Registration Dossier

Administrative data

Endpoint:
acute toxicity: inhalation
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
the study does not need to be conducted because exposure of humans via inhalation is not likely taking into account the vapour pressure of the substance and/or the possibility of exposure to aerosols, particles or droplets of an inhalable size
other:
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Reason / purpose:
data waiving: supporting information
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
1964
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
other: Documentation insufficient for assessment. Substance purity is not mentioned.
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
yes
Remarks:
no details on test animals and environmental conditions; no details on results
Principles of method if other than guideline:
Not applicable
GLP compliance:
not specified
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Osborne-Mendel
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: no data
- Age at study initiation: young adult
- Weight at study initiation: no data
- Fasting period before study: approximately 18 hours
- Housing: divided by sex
- Diet (e.g. ad libitum): ad libitum, except during administration of test material
- Water (e.g. ad libitum): ad libitum
- Acclimation period: no data

ENVIRONMENTAL CONDITIONS
No data
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
No data
Doses:
No data
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
Statistics:
Method of Litchfield and Wilcoxon (1949)
Preliminary study:
Not applicable
Sex:
male/female
Dose descriptor:
LD50
Effect level:
18 500 mg/kg bw
Based on:
test mat.
95% CL:
16 930 - 20 260
Mortality:
Mortality was observed from 4 h to 5 days after administration of test material.
Clinical signs:
Mortality was observed from 4 h to 5 days after administration of test material.
Body weight:
No data
Gross pathology:
No data
Other findings:
None

None

Interpretation of results:
GHS criteria not met
Conclusions:
The oral LD50 for Aldehyde C-14 (γ-undecalactone) is higher than 5000 mg/kg bw in rats. Therefore it is not classified according to the Annex I of the Regulation (EC) No. 1272/2008 (CLP) and to the GHS.
Executive summary:

In an acute oral toxicity study, groups (5/sex) of Osborne-Mendel rats were given a single oral dose of Aldehyde C-14 (γ-Undecalactone) by oral intubation. Animals were then observed for mortality and clinical signs for 2 weeks. LD50 was calculated using the method of Litchfield & Wilcoxon (1949).

Mortality was observed from 4 h to 5 days after administration of test material. Depression occurred within 10 minutes and wet fur was noticed.

Oral LD50 Combined = 18500 mg/kg bw (16930-20260).

Under the test conditions, the oral LD50 for γ-Undecalactone is higher than 5000 mg/kg bw in rats and therefore it is not classified according to the Annex I of the Regulation (EC) No. 1272/2008 (CLP) and to the GHS.

Reason / purpose:
data waiving: supporting information
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
1972
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
Study conducted similarly to OECD Guideline 401 with minor deviations: certificate of analysis not included, few details on test animals and environmental conditions, no data on number of animals showing signs of toxicity and pathological findings. γ-nonalactone, as a linear saturated 4-hydroxycarboxylic acid derived-lactones, is considered adequate for read-across purpose (see §"Toxicokinetics").
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
yes
Remarks:
no data on age and source of animals; no data on housing and environmental conditions, number of animals showing signs of toxicity and pathological findings
Principles of method if other than guideline:
Not applicable
GLP compliance:
no
Remarks:
pre-GLP
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 200-250 g
- Fasting period before study (minimum): 16 h
- Food and water: ad libitum
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
No data
Doses:
4000, 5000, 6250, 7800 and 9700 mg/kg bw
No. of animals per sex per dose:
10 males/dose
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Observations for mortality were made at 1 and 6 h after dosing and daily thereafter for 14 days.
- Necropsy of survivors performed: Yes
Statistics:
None
Preliminary study:
None
Sex:
male
Dose descriptor:
LD50
Effect level:
6 600 mg/kg bw
Based on:
test mat.
95% CL:
5 800 - 7 400
Mortality:
- Deaths occurred overnight to two days following administration of the test material.
- Mortalities in rats were 0, 30, 40, 80 and 100 % at 4000, 5000, 6250, 7800 and 9700 mg/kg bw, respectively.
Clinical signs:
Piloerection and lethargy
Body weight:
No data
Gross pathology:
No data
Other findings:
None

None

Interpretation of results:
GHS criteria not met
Conclusions:
The oral LD50 for γ-Nonalactone is higher than 5000 mg/kg bw in male rats therefore it is not classified according to the Annex I of the Regulation (EC) N° 1272-2008 (CLP) and to the GHS.
Executive summary:

In an acute oral toxicity study performed similarly to OECD test Guideline No. 401, groups of Wistar rats (10 males/dose) were given a single oral dose of γ-Nonalactone at 4000, 5000, 6250, 7800 or 9700 mg/kg bw. Animals were then observed for mortality at 1 and 6 h after dosing and daily thereafter for 14 days. Gross necropsies were performed on all survivors.

