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Administrative data

Description of key information

The substance was harmful ofter single oral administration to rats. Inhalation exposure is unlikely due to the low vapour pressure of the substance. Based on the physical chemical properties dermal absorption is likely less than the uptake by the oral route. Dermal contact has to be minimized due to the skin sensitizing properties of the compound.

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:
25 Feb to 22 April 2008 in life
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Follows existing guidelines, GLP requirements, and well documented. The initial dose given the first animal was selected as specified in the Acute Oral Toxicity-Fixed Dose method in error. All subsequent doses were chosen by the AOT425 Statistical program. This error was not considered to affect the purpose or integrity of the study.
Reference:
Composition 1
Qualifier:
according to
Guideline:
OECD Guideline 425 (Acute Oral Toxicity: Up-and-Down Procedure)
Version / remarks:
US EPA OPPTS 870.1100 Acute Oral Toxicity, 2002
Deviations:
yes
Remarks:
Initial dose was chosed as per Acute Oral Toxicity - Fixed Dose method. Subsequent doses chosen by AOT425 Statistical program.
GLP compliance:
yes (incl. certificate)
Test type:
up-and-down procedure
Test material information:
Composition 1
Species:
rat
Strain:
Sprague-Dawley
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River (UK) Ltd, Margate, Kent, UK
- Age at study initiation: 8 to 12 weeks of age
- Weight at study initiation: 222 grams to 258 grams
- Fasting period before study: overnight
- Housing: individually in suspended solid floor polypropylene cages with woodflakes
- Diet (e.g. ad libitum): Certified Rat and Mouse Diet ad libitum
- Water (e.g. ad libitum): mains drinking water ad libitum
- Acclimation period: 5 days minimum

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

IN-LIFE DATES: From: 2008/02/25 To: 2008/04/22
Route of administration:
oral: gavage
Vehicle:
arachis oil
Details on oral exposure:
Maximum dose of 2000 mg/kg used undiluted material. . Other dose levels used dilutions of test material in arachis oil. The test article did not dissolve or suspend in distilled water.

Concentrations and dose volumes:
175 mg/kg - 17.5 mg/ml - 10 ml
300 mg/kg - 30 mg/ml - 10 ml
550 mg/kg - 55 mg/ml - 10 ml
2000 mg/kg - as supplied, specific gravity 0.824 - 2.43 ml

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: Initial dose was chosen as per Acute Toxicity - Fixed Dose method by error. Subsequent doses chosen by AOT425 Statistical program with the slope of the dose-response curve set to default (sigma = 0.5). The statistical program gave a recommended progression of 2000, 550, 175, 55.0, 17.5, 5.5 and 1.75 mg/kg.

Doses:
175 mg/kg, 300 mg/kg, 550 mg/kg, 2000 mg/kg
No. of animals per sex per dose:
8 total female animals; 1 at 175 mg/kg, 1 at 300 mg/kg, 4 at 550 mg/kg, 2 at 2000 mg/kg
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Observed at 1/2, 1, 2, and 4 hours after dosing, then daily for up to 14 days. Weighed prior to dosing and at 7 and 14 days or at death
- Necropsy of survivors performed: yes - gross observation
- Other examinations performed: clinical signs, body weights
Statistics:
The Oral LD50 was calculated by the maximum likelihood method. Using the mortality data obtained, an estimate of the acute oral median lethal dose was obtained. (LD50), with 95% confidence limits. An assumed sigma of 0.5 was used.
Sex:
female
Dose descriptor:
LD50
Effect level:
ca. 550 mg/kg bw
Based on:
test mat.
95% CL:
>= 232.9 - <= 1 560
Mortality:
All animals at 2000 mg/kg and two of the animals treated at 550 mg/kg were found dead the day of dosing or within two or three days of dosing.
Clinical signs:
Signs of systemic toxicity noted were hunched posture, lethargy, ataxia, decreased respiratory rate, labored respiration, pilo-erection and pallor of the extremities. Surviving animals appeared normal 6 to 11 days after dosing.
Body weight:
Surviving animals showed expected gains in bodyweight over the study period except for one animal at a dose level of 550 mg/kg which showed bodyweight loss during the first week, but expected gain in bodyweight during the second week.
Gross pathology:
Abnormalities noted in deceased animals during the study were hemorhagic or abnormally red lungs, dark liver, dark kidneys, and slight hemorrhage of the gastric mucosa. No abnormalities were seen at necropsy of animals that survived to the end of the study.

  Mortality Data
 Dose level (mg/kg)  Number survived  Number died  Total animals  Day/time of Death
 175  1  0  1  
 300  1  0  1  
 550  2  2  4  Day 2, Day 3
 2000  0  2 2 Dosing day (1 hr, 2 hr)
 All doses  4  4  8  Dosing day, Day 2 or Day 3
Conclusions:
The acute oral median lethal dose (LD50) and 95% confidence limits of the test material in the female Sprague-Dawley CD strain rat were calculated to be 550 (232.9-1560) mg/kg bodyweight (based on an assumed sigma of 0.5).
Executive summary:

The acute oral median lethal dose (LD50) and 95% confidence limits of the test material in the female Sprague-Dawley CD strain rat were calculated to be 550 (232.9-1560) mg/kg bodyweight (based on an assumed sigma of 0.5). An up and down method (OECD 425 - Acute Oral Toxicity - Up-and-down procedure) was used. Test article was administered once by gavage either undiluted (2000 mg/kg) or diluted with arachis oil (175, 300, or 550 mg/kg). Animals were observed at 1/2, 1, or 2 hours after dosing, and for 14 days thereafter. All animals at the high dose level died (1 to 2 hours post dose) and 2 of the animals treated at 550 mg/kg (days 2 and 3 post dosing). Signs of systemic toxicity observed during the study were hunched posture, lethargy, ataxia, decreased respiratory rate, labored breathing, pilo-erection and pallor of the extremities. Surviving animals appeared normal 6 to 11 days after dosing. No abnormalities were seen at gross necropsy at day 14 in surviving animals. Findings in animals that died during the study included hemorrhagic or abnormally red lugs, dark liver, dark kidneys, and slight hemorrhage of the gastric mucosa.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
550 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

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Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2012-02-12 to 2012-03-28
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study performed unde GLP
Reference:
Composition 1
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Version / remarks:
1987
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Version / remarks:
2008
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
standard acute method
Limit test:
yes
Test material information:
Composition 1
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Harlan Laboratories UK Ltd., Oxon UK
- Age at study initiation: 8 to 12 weeks
- Weight at study initiation: 200 g +- 20%
- Fasting period before study: no
- Housing: suspended solid-floor polypropylene cages with woodflakes as bedding material
- Diet: ad libitum
- Water : ad libitum

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

IN-LIFE DATES: From: 2012-02-27 To: 2012-03-09
Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- % coverage: 10 % of body surface
- Type of wrap if used: surgical gauze plus semiocclusive self-adhesive bandage

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

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2.43 mg/kg bw (specifc gravity: 0.824)

Duration of exposure:
24 h
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
5
Control animals:
not required
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations: after 1/2, 1, 2, 4 hours after dosing and thereafter once daily
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, primary irritation on the site of contact, body weight at day 0, 7 and 14
Sex:
male/female
Dose descriptor:
LDLo
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No deaths occurred during the study period
Clinical signs:
No signs of toxicity were observed.
Body weight:
Nine animals showed body weight loss during the first week, but the expected weight gain during the second week.
Gross pathology:
No gross abnormalities were observed.
Other findings:
Dermal reactions: very slight to slight erythema was noted in all animals throughout the observation period. Very slight to slight oedema was noted in 3 malesand 4 females from day 2 to 3 until day 6 to 13. Several animals showed light brown discoloration of the epidermis, crust formation, haemorrhage of dermal capillaries, blanching of the skin, small superficial scattered scabs, hardened light brown or hardened dark scab, scab cracking, scab lifitng to reveal glossy skin and scab lifitng on edges to reveal dried blood.
Interpretation of results:
practically nontoxic
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The test item was not acutely toxic to rats by the dermal route up to a limit dose of 2000 mg/kg bw. The only effects observed were reversible reductions in body weight and local skin reactions.
Executive summary:

In a standard dermal toxicity test according to OECD TG 402 and GLP in five male and female Wistar rats no mortality was observed at the limit dose of 2000 mg/kg bw. The only effects observed were reversible reductions in body weight and local skin reactions. The substance is therfore not classified for acute dermal toxicity according to EU-Regulation 1907/2006 and amendments and EU Dir 67/548/EEC and amendments.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating dose
2 000 mg/kg bw

Additional information

The acute oral toxicity was studied using the up and down method (OECD 425 - Acute Oral Toxicity - Up-and-down procedure) The test article was administered once by gavage either undiluted (2000 mg/kg) or diluted with arachis oil at dose levels of 175, 300, or 550 mg/kg. The animals were observed at 1/2, 1, or 2 hours after dosing, and for 14 days thereafter. All animals (2 females) at the high dose level died (1 to 2 hours post dose) and 2 of the 4 animals treated at 550 mg/kg (days 2 and 3 post dosing).

The acute oral median lethal dose (LD50) and 95% confidence limits of the test material in the female Sprague-Dawley CD strain rat were calculated to be 550 (232.9-1560) mg/kg bodyweight (based on an assumed sigma of 0.5).

Signs of systemic toxicity observed during the study were hunched posture, lethargy, ataxia, decreased respiratory rate, labored breathing, pilo-erection and pallor of the extremities. Surviving animals appeared normal 6 to 11 days after dosing. No abnormalities were seen at gross necropsy at day 14 in surviving animals. Findings in animals that died during the study included hemorrhagic or abnormally red lugs, dark liver, dark kidneys, and slight hemorrhage of the gastric mucosa.

In a standard dermal toxicity test according to OECD TG 402 and GLP in five male and female Wistar rats no mortality was observed at the limit dose of 2000 mg/kg bw. The only effects observed were reversible reductions in body weight and local skin reactions. The substance is therfore not classified for acute dermal toxicity according to EU-Regulation 1907/2006 and amendments and EU Dir 67/548/EEC and amendments.

Justification for classification or non-classification

Based on an LD50 of 550 mg/kg bw the substance is classified as acutely toxic category 4 CLP (Reg. 1907/2006 and amendments) by the oral route.

According to Dir. 67/548/EC and adaptations the substance is classified as harmful if swallowed (R22).

Based on an LD50 of > 2000 mg/kg bw in a dermal study in rats the substance is not classified for acute dermal toxicity according to EU-Regulation 1907/2006 and amendments and EU Dir 67/548/EEC and amendments.