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Administrative data

Description of key information

LD50 (oral; males/females) = 4500 mg/kg bw (3810 - 5310, 95% C.I)  (Equivalent/similar to 401)

LD50 (dermal; males/females) = >5000 mg/kg bw (Equivalent/similar to 402)

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
Reliability:
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.
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
GLP compliance:
no
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
other: Albino rats (TacN(SD)fBR)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- 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- Fasting period before study: Food withdrawn at 3:00 pm on the day prior to treatment and the rats were fasted overnight.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


Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
MAXIMUM DOSE VOLUME APPLIED:

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.
Doses:
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:
no
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
Statistics:
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
Sex:
male/female
Dose descriptor:
LD50
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
Sex:
male
Dose descriptor:
LD50
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
Sex:
female
Dose descriptor:
LD50
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
Mortality:
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:
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. Irritability was characterised by clicking and biting the tongue, scratching and biting the cage walls and floor. Some rats appeared to be searching (for food or water?) . Signs of irritability subsided in about 1 hour and from 24 hrs to 48 hrs after dosing, rats tended to be subdued.

No clinical signs specific to treatment were noted after Day 3 or 4, but general signs of toxicity such as piloerection, chromodacryorrhea and chromorhinorrhea, and soiled perinal fur continued sporadically throughout the study at all dose levels.

Study report attachment: Appendix II Clinical Signs (0061)
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.

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

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

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

Interpretation of results:
GHS criteria not met
Remarks:
Not classified according to CLP
Conclusions:
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.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
4 500 mg/kg bw
Quality of whole database:
The key study was the only study available and was assigned a Klimisch score of 2. The overall quality of the database is high.

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Equivalent or similar to OECD 402. 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.
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
GLP compliance:
no
Test type:
standard acute method
Limit test:
yes
Species:
rabbit
Strain:
other: albino New Zealand type
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: C.S.E. Colony located in Branchville, N.J. USA.
- Age at study initiation: young adult
- Weight at study initiation: 2.34 to 3.09 kg at the start of dosing
- Housing: Standard laboratory conditions
- Diet (e.g. ad libitum): Purina rabbit chow
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: 7 days

Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: dorsal surface of the trunk
- % coverage: approximately 20%
- Type of wrap if used: Open plastic sleeves ("baggies") placed over trunk and the anterior end was taped against the rabbit. The substance was applied and then the posterior end of the sleeve ws taped against the rabbit, allowing the central portion to balloon.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): Excess material cleansed from skin using disposable napkin moistened with saline
- Time after start of exposure: 24 hrs

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): Dose - 5 mL/kg bw
- Constant volume or concentration used: Variable volume (11.70 mL - 15.45 mL) based on body weight


Duration of exposure:
24 hrs
Doses:
5 mL/kg bw
No. of animals per sex per dose:
6 animals (3 male, 3 female)
Control animals:
not required
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Observations - Twice daily (weekdays) and once daily (weekends). Weighing - Before dosing and all survivors weighed before necropsy
- Necropsy of survivors performed: yes (gross necropsy)
- Other examinations performed: clinical signs, body weight, qualitative estimate of dermal irritation.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Remarks on result:
other: Given as mL/kg bw in report; converted to mg/kg bw using density: 1.001 g/mL
Mortality:
There were no deaths (Appendix 1).
Clinical signs:
Application of the test article to the skin appeared to be tolerated well by the rabbits and slight to moderate erthema only was observed during the first 24 hours after application. Treated skin lost pliability and became thickened and dry by Day 6. By Day 14, the texture of the skin was reverting to normal in all animals. No signs of overt systemic toxicity were observed (Appendix I).



Body weight:
Bodyweights are presented in Appendix II.

Gross pathology:
Positive findings were restricted to the treated skin. In all rabbits the skin was scaled and the surface dry and the underlying fascia appeared sparse. (Appendix III)

Study report attachments:

Appendix I (Clincial signs) & II (Body weight) (CSE 0056)

Appendix III Gross Necropsy Findings (CSE 0056)

Interpretation of results:
GHS criteria not met
Remarks:
Not classified according to CLP
Conclusions:
A dose of >5000 mg/kg bw/day of the test substance maintained in contact with the skin for 24 hrs did not cause any mortalities, so the substance is considered non-toxic.
Executive summary:

In an acute dermal toxicity study (CSE 0056), groups of young adult albino New Zealand rabbits (3 males and 3 females) were dermally exposed to methyl cedryl ketone for 24 hours (approximately 20% body surface area) at doses of 5 mL/kg bw. Animals were then observed for 14 days.

Dermal LD50 Males/Females = >5000 mg/kg bw (limit test)

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

No mortalities or signs of overt systemic toxicity were observed. The only treatment related clinical signs and necropsy findings related to the skin. Application of the test article to the skin caused transient moderate erythema and drying and scaliness by Day 8, which persisted through termination. Gross necropsy of each individual animal revealed effects were restricted to the skin. In all rabbits the skin was scaled and the surface dry and the underlying fascia appeared sparse.

This acute dermal study is classified as acceptable. It does satisfy the guideline requirement for an acute dermal study (OECD 402) in the rabbit.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
5 000 mg/kg bw
Quality of whole database:
The key study was the only study available and was assigned a Klimisch score of 2. The overall quality of the database is high.

Additional information

Acute oral toxicity

There is one acute oral toxicity study in rats available.

In an acute oral toxicity study (equivalent/similar to 401) 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. 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. The LD50 (males) was 4600 mg/kg bw (3360 - 6300, 95% C.I.). The LD50 (females) was 4600 mg/kg bw (3830 - 5520, 95% C.I.). The LD50 (combined) was 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)

Acute dermal toxicity

There is one acute dermal toxicity study in rats available.

In an acute dermal toxicity study (equivalent/similar to 402), groups of young adult albino New Zealand rabbits (3 males and 3 females) were dermally exposed to methyl cedryl ketone for 24 hours (approximately 20% body surface area) at doses of 5 mL/kg bw. Animals were then observed for 14 days.

No mortalities or signs of overt systemic toxicity were observed. The only treatment related clinical signs and necropsy findings related to the skin. Application of the test article to the skin caused transient moderate erythema and drying and scaliness by Day 8, which persisted through termination. Gross necropsy of each individual animal revealed effects were restricted to the skin. In all rabbits the skin was scaled and the surface dry and the underlying fascia appeared sparse. The LD50 (males/females) was >5000 mg/kg bw (limit test). (LD50 values given as mL/kg bw in study report; LD50 values were converted to mg/kg bw using density: 1.001 g/mL).

Both studies are suitable for use in the human health risk assessment.

Justification for classification or non-classification

Based on the available information in the dossier, the substance Methyl Cedryl Ketone (CAS No. 32388-55-9) does not need to be classified for acute toxicity or specific target organ toxicity - single exposure when the criteria outlined in Annex I of 1272/2008/EC are applied.