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Administrative data

Description of key information

Rat oral acute LD₅₀ 5470 mg/kg bw (non-guideline); guinea pig oral acute LD₅₀ 4050 mg/kg bw (non-guideline); Rat oral acute LD₅₀ >5000 mg/kg bw (non-guideline).
Rat dermal acute LD₅₀ > 2000 mg/kg bw (OECD 402); rat dermal acute LD₅₀ >5000 mg/kg bw (non-guideline).

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:
weight of evidence
Study period:
No data
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
other: Insufficient experimental details given in incomplete study report.
Principles of method if other than guideline:
Method not specified.
GLP compliance:
no
Remarks:
Study predates adoption of GLP
Test type:
other: No data
Species:
rat
Strain:
not specified
Sex:
not specified
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: No data
- Age at study initiation: No data
- Weight at study initiation: No data
- Fasting period before study: No data
- Housing: No data
- Diet (e.g. ad libitum): No data
- Water (e.g. ad libitum): No data
- Acclimation period: No data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): No data
- Humidity (%): No data
- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light): No data
Route of administration:
oral: unspecified
Vehicle:
not specified
Details on oral exposure:
VEHICLE
- Concentration in vehicle: No data
- Amount of vehicle (if gavage): No data
- Justification for choice of vehicle: No data
- Lot/batch no. (if required): No data
- Purity: No data

MAXIMUM DOSE VOLUME APPLIED: Up to 5 g/kg body weight

DOSAGE PREPARATION (if unusual): No data

CLASS METHOD (if applicable)
- No data
Doses:
Up to 5 g/kg body weight
No. of animals per sex per dose:
10 animals used, details unclear.
Control animals:
not specified
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Observation daily on days 1-14
- Necropsy of survivors performed: No data
- Other examinations performed: clinical signs, body weight, organ weights, histopathology, other: No data
Statistics:
No data
Sex:
not specified
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Based on:
test mat.
Mortality:
0/10
Clinical signs:
No data
Body weight:
No data
Gross pathology:
No data
Other findings:
- Organ weights: No data
- Histopathology: No data
- Potential target organs: No data
Interpretation of results:
practically nontoxic
Remarks:
Migrated information
Conclusions:
The acute oral LD₅₀ of the test material ethyl 2,3-epoxy-3-phenylbutyrate was determined as >5000 mg/kg bw.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
5 000 mg/kg bw

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
Study period:
2012-01-30 to 2012-02-13
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Study conducted in compliance with agreed protocols, with no or minor deviations from standard test guidelines and/or minor methodological deficiencies, which do not affect the quality of the relevant results. The study report was conclusive, done to a valid guideline and the study was conducted under GLP conditions.
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
Five male and five female Wistar (RccHan:WIST) strain rats were supplied by Harlan Laboratories UK Ltd., Oxon, UK. On receipt the animals were randomly allocated to cages. The females were nulliparous and non pregnant. After an acclimatisation period of at least five days the animals were selected at random and given a number unique within the study by indelible ink-marking on the tail and a number written on a cage card. At the start of the study the animals weighed at least 200g, and were eight to twelve weeks of age. The weight variation did not exceed ±20% of the mean weight for each sex.
The animals were housed in suspended solid floor polypropylene cages furnished with woodflakes. The animals were housed individually during the 24 Hour exposure period and in groups of five, by sex, for the remainder of the study. Free access to mains drinking water and food (2014C Teklad Global Rodent diet supplied by Harlan Laboratories UK Ltd., Oxon, UK) was allowed throughout the study. The diet, drinking water and bedding were routinely analysed and were considered not to contain any contaminants that could reasonably be expected to affect the purpose or integrity of the study.
The temperature and relative humidity were set to achieve limits of 19 to 25°C and 30 to 70% respectively. Any occasional deviations from these targets were considered not to have affected the purpose or integrity of the study. The rate of air exchange was at least fifteen changes per hour and the lighting was controlled by a time switch to give twelve hours continuous light (06:00 to 18:00) and twelve hours darkness.
The animals were provided with environmental enrichment items which were considered not to contain any contaminant of a level that might have affected the purpose or integrity of the study.
Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
The calculated volume of test item, as received, was applied as evenly as possible to an area of shorn skin (approximately 10% of the total body surface area) using a graduated syringe.
Duration of exposure:
24 hours
Doses:
2000 mg/kg
No. of animals per sex per dose:
5 male
5 female
Control animals:
not required
Details on study design:
On the day before treatment the back and flanks of each animal were clipped free of hair.
Using available information on the toxicity of the test item, a single group of animals was treated as follows:

Dose Level Specific Gravity Dose Volume Number of Rats
(mg/kg) (ml/kg) Male Female
2000 1.079 1.86 5 5

The calculated volume of test item, as received, was applied as evenly as possible to an area of shorn skin (approximately 10% of the total body surface area) using a graduated syringe. A piece of surgical gauze was placed over the treatment area and semi occluded with a piece of self adhesive bandage. The animals were caged individually for the 24 Hour exposure period. Shortly after dosing the dressings were examined to ensure that they were securely in place.
After the 24 Hour contact period the bandage was carefully removed and the treated skin and surrounding hair wiped with cotton wool moistened with arachis oil BP to remove any residual test item. The animals were returned to group housing for the remainder of the study period.
The animals were observed for deaths or overt signs of toxicity ½, 1, 2 and 4 hours after dosing and subsequently once daily for fourteen days.

