Registration Dossier

Administrative data

Description of key information

Acute toxicity: oral: LD50combined > 2000 mg/kg bw (OECD 420, GLP, K, rel. 1)
Acute toxicity: dermal: LD50combined > 2000 mg/kg bw (OECD 402, GLP, K, rel. 1)
Acute toxicity: inhalation: Waiver

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
Study period:
From 29 Nov. 1994 to 21 Dec. 1994
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)
Version / remarks:
Adopted 17th July 1992
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.1 bis (Acute Oral Toxicity - Fixed Dose Procedure)
Deviations:
no
Principles of method if other than guideline:
not applicable
GLP compliance:
yes (incl. certificate)
Test type:
fixed dose procedure
Limit test:
no
Specific details on test material used for the study:
Storage conditions: refrigerator in the dark
Species:
rat
Strain:
other: Crl: CD (SD) BR strain (VAF plus)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River (UK)Limited, Margate, Kent- U.K.
- Age at study initiation: 4-6 weeks
- Weight at study initiation: See Tables of results
- Fasting period before study: yes overnight
- Housing: in groups ofup to 5, by sex, in grid-bottomed cages suspended over cardboard lined excreta trays. Cardboard tray liners were changed as often as necessary to maintain hygiene.
- Diet (e.g. ad libitum): ad libitum apart from an overnight fast before dosing (a pelleted diet (SQC Rat and Mouse Maintenance Diet No.1 Expanded, produced by Special Diets Services, Witham, Essex). Certificates of analysis for both diet and drinking water are held on file at Toxicol Laboratories.
- Water (e.g. ad libitum): ad libitum apart from an overnight fast before dosing
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-24 °C
- Humidity (%): 40-66%
- Air changes (per hr): air conditionned room
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 25 & 100 mg/mL
- Amount of vehicle (if gavage): 20 mL/kg bw

MAXIMUM DOSE VOLUME APPLIED: 20 mL/kg bw

DOSAGE PREPARATION (if unusual): N.A.
Doses:
Preliminary range finding study: 1 female with 500 mg/kg bw, then another female with 2000 mg/kg bw.
Main Study: 2000 mg/kg/bw (5 males + 5 females)
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 and weighing: Observations: after 0.5, 1, 2, 4 hours and daily during 14 days. Weighing: Before dosing and weekly therafter (days 1, 8 and 15).
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight.
Statistics:
Not applicable/relevant
Preliminary study:
1 female with 500 mg/kg bw: no clinical signs
1 female with 2000 mg/kg bw: no clinical signs
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
none (see "Illustration" for detailed results)
Clinical signs:
none (see "Illustration" for detailed results)
Body weight:
no significant changes (see "Illustration" for detailed results)
Gross pathology:
no significant effects (see "Illustration" for detailed results)
Other findings:
None

none

Interpretation of results:
GHS criteria not met
Conclusions:
Oral LD50 combined > 2000 mg/kg bw
Executive summary:

Introduction. The purpose of this study was to assess the acute oral toxicity of Fructalate, in the rat using the Fixed Dose Method. The study complies with the requirements of OECD Guideline for the Testing of Chemicals No 420, adopted 17th July 1992 and method B.1bis described in 0.J. L 383 A, an Annex to EEC Commission Directive 92/69/EEC of 31st July 1992.

These guidelines require that the main study be conducted at one (or more if necessary) of the following fixed dose levels: 5, 50, 500 or 2000 mg/kg bw.

Method. In a preliminary range finding study, the test article was administered orally at a dose level of 500 mg/kg bw to a single female rat. As this first animal was still alive 24 hours after dosing, a second female wasdosed with 2000 mg/kg bw test article. Both animals were examined frequently on the day of dosing and daily thereafter for a further 7 days. As neither animal exhibited clinical signs of toxicity and both were alive at the end of the observation period, no further range finding animals were dosed.

Since the results of the range finding study indicated that a test article dose of 2000 mg/kg bw produced no significant toxicity, in the main study, the test article was administered as a single oral dose of 2000mg/kg bw to a group of 5 male and 5 female rats which had been fasted overnight. The animals were examined frequently on the day of dosing and daily thereafter for a further 14 days at the end of which, they were killed and subjected to necropsy.

None of the animals died and all maintained a healthy appearance throughout the 15 days observation period.

There was no adverse effect on bodyweight gain in animals of either sex.

At necropsy, the submandibularlymph nodes were swollen in one male. No abnormalities were detected in the remaining animals.

Conclusions. Both the discriminating dose and the minimum lethal dose of the test material are estimated to be in excess of 2000 mg/kg bodyweight. According to the criteria in the guidelines quoted above, the test material is considered not to have significant acute toxicity under the conditions of this study.

