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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:
November 9, 1979 - December 5, 1979
Reliability:
2 (reliable with restrictions)
Cross-reference
Reason / purpose for cross-reference:
reference to same study
Reference
Endpoint:
acute toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
November 9, 1979 - December 5, 1979
Reliability:
2 (reliable with restrictions)
Justification for type of information:
ANALOGUE APPROACH

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
The structures of the target and source substances are identical and differ only with respect to the ratio of enantiomers where the target substance is a single pure L-isomer and the source substance is an equimolar mixture of L and D isomers.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
The target substance, L-Citronellyl nitrile, is a mono-constituent substance (EC No. 695-909-8, CAS no. 35931-93-2).
The source substance, DL-Citronellyl nitrile, is a mono-constituent substance (EC No. 257-288-8, CAS no. 51566-62-2).
The source and target substances are both of high purity with a low concentration of impurities.

3. ANALOGUE APPROACH JUSTIFICATION
The read across hypothesis is based on structural similarity where the only difference between target and source molecules is the enantiomeric ratio. In a non-chiral environment the target and source chemicals will have identical properties but in the chiral environment of living organisms the enantiomers may possess different carcinogenicity and teratogenicity (in a chiral environment, stereoisomers might experience selective absorption, protein binding, transport, enzyme interactions and metabolism, receptor interactions, and DNA binding). Therefore, as a precaution for the developmental toxicity endpoint it is suggested that the NOAEL 250 mg/kg bw/day for L-Citronellyl nitrile is used instead of 500 mg/kg bw/day, as it is not known which form is more potent in vivo. All other endpoints are considered to be acceptable for this substance assuming that 50% of the target compound is available in the test material.

4. DATA MATRIX
Please refer to the data matrix included in the read-across justification document attached in Section 13.2.
Reason / purpose for cross-reference:
read-across source
Qualifier:
no guideline available
Principles of method if other than guideline:
Study carried out in 1979.
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Wistar
Remarks:
albino
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age at study initiation: approximately 6 to 8 weeks of age
- Weight at study initiation: 200 - 266 g
- Fasting period before study: 18 hours of fasting
- Housing: galvanized cages with indirect bedding
- Diet: ad libitum.
- Water: ad libitum.
- Acclimation period: at least 2 days

ENVIRONMENTAL CONDITIONS
- Temperature: controlled
- Photoperiod: 12 hour lightldark cycle
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Doses:
3.15, 3.96, 4.46, 6.30 and 7.94 g/kg
No. of animals per sex per dose:
3
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations: 1, 3, 6, and 24 hours after treatment, and daily thereafter for a total of 14 days.
- Necropsy of survivors performed: yes
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
4.49 other: g/kg
Based on:
test mat.
Mortality:
See attachment
3.15 g/kg: 16.7%
3.96 g/kg: 33.3%
4.46 g/kg: 83.3%
6.30 g/kg: 83.3%
7.94 g/kg: 83.3%
Clinical signs:
See attachment
Body weight:
See attachment
Gross pathology:
See attachment
3.15 g/kg: Animal #la: Fibrous tissue encasing heart and lungs (died on day 11). #2,#3,#4a,#5,#6: No gross changes observed.
3.96 g/kg: Animal #1: Fibrous tissue encasing heart and lungs. #2,#5,#6: No gross changes observed. #3: No gross changes observed. #4: Head partially cannibalized. Pyloric mucosa severely reddened. Stomach ruptured. All abdominal viscera adhered to body wall and covered with a thin layer of fibrous tissue.
4.46 g/kg: Animal #1,#2: No gross changes observed. #3: Liver extremely pale. Intestines ruptured. #4,#6: Partially cannibalized. No gross changes observed.
#5a: No gross changes observed.
6.30 g/kg: Animal #1,#2,#6: Moderately reddened pyloric mucosa. #3a: Test article in stomach. No gross changes observed. #4: No gross changes observed. #5: No gross changes observed.
7.94 g/kg: Animal #1: No gross changes observed. a #2: Partially cannibalized. No gross changes observed. #3: No gross changes observed.#4-#6: No gross changes observed.
Other findings:
See attachment
Interpretation of results:
Category 5 based on GHS criteria
Conclusions:
LD50 = 4.49 (3.74 - 5.39) g/kg

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1979
Report date:
1979

Materials and methods

Test guideline
Qualifier:
no guideline available
Principles of method if other than guideline:
Study carried out in 1979.
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
3,7-dimethyloct-6-enenitrile
EC Number:
257-288-8
EC Name:
3,7-dimethyloct-6-enenitrile
Cas Number:
51566-62-2
Molecular formula:
C10H17N
IUPAC Name:
3,7-dimethyloct-6-enenitrile
Details on test material:
Chemical nature: 3,7-dimethyl-6-octenonitrile
CAS Number: 51566-62-2
Appearance: colourless liquid

Test animals

Species:
rat
Strain:
Wistar
Remarks:
albino
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age at study initiation: approximately 6 to 8 weeks of age
- Weight at study initiation: 200 - 266 g
- Fasting period before study: 18 hours of fasting
- Housing: galvanized cages with indirect bedding
- Diet: ad libitum.
- Water: ad libitum.
- Acclimation period: at least 2 days

ENVIRONMENTAL CONDITIONS
- Temperature: controlled
- Photoperiod: 12 hour lightldark cycle

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Doses:
3.15, 3.96, 4.46, 6.30 and 7.94 g/kg
No. of animals per sex per dose:
3
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations: 1, 3, 6, and 24 hours after treatment, and daily thereafter for a total of 14 days.
- Necropsy of survivors performed: yes

Results and discussion

Effect levels
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
4.49 other: g/kg
Based on:
test mat.
Mortality:
See attachment
3.15 g/kg: 16.7%
3.96 g/kg: 33.3%
4.46 g/kg: 83.3%
6.30 g/kg: 83.3%
7.94 g/kg: 83.3%
Clinical signs:
See attachment
Body weight:
See attachment
Gross pathology:
See attachment
3.15 g/kg: Animal #la: Fibrous tissue encasing heart and lungs (died on day 11). #2,#3,#4a,#5,#6: No gross changes observed.
3.96 g/kg: Animal #1: Fibrous tissue encasing heart and lungs. #2,#5,#6: No gross changes observed. #3: No gross changes observed. #4: Head partially cannibalized. Pyloric mucosa severely reddened. Stomach ruptured. All abdominal viscera adhered to body wall and covered with a thin layer of fibrous tissue.
4.46 g/kg: Animal #1,#2: No gross changes observed. #3: Liver extremely pale. Intestines ruptured. #4,#6: Partially cannibalized. No gross changes observed.
#5a: No gross changes observed.
6.30 g/kg: Animal #1,#2,#6: Moderately reddened pyloric mucosa. #3a: Test article in stomach. No gross changes observed. #4: No gross changes observed. #5: No gross changes observed.
7.94 g/kg: Animal #1: No gross changes observed. a #2: Partially cannibalized. No gross changes observed. #3: No gross changes observed.#4-#6: No gross changes observed.
Other findings:
See attachment

Applicant's summary and conclusion

Interpretation of results:
Category 5 based on GHS criteria
Conclusions:
LD50 = 4.49 (3.74 - 5.39) g/kg