After removal of the dressings and subsequently once daily for fourteen days, the test sites were examined for evidence of primary irritation and scored according to the following scale from Draize J H (1977) "Dermal and Eye Toxicity Tests" In: Principles and Procedures for Evaluating the Toxicity of Household Substances, National Academy of Sciences, Washington DC p.31:

EVALUATION OF SKIN REACTIONS
Erythema and Eschar Formation Value

No erythema 0
Very slight erythema (barely perceptible) 1
Well-defined erythema 2
Moderate to severe erythema 3
Severe erythema (beef redness) to slight eschar formation (injuries in depth) 4

Oedema Formation

No oedema 0
Very slight oedema (barely perceptible) 1
Slight oedema (edges of area well-defined by definite raising) 2
Moderate oedema (raised approximately 1 millimetre) 3
Severe oedema (raised more than 1 millimetre and extending beyond the area of exposure) 4

Any other skin reactions, if present were also recorded.
Individual bodyweights were recorded prior to application of the test item on Day 0 and on Days 7 and 14.
At the end of the study the animals were killed by cervical dislocation. All animals were subjected to gross necropsy. This consisted of an external examination and opening of the abdominal and thoracic cavities. The appearance of any macroscopic abnormalities was recorded. No tissues were retained.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: 95% confidence limits not calculable.
Mortality:
Individual mortality data are given in Table 1.
There were no deaths.
Clinical signs:
Individual clinical observations are given in Table 1.
There were no signs of systemic toxicity.
Body weight:
Individual bodyweights and weekly bodyweight changes are given in Table 4.
Animals showed expected gains in bodyweight over the study period, except for one female which showed no gain in bodyweight during the first week but expected gain in bodyweight during the second week.
Gross pathology:
Individual necropsy findings are given in Table 5.
No abnormalities were noted at necropsy.
Other findings:
Dermal Reactions
Individual dermal reactions are given in Table 2 and Table 3 (attachment2).
Very slight erythema and/or crust formation were noted at the test sites of five animals. Small superficial scattered scabs were also noted at the test site of one male. There were no signs of dermal irritation noted at the test sites of five animals.

Evaluation of Data

Data evaluations included the relationship, if any, between the exposure of the animal to the test item and the incidence and severity of all abnormalities including behavioural and clinical observations, gross lesions, bodyweight changes, mortality and any other toxicological effects.

Using the mortality data obtained, an estimate of the acute dermal median lethal dose (LD50) of the test item was made.

Table 1              Individual Clinical Observations and Mortality Data

Dose Level

mg/kg

Animal Number and Sex

Effects Noted After Initiation of Exposure (Hours)

Effects Noted After Initiation of Exposure (Days)

½

1

2

4

1

2

3

4

5

6

7

8

9

10

11

12

13

14

2000

1-0

Male

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

1-1

Male

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

1-2

Male

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

1-3

Male

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

1-4

Male

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

2-0

Female

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

2-1

Female

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

2-2

Female

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

2-3

Female

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

2-4

Female

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0= No signs of systemic toxicity