The test material does not meet the criteria for classification according to the Regulation( EC) No. 1278/2008 (CLP)

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw
Quality of whole database:
The key study is GLP-compliant and of high quality (Klimisch score = 1

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Data waiving:
other justification
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
Justification for type of information:
JUSTIFICATION FOR DATA WAIVING
In accordance with Column 2 of REACH Annex VIII, in addition to the oral route (8.5.1), for substances other than gases, the information mentioned under 8.5.2 (acute toxicity by inhalation) and 8.5.3 (acute toxicity by the dermal route) shall be provided for at least one other route. The choice for the second route will depend on the nature of the substance and the likely route of human exposure In the present case, inhalation exposure will be lower than dermal exposure because the registered substance has a low vapour pressure (0.2 Pa at 25°C) and a low freezing point (-12°C), so the potential for the generation of inhalable forms is low. Dermal exposure is the more likely route of exposure based on physico-chemical properties (Log Kow = 2.61 at 20°C, WS = 1.28 g/L at 20°C).
Reason / purpose:
data waiving: supporting information
Reason / purpose:
data waiving: supporting information
Reason / purpose:
data waiving: supporting information
Endpoint conclusion
Endpoint conclusion:
no study available
Quality of whole database:
In accordance with Column 2 of REACH Annex VIII, in addition to the oral route (8.5.1), for substances other than gases, the information mentioned under 8.5.2 (acute toxicity by inhalation) and 8.5.3 (acute toxicity by the dermal route) shall be provided for at least one other route. The choice for the second route will depend on the nature of the substance and the likely route of human exposure
In the present case, inhalation exposure will be lower than dermal exposure because the registered substance has a low vapour pressure (0.2 Pa at 25°C) and a low freezing point (-12°C), so the potential for the generation of inhalable forms is low. Dermal exposure is the more likely route of exposure based on physico-chemical properties (Log Kow = 2.61 at 20°C, WS = 1.28 g/L at 20°C).

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:
From 23 August 1999 to 06 September 1999
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Version / remarks:
Adopted 24 February 1987
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Deviations:
no
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)
- Age at study initiation: 8-12 weeks old
- Weight at study initiation: males: 200-210 g , females: 200-222 g
- Fasting period before study: no
- Housing: suspende polypropylene cages furnished with woodflakes. Animals individually housed during exposure period (24h), then in group of 5, by sex.
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-25
- Humidity (%): 30-70
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 03 August (start of dosing) To: 18/19 August (necropsy)
Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- % coverage: ca 10% of body surface
- Type of wrap if used: surgical gauze semi-occluded with a piece of self-adhesive bandage

REMOVAL OF TEST SUBSTANCE
- Washing (if done): with cotton wool moistened with distilled water
- Time after start of exposure: 24h

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 1.92 mL/kg
- Constant volume or concentration used: yes
Duration of exposure:
24 h
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
5 per sex per dose
Control animals:
not required
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
Observations: after 30 min, 1, 2, 4 hours after dosing, then daily for 14 days
Weighing: Days 0 (prior application), 7 and 14
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, pathological observation (external observation & opening of the abdominal and thoracic cavities to check macroscopic abnormalities).
Statistics:
Not applicable/Nor required
Preliminary study:
not applicable
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
None
Clinical signs:
no signs of systemic toxicity
Body weight:
Animals showed expected gain in bodyweight during the study
Gross pathology:
No abnormalities detected
Other findings:
No signs of dermal irritation (erythema or oedema) were observed from day 1 to day 14 in all the animals treated.

none

Interpretation of results:
GHS criteria not met
Conclusions:
Dermal LD50 Combined > 2000 mg/kg bw
Executive summary:

Introduction. A study was performed to assess the acute dermal toxicity of the test material in the Sprague-Dawley CD strain rat. The method used followed that described in the OECD Guidelines for Testing of Chemicals No. 402 "Acute Dermal Toxicity" (adopted 24 February 1987) and Method B3 of Commission Directive 92/69/EEC (which constitutes Annex V of Council Directive 67/548/EEC).

The results may be used as a basis for classification and labelling under Annex VI of Council Directive 67/548/EEC (as adapted to technical progress by Commission Directive 93/21/EEC) relating to the classification, packaging and labelling of dangerous substances.

 

Methods A group of ten animals (five males and five females) was given a single 24-hour, semi-occluded dermal application to intact skin at a dose level of 2000 mg/kg bodyweight. The animals were observed for fourteen days after the day of treatment and were then killed for gross pathological examination.

 

Results and Conclusion There were no deaths. No signs of systemic toxicity or skin irritation were noted.