Mortalities in rats were 0, 30, 40, 80 and 100 % at 4000, 5000, 6250, 7800 and 9700 mg/kg bw, respectively. Clinical signs noted were piloerection and lethargy.

Oral LD50 Males = 6600 mg/kg bw (5800-7400).

Under the test conditions, the oral LD50 for γ-Nonalactone is higher than 5000 mg/kg bw in male rats therefore it is not classified according to the Annex I of the Regulation (EC) No. 1272/2008 (CLP) and to the GHS.

This study is considered as acceptable and satisfies the requirement for acute oral toxicity endpoint.

Reason / purpose:
data waiving: supporting information
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
From 2002-07-02 to 2002-09-24
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
Test was conducted in accordance with Japanese guideline for medicine (yakushin yaku No.88, 1993-08-10) which is similar to OECD test guideline No. 420 but without GLP compliance. γ-caprolactone, as a linear saturated 4-hydroxycarboxylic acid derived-lactones, is considered adequate for read-across purpose (see §"Toxicokinetics").
Qualifier:
according to
Guideline:
other: Japanese guideline for medicine (yakushin yaku No.88, 1993-08-10)
Deviations:
no
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)
Deviations:
yes
Remarks:
housing of animals not reported
Principles of method if other than guideline:
not applicable
GLP compliance:
no
Test type:
fixed dose procedure
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles Liver Japan
- Age at study initiation: purchased at age of week 4
- Weight at study initiation: male: 87-96g, female: 70-82g when reveived
- Fasting period before study: 17-18 hr
- Housing: no data
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 1 week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23+/-3
- Humidity (%): 50+/-20
- Air changes (per hr): 10-15/hr
- Photoperiod (hrs dark / hrs light): 12 hr/12 hr

IN-LIFE DATES: From: 2002-07-03 To: 2002-07-24
Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
VEHICLE
- Amount of vehicle (if gavage): 20 mL/kg
- Justification for choice of vehicle: test substance is dissolved in water at 10% and stable in water
- Lot/batch no. (if required): 1XA1 (Japanese pharmacopoeia)

MAXIMUM DOSE VOLUME APPLIED: 20 mL/kg

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: administered at 2000 mg/kg due to low toxicity expected
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
5 animals per sex per dose
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: clinical signs, mortality, behavior: after administration to 1, 2, and 4 hourr, 1 to 14 day (every day); bodyweight: day 0, 1, 3, 5, 7, 10 and 14.
- Necropsy of survivors performed: yes
- Other examinations performed: After opening the thoracic and abdominal cavities, a macroscopic examination of the main organs was performed:
Statistics:
not performed
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No deaths occurred at the dose levels of 2000 mg/kg bw during the observation period.
Clinical signs:
No clinical signs were observed in the animals treated at the dose level of 2000 mg/kg bw.
Body weight:
The body weight gain of the animals was normal at 2000 mg/kg bw.
Gross pathology:
No macroscopic lesions were observed at 2000 mg/kg bw.
Other findings:
None

None

Interpretation of results:
GHS criteria not met
Conclusions:
Under the test conditions, Oral LD50(Combined) > 2000 mg/kg bw.
Executive summary:

In a limit acute oral toxicity study performed according to Japanese guideline for medicines (which is similar to the OECD test guideline No. 420) but not in compliance with GLP, 5 Sprague-Dawley rats/sex were administered a single oral dose of 2000 mg/kg bw of the γ-caprolactone (97.4 % pure). The animals were observed for mortality, clinical signs and body weight for 14 days and then necropsied for macroscopic observations.

No animal died. No clinical signs or effects on body weight were observed at 2000 mg/kg bw. Gross pathological examinations at 14 days (terminal necropsy) revealed no test substance-related findings.

Oral LD50Combined > 2000 mg/kg bw

 

Under the test conditions, γ-caprolactone is not classified according to the annex I of the Regulation EC No. 1272/2008 (CLP) and to the GHS.

This study is considered as acceptable and satisfies the requirement for acute oral toxicity endpoint.

