Registration Dossier

Diss Factsheets

Administrative data

acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Equivalent or similar to OECD 401. There is no GLP compliance statement in the report but it is indicated that the study was designed to ensure compliance with the Code of GLP published in the Federal Register, December 1978.

Data source

Reference Type:
other company data

Materials and methods

Test guideline
equivalent or similar to guideline
OECD Guideline 401 (Acute Oral Toxicity)
GLP compliance:
Test type:
standard acute method
Limit test:

Test material

Constituent 1
Chemical structure
Reference substance name:
EC Number:
EC Name:
Cas Number:
Molecular formula:
Test material form:
other: viscous yellow liquid
Details on test material:
- Name of test material (as cited in study report): IFF #78-059-04 , which is confirmed as Methyl Cedryl Ketone by data holder IFF
- Physical state: viscous yellow liquid

Test animals

other: Albino rats (TacN(SD)fBR)
Details on test animals or test system and environmental conditions:
- Source: Taconic Farms (Germantown, N.Y.)
- Age at study initiation: Young adult
- Weight at study initiation: 180 - 220 g
- Housing: Housed singly in wire cages under standard lab conditions meeting the standards described in the 'Guide for the Care and Use of Laboratory Animals' (DHEW Publication No. (NIH) 78-23, Revised 1978).
- Diet (e.g. ad libitum): purina rodent laboratory chow 5001.
- Fasting period before study: Food withdrawn at 3:00 pm on the day prior to treatment and the rats were fasted overnight.
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 7 days

Administration / exposure

Route of administration:
oral: gavage
unchanged (no vehicle)
Details on oral exposure:

Range Finding: Two fasted female rats per dose were treated by gavage with a single dose of test article, and were observed for the next 72 hours to determine the mortality only. In other respects, the test system was similar to the main test conditions. The dosages were 1.0, 2.0 3.0, 4.0 and 5.0 mL per kg bw. One animal given 5.0mL/kg died during the 72 hour observation period.

Therefore the test doses selected for the main study were 2.0, 3.18, 4.0, 5.04 (repeated in females), 7.98 and 12.65 mL per kg bw.
2.0, 3.18, 4.0, 5.04 (repeated in females), 7.98 and 12.65 mL per kg bw.
No. of animals per sex per dose:
8 male and 8 female animals per dose; 8 females were also dosed again with 5.04 mL per kg bw.
Control animals:
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Observations - 1,3, 5 and 24 hrs post-dosing and twice daily (once at weekends) for 14 days; Weighing - before dosing.
- Necropsy of survivors performed: Yes, gross necropsy
- Other examinations performed: clinical signs, necropsy findings
The LD50 values, slopes and fiducial limits of males and females - Litchfield and Wilcoxon Method (1949).
Statistical significance of estimated standard deviation from LD50 and slope values: two sample independent T test

Results and discussion

Effect levelsopen allclose all
Dose descriptor:
Effect level:
4 500 mg/kg bw
95% CL:
3 810 - 5 310
Remarks on result:
other: Given as mL/kg bw in report; converted to mg/kg bw using density: 1.001 g/mL
Dose descriptor:
Effect level:
4 600 mg/kg bw
95% CL:
3 360 - 6 300
Remarks on result:
other: Given as mL/kg bw in report; converted to mg/kg bw using density: 1.001 g/mL
Dose descriptor:
Effect level:
4 600 mg/kg bw
95% CL:
3 830 - 5 520
Remarks on result:
other: Given as mL/kg bw in report; converted to mg/kg bw using density: 1.001 g/mL
No deaths occurred in the first 5 hours after dosing. The majority of deaths occurred on Days 2,3 and 4 at doses of 4.0 mL/kg and above. Only one female died of the 32 rats treated at 2.0 or 3.18 mL/kg. The number of deaths per dose for each sex are listed for each day in Table 1.
Clinical signs:
other: Within 5 minutes of dosing animals at all dose levels became subdued, but almost immediately thereafter many of the animals became irritable and for the first hour or two the animals fluctuated between the two states of passivity and irritability. Irritab
Gross pathology:
Animals which died: Only one female died of the rats treated at 2.0 and 3.18 mL/kg. No lesions were observed at necropsy of this rat.

At doses of 4.0 mL/kg and above, the most obvious observations on the carcassess were yellow wetting and staining of the perineal area (at minimum) or of the whole ventral abdomen with a bright yellow colour, presumably urine, and apparently self-inflicted injuries to the mouths and feet of hte rats.

In the abdomen, the most marked change was congestion of hte intestine, occassionally the colon was the most affected portion. Several of the rats at the higher doses had stomachs and colons markedly distended with food, with little material present in the remainder of the bowel. Fragile black plaques were frequently present in the contents of the stomach and they could have been residual digested blood ingested from wounds about the mouth and the feet.

Other lesions noted were sporadic and could not be related to treatment.

Animals killed at term: There were no meaningful necropsy findings.

Any other information on results incl. tables

Table 1: Mortality by sex, day and dose level.

Dose mL/kg Sex 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Total deaths per sex Total

Male (8*)  

0 1 0 No mortality 1 1/16
Female (8)  0 No mortality 0
3.18 Male  (8*)     No mortality 0 0/16
Female (8)  No mortality 0
4 Male  (8)     0 1 1 0 1 0 0 1 0 No mortality    4 6/16
Female (8)  0 1 1 0 No mortality 2
5.04 Male  (8)     0 0 1 3 0 No mortality 4 17/24
Female (16)  0 8 2 1 0 2 0 No mortality 13
7.98 Male  (8)     0 2 0 3 1 0 No mortality 6 13/16
Female (8)  0 0 5 2 0 No mortality 7
12.65 Male  (8)     0 1 3 4 No survivors 8 16/16
Female (8)  0 4 4 No survivors 8

 *Number of animals per group

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
Not classified according to CLP
Daily oral administration of a single dose of the test substance to 6 groups of 8 male and female Albino rats (TacN(SD)fBR) rats was associated with transient irritability and passivity up to 48 hours. No other treatment related findings were noted. Based on the findings in this study, the LD50 (males/females) is considered to be 4500 mg/kg bw.
Executive summary:

In an acute oral toxicity study (0061) groups of fasted, young adult Albino rats (TacN(SD)fBR) (8 male and female) were given a single oral dose of methyl cedryl ketone (no vehicle) at doses of 2.0, 3.18, 4.0, 5.04 7.98 and 12.65 mL per kg bw and observed for 14 days.

Oral LD50 Males = 4600 mg/kg bw (3360 - 6300, 95% C.I.)

Oral LD50 Females = 4600 mg/kg bw (3830 - 5520, 95% C.I.)

Oral LD50 Combined = 4500 mg/kg bw (3810 - 5310, 95% C.I)

(LD50 values given as mL/kg bw in study report; LD50 values were converted to mg/kg bw using density: 1.001 g/mL)

Clinical signs (irritability and passivity) were noted very soon after dosing; irritability was resolved after 1 hour but animals remained subdued up to 48 hours. No clinical signs specific to treatment were noted after Day 3 or 4. Necropsy of animals that died during the study or at term did not reveal any treatment-related effects.

This acute oral study is classified as acceptable. It does satisfy the guideline requirement for an acute oral study (OECD 401) in the rat.