Animals showed expected gain in bodyweight during the study.

No abnormalities were noted at necropsy.

The acute dermal median lethal dose (LD50) of the test material in the Sprague Dawley CD strain rat was found to be greater than 2000 mg/kg bodyweight. No symbol and risk phrase are required according to the Regulation (EC) No. 1272/2008 (CLP).

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw
Quality of whole database:
The key study is GLP-compliant and of high quality (Klimisch score = 1)

Additional information

Acute toxicity: oral

A key study was identified (Toxicol, 1995, rel. 1). In this Fixed Dose Method study, performed according to the OECD test guideline No. 420 and in compliance with GLP, rats were administered a single oral dose of 2000 mg/kg bw by gavage. None of the animals died and all maintained a healthy appearance throughout the 15 days observation period.There was no adverse effect on bodyweight gain in animals of either sex.At necropsy, the submandibular lymph nodes were swollen in one male. No abnormalities were detected in the remaining animals.

Oral LD50Combined > 2000 mg/kg bw.

Acute toxicity: dermal

A key study was identified (Safepharm, 1999, rel. 1). In this limit test performed according to OECD test guideline No. 402 and in compliance with GLP, rats weregiven a single 24-hour, semi-occluded dermal application of the test material to intact skin at a dose level of 2000 mg/kg bodyweight. There were no deaths. No signs of systemic toxicity or skin irritation were noted. Animals showed expected gain in bodyweight during the study. No abnormalities were noted at necropsy.

Dermal LD50Combined > 2000 mg/kg bw

Acute toxicity: inhalation

No data was available. However, in accordance with Column 2 of REACH Annex VIII, in addition to the oral route (8.5.1), for substances other than gases, the information mentioned under 8.5.2 (acute toxicity by inhalation) and 8.5.3 (acute toxicity by the dermal route) shall be provided for at least one other route. The choice for the second route will depend on the nature of the substance and the likely route of human exposure In the present case, inhalation exposure will be lower than dermal exposure because the registered substance has a low vapour pressure (0.2 Pa at 25°C) and a low freezing point (-12°C), so the potential for the generation of inhalable forms is low. Dermal exposure is the more likely route of exposure based on physico-chemical properties (Log Kow = 2.61 at 20°C, WS = 1.28 g/L at 20°C).

Justification for classification or non-classification

Harmonized classification:

The substance has no harmonized classification according to the Regulation (EC) No. 1272/2008.

Self-classification:

Acute toxicity via Oral route:

Based on the available data, the substance is not classified according to the Regulation (EC) No. 1272/2008 as the LD50 is greater than 2000 mg/kg bw.

Acute toxicity via Dermal route:

Based on the available data, the substance is not classified according to the Regulation (EC) No. 1272/2008 as the LD50 is greater than 2000 mg/kg bw.

Acute toxicity (Inhalation):

No data was available.

Specific target organ toxicity: single exposure (Oral):

The classification criteria according to the Regulation (EC) No. 1272/2008 as specific target organ toxicant (STOT) – single exposure, oral are not met since no reversible or irreversible adverse health effects were observed immediately or delayed after exposure and no effects were observed at the guidance value (oral) for a Category 1 classification (C≤ 300 mg/kg bw) and at the guidance value (oral) for a Category 2 classification (2000 mg/kg bw≥C > 300 mg/kg bw). No classification is required.

The criteria for Transient Organ effects (STOT-SE Category 3) according to the Regulation (EC) No. 1272/2008 are not met since narcotic effects were not observed in the acute oral toxicity study.

Specific target organ toxicity: single exposure (Dermal):

The classification criteria according to the Regulation (EC) No 1272/2008 as specific target organ toxicant (STOT) – single exposure, dermal are not met since no reversible or irreversible adverse health effects were observed immediately or delayed after exposure and no effects were observed at the guidance value (dermal) for a Category 1 classification (C≤ 1000 mg/kg bw) and at the guidance value (dermal) for a Category 2 classification (2000 mg/kg bw≥C > 1000 mg/kg bw). No classification is required.

The criteria for Transient Organ effects (STOT-SE Category 3) according to the Regulation (EC) No. 1272/2008 are not met since narcotic effects were not observed in the acute dermal toxicity study.

Specific target organ toxicity: single exposure (Inhalation):

No data was available. However, the registered substance is not a skin or an eye irritant, therefore respiratory tract irritation is not expected.

 

Aspiration hazard:

The substance is not a hydrocarbon and no effects were observed on lungs in oral studies, therefore the criteria for aspiration toxicity according to the Regulation (EC) No. 1272/2008 are not met.