Reason / purpose:
data waiving: supporting information
Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
22 July - 05 August 1999
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
GLP study conducted according to OECD Guideline 402 with minor deviations: no certificate of analysis of the test substance
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
yes
Remarks:
no certificate of analysis of the test substance
Principles of method if other than guideline:
Not applicable
GLP compliance:
yes (incl. certificate)
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River (UK) Ltd, Kent, UK
- Age at study initiation: 8-12 weeks
- Weight at study initiation: Males: 222-233 g; females: 211-226 g
- Housing: Animals were housed in suspended polypropylene cages furnished with woodflakes. Animals were housed individually during the 24 h exposure period and in groups of 5/sex for the remainder of the study.
- Diet: Rat and Mouse Expanded Diet No. 1 (Special Diets Services Limited, Essex, UK), ad libitum
- Water: Mains drinking water, ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature: 19-25 °C
- Humidity: 30-70 %
- Air changes: Approximately 15/h
- Photoperiod: 12 h darkness / 12 h continuous light
Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: Test material was applied on the shorn skin of back and flank region.
- % coverage: Approximately 10 % of the total body surface area
- Type of wrap if used: A piece of surgical gauze was placed over the treatment area and semi-occluded with a piece of self-adhesive bandage.

REMOVAL OF TEST SUBSTANCE
- Washing: After 24 h contact period, the bandage was carefully removed and the treated skin and surrounding hair wiped with cotton wool moistened with distilled water to remove any residual test material.

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2.14 mL/kg bw
- Constant volume or concentration used: Yes
Duration of exposure:
24 h
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations: Animals were observed for deaths or overt signs of toxicity at 0.5, 1, 2 and 4 h after dosing and subsequently once daily for 14 days.
- Frequency of weighing: Individual body weights were recorded prior to application of the test material on Day 0 and on Days 7 and 14.
- Necropsy of survivors performed: Yes, all the animals were killed by cervical dislocation at the termination of study and subjected to gross pathological examination.
- Other examinations performed: After removal of the dressings and subsequently once daily for 14 days, the test sites were examined for evidence of primary irritation and scored according to the method of Draize (1977).
Statistics:
None
Preliminary study:
None
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality was observed.
Clinical signs:
No signs of systemic toxicity or skin irritation were noted.
Body weight:
Animals showed an expected gain in body weight during the study.
Gross pathology:
No abnormalities were noted at necropsy.
Other findings:
None

None

Interpretation of results:
GHS criteria not met
Conclusions:
The acute dermal LD50 of γ-Undecalactone, is higher than 2000 mg/kg bw in rats therefore it is not classified according to the Regulation (EC) No. 1272/2008 (CLP) and to the GHS.
Executive summary:

In an acute dermal toxicity study (limit test) performed according to OECD Guideline 402 and in compliance with GLP, a groups of 10 rats (5/sex) of Sprague-Dawley CD (Crl:CD (SD) IGS BR) strain was administered a single dermal dose of γ-Undecalactone, at 2000 mg/kg bw on clipped skin using a semi-occlusive patch for 24 h. Animals were then observed for mortality, clinical signs, bodyweights and dermal reactions for 14 days and were all macroscopically necropsied after sacrifice.

No deaths occurred throughout the study. No signs of systemic toxicity or skin irritation were noted. Animals showed an expected gain in body weight during the study. No abnormalities were noted at necropsy. In this study, the acute dermal LD50 of γ-Undecalactone, was considered to be higher than 2000 mg/kg bw in rats.

Under the test conditions, the combined acute dermal LD50 of γ-Undecalactone, is higher than 2000 mg/kg bw in rats therefore it is not classified according to the Regulation (EC) No. 1272/2008 (CLP) and to the GHS.

This study is considered as acceptable and satisfies the requirement for acute dermal toxicity endpoint.

Reason / purpose:
data waiving: supporting information
Reference

Low volatility (from QSAR).

Vapour pressure:
0.274 Pa
at the temperature of:
25 °C

No experimental study is available on the substance. Therefore, the vapour pressure was assessed using a QSAR model on the parent, and extrapolation from a publication relating to enthalpy of vaporization of analogues. Results were considered consistent to support the weight of evidence for low volatility, but values were quite different respectively 0.274 and 0.024 Pa at 25°C. Considering the reliability of the publication could not be assigned, while the QSAR demonstrated good predictibility, and also gave the worst-case result, the calculated

value was retained as key value for purpose of CSA.

Data source

Materials and methods

Results and discussion

Applicant's summary and conclusion