%): 30 - 70%
- Air changes (per hr): not stated
- Photoperiod (hrs dark / hrs light): 12:12

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

VEHICLE
- Concentration in vehicle: undiluted
- Amount of vehicle (if gavage): not stated
- Purity: not stated

MAXIMUM DOSE VOLUME APPLIED: not stated; the test material was administered undiluted

Doses:

The test substance was orally administrated as a single dose to four groups. The dose ranges were: Group I 1429 mg/kg bw; Group II 2000 mg/kg bw; Group III 2800 mg/kg bw; and Group IV 3920 mg/kg bw. Doses are expressed as weight (mg) per unit weight of the test animal (kg bw).

No. of animals per sex per dose:

Group I (1429 mg/kg bw) 5 females (n=5)
Group II (2000 mg/kg bw) 5 females and 5 males (n=10)
Group III (2800 mg/kg bw) 5 females and 5 males (n=10)
Group IV (3920 mg/kg bw) 5 males (n=5)

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: two observations on the day of administration (5 minutes and 4 hours), followed by daily observations
- Necropsy of survivors performed: yes
- Judgement: mortality, LD50, body weight, behaviour, toxicological symptoms and pathological examination
- Other examinations performed: clinical signs (apathy, feed refusal, ruffled fur, motor activity, body rigidity, hunched posture) , body weight and histopathology.

Statistics:

As the dose-response relationship was non-linear the LD50 value was not quantifiable according to the Litchfield and Wilxocon (1949) or Shayne and Weil (1984) methods, as 50% mortality was not observed. The LD50 was stated as >2000 mg/kg bw.

Key result

Sex:

male/female

Dose descriptor:

approximate LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

The LD50 value was unquantifiable due to the non-linear dose relationship of the mortality observed. The authors suggested that the mortality rate is greater than 2000 mg/kg bw.

Clinical signs:

other: Acute toxicological symptoms were observed in 3 rats dosed with 1429 mg/kg bw, in 3 rats dosed with 2000 mg/kg bw and in all rats dosed with the higher dose groups (2800 mg/kg bw and 3920 mg/kg bw).

Gross pathology:

No macroscopical organ changes were detected in the pathological examination of any dose groups (1429, 2000, 2800 or 3920 mg/kg bw).

The mortality observed in the study is shown in the table below.

Group	I (1429 mg/kg bw)	II (2000 mg/kg bw)	III (2800 mg/kg bw)	IV (3920 mg/kg bw)
Mortality male	not tested	1 (1/5)	2 (2/5)	1 (1/5)
Mortality female	0 (0/5)	2 (2/5)	0 (0/5)	not tested
Total mortality	0 (0/5)	3 (3/10)	2 (2/10)	1 (1/5)

Interpretation of results:

GHS criteria not met

Conclusions:

The oral LD50 value is greater than 2000 mg/kg bw. There was no evidence of intrinsic acute oral toxicity requiring classification or substance specific risk mitigation measures (RMM).

Executive summary:

Sprague-Dawley rats were exposed to a single dose of the test item via oral gavage at 1429 mg/kg bw (n=5), 2000 mg/kg bw (n=10), 2800 mg/kg bw (n=10) and 3920 mg/kg bw (n=5). Acute toxicological symptoms attributed to the test item were observed in 3/5 rats dosed with 1429 mg/kg bw, 3/10 rats receiving 2000 mg/kg bw and in all rats dosed with >2800 mg/kg bw (15/15). No macroscopic organ changes were detected in pathological examinations post-mortem. Fifty percent mortality was not observed at any tested dose level, consequently, the LD50 value was not quantifiable according to the statistical methods of Litchfield & Wilcoxon (1949) or Shayne & Weil (1984). The authors suggested a value >2000 mg/kg bw.

 

Litchfield JT, Wilcoxon F (1949) J. Pharmaol. Exp. Ther. 96: 99-113.

Shayne CG & Weil CS (1984) Principles and Methods of Toxicology, Raven Press, New York.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

Reliable, adequate and relevant data available to fulfil the tonnage-driven data requirements of REACH.

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

An assessment of acute toxicity is required to fulfil REACH Annex VII information requirements. The acute oral toxicity study was conducted according to OECD TG 401, which was removed from the OECD Test Guidelines Programme in 2001. The GLP compliant study is considered reliable without restriction (Klimisch 1) and equivalent to OECD 420, EU B.1bis (Commission directive 2004/73/EC). Fifty percent mortality was not observed at any tested dose level, and the LD50 was expected to be >2000 mg/kg. There is no evidence of a relevant intrinsic acute oral toxicity requiring classification or substance specific risk mitigation measures (RMM).