Table 4              Individual Bodyweights and Weekly Bodyweight Changes

Dose Level mg/kg

Animal Number and Sex

Bodyweight (g) at Day

Bodyweight Change (g) During Week

0

7

14

1

2

2000

1-0 Male

231

251

281

20

30

1-1 Male

234

262

281

28

19

1-2 Male

243

266

273

23

7

1-3 Male

244

277

284

33

7

1-4 Male

231

257

276

26

19

2-0 Female

204

208

217

4

9

2-1 Female

208

209

220

1

11

2-2 Female

208

225

232

17

7

2-3 Female

205

212

219

7

7

2-4 Female

200

200

207

0

7

Table 5              Individual Necropsy Findings

Dose Level

mg/kg

Animal Number
and Sex

Time of Death

Macroscopic Observations

2000

1-0

Male

Killed Day 14

No abnormalities detected

1-1

Male

Killed Day 14

No abnormalities detected

1-2

Male

Killed Day 14

No abnormalities detected

1-3

Male

Killed Day 14

No abnormalities detected

1-4

Male

Killed Day 14

No abnormalities detected

2-0

Female

Killed Day 14

No abnormalities detected

2-1

Female

Killed Day 14

No abnormalities detected

2-2

Female

Killed Day 14

No abnormalities detected

2-3

Female

Killed Day 14

No abnormalities detected

2-4

Female

Killed Day 14

No abnormalities detected

Interpretation of results:
not classified
Remarks:
Migrated information The acute dermal median lethal dose (LD₅₀) of the test item in the Wistar strain rat was found to be greater than 2000 mg/kg bodyweight. Criteria used for interpretation of results: EU
Conclusions:
The acute dermal median lethal dose (LD₅₀) of the test item in the Wistar strain rat was found to be greater than 2000 mg/kg bodyweight.
Executive summary:
Introduction. The study was performed to assess the acute dermal toxicity of the test item in the Wistar strain rat. The method was designed to be compatible with the following: OECD Guidelines for the Testing of Chemicals No. 402 "Acute Dermal Toxicity" (adopted 24 February 1987) Method B3 Acute Toxicity (Dermal) of Commission Regulation (EC) No. 440/2008 Method. A group of ten animals (five males and five females) was given a single, 24 hour, semi‑occluded dermal application of the undiluted test item to intact skin at a dose level of 2000 mg/kg bodyweight. Clinical signs and bodyweight development were monitored during the study. All animals were subjected to gross necropsy.

Mortality. There were no deaths.

Clinical Observations. There were no signs of systemic toxicity.

Dermal Irritation. Very slight erythema and/or crust formation were noted at the test sites of five animals. Small superficial scattered scabs were also noted at the test site of one male. There were no signs of dermal irritation noted at the test sites of five animals.

Bodyweight. Animals showed expected gains in bodyweight over the study period, except for one female which showed no gain in bodyweight during the first week but expected gain in bodyweight during the second week.

Necropsy. No abnormalities were noted at necropsy.

Conclusion. The acute dermal median lethal dose (LD₅₀) of the test item in the Wistar strain rat was found to be greater than 2000 mg/kg bodyweight.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
5 000 mg/kg bw

Additional information

Acute oral toxicity

Jenner et al. (1964) obtained acute oral toxicity LD₅₀ values in two species, rats and guinea pigs, of 5470 mg/kg bw and 4050 mg/kg bw respectively. In Leberco study No. 62956 an LD₅₀ value for acute oral toxicity for the substance in rats was obtained which was > 5000 mg/kg bw. We would not normally expect studies from this era to be particularly reliable, especially given the analysis made by Mason et al. (1978) of commercially available strawberry aldehydes that identified variability in specifications of those substances, and criticism by Mason et al. of previous studies based on this. Nevertheless, high LD₅₀ values were reported. The tests conducted are not particularly sophisticated so any toxicity would be detected despite the deficiencies of the study. Furthermore, there is also a general expectation that the substance will not be particularly toxic, and the general expectation that this class of substance should be of low toxicity. For animal welfare reasons it was therefore decided not to proceed with an animal testing programme for this substance. For the key value for the chemical safety assessment for acute oral toxicity, the value of 5000 mg/kg bw has been adopted.

Acute dermal toxicity

Harlan study No. 41104979, the LD₅₀ value for acute dermal toxicity of the test material was found to be > 2000 mg/kg bw. In Leberco study No. 62956 an LD₅₀ value for acute dermal toxicity for the substance in rats was obtained which was > 5000 mg/kg bw. This study supports the findings of the Harlan study that the substance is non-toxic.

Acute inhalation toxicity

No studies for this endpoint were available. Testing for this endpoint has been waived on exposure considerations. From the low toxicity values for the other endpoints, and the lack of systematic toxicity found in these studies, it is expected that there will be negligible toxicity via the inhalation route.


Justification for selection of acute toxicity – oral endpoint
Most recent study

Justification for classification or non-classification

According to Regulation (EC) No. 1272/2008, Section 3.1.2, Criteria for Classification of Substances as Acutely Toxic, substances should be classified as being acutely toxic via the oral route if the LD₅₀ or equivalent Acute Toxicity Estimate (ATE) is ≤ 2000 mg/kg bw. All available studies indicate that the LD₅₀ is above the threshold value of 2000 mg/kg bw, so this substance should not be classified for acute oral toxicity.

Also according to Regulation (EC) No. 1272/2008, Section 3.1.2, Criteria for Classification of Substances as Acutely Toxic, substances should be classified as being acutely toxic via the dermal route if the dermal LD₅₀ or equivalent ATE is ≤ 2000 mg/kg bw. The available evidence indicates that the LD₅₀ is above the threshold value of 2000 mg/kg bw, so this substance should not be classified for acute oral toxicity.

Due to a combination of low vapour pressure and lack of systemic toxicity, classification is not expected for acute inhalation toxicity.