Registration Dossier

Oral acute toxicity: LD50> 2000 mg/kg bw , key study with 6 female rats according to OECD Test Guideline 423.

Dermal acute toxicity: LD50> 2000 mg/kg bw, extrapolation from oral data.

Inhalation acute toxicity: LC50 > 50 mg/l, extrapolation from oral data.

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

From 16th June 2004 to 30th June 2004

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Remarks:

OECD guideline 423. GLP study.

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Deviations:

no

GLP compliance:

yes

Test type:

acute toxic class method

Limit test:

no

Species:

rat

Strain:

Crj: CD(SD)

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Japan.
- Age at study initiation: 7 weeks
- Weight at study initiation: 183-190 g
- Fasting period before study: yes (from about 18 hours and 30 minutes from the evening of the day before administration to about 6 hours after administration)
- Housing: stainless-steel cages
- Diet (e.g. ad libitum): solid feed (CRF-1, Oriental Yeast Co., Ltd.), ad libitum.
- Water (e.g. ad libitum): free bottle of water intake tap water
- Acclimation period: 2 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23ºC
- Humidity (%): 55%
- Air changes (per hr): 12
- Photoperiod: 12 hrs dark / 12 hrs light (6 am to 6 pm)

Route of administration:

oral: gavage

Vehicle:

CMC (carboxymethyl cellulose)

Remarks:

1% sodium carboxymethylcellulose solution

Doses:

2000 mg/kg

No. of animals per sex per dose:

2 groups of 3 female rats

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: 1time/day
- Necropsy of survivors performed: yes

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortality was observed

Clinical signs:

other: No clinical signs

Gross pathology:

No autopsy findings for pathological damage.

Other findings:

Bluish feces in the 3 female rats of a group at 1st day after administration derived from the color of the test material.

Interpretation of results:

not classified

Remarks:

(EU criteria)

Conclusions:

The result was as follows: LD50 >2000 mg/kg bw

Executive summary:

The aim of the test was to study the single dose oral toxicity of the test material according to OECD Test Guideline 423.

The test material was studied in 6 female rats (2 groups with 3 female rats per group) in a single dose oral toxicity test at 2000 mg/kg bw. On observation for general signs, only bluish feces, derived from the color of the test material, were noted. The result was as follows: LD50 >2000 mg/kg bw

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 001 mg/kg bw

Quality of whole database:

The study is a GLP compliant and has Klimisch score 1.

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

other: extrapolation from results obtained by the oral route

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Extrapolation based on available guidelines on route-to-route extrapolation of toxicity data when assessing health risks of chemicals.

Principles of method if other than guideline:

Extrapolation based on available guidelines on route-to-route extrapolation of toxicity data when assessing health risks of chemicals.

Dose descriptor:

LC50

Effect level:

> 50 mg/L air

Based on available guidelines on route-to-route extrapolation of toxicity data when assessing health risks of chemicals, an extrapolation based on the acute oral toxicity data is calculated for the inhalation route.

From the available data on two acute oral toxicity studies, it is concluded that the oral LD50 for the substance is greater than 2000 mg/kg bw (study 1: no mortality was observed) and greater from 10000 mg/kg bw (study 2: mortality was observed). As recommended in the corresponding guidelines, where data from the oral route is being used as the starting point, if no data are available on oral bioavailability, it is appropriate to assume that 100% of an orally administered dose is systemically available. Since no data is available on inhalation absorption, the most precautionary default would be to assume 100% absorption by this route.

Based on this acute oral toxicity data, an oral NOAEL may be identified as greater than 10000 mg/kg bw. This NOAEL can be modified into an inhalation NOAEL using a route-to-route extrapolation based on the assumptions stated above. Taking into account an exposure of 4 hours for the acute inhalation toxicity study, the value of the oral LD50 is divided by the default physiological parameter under the allometric scaling principle which is approximately 0.2 m3/kg bw for rats. This extrapolation leads to a value of 10 mg/l (study 1) and 50 mg/l (study 2). Therefore, the 4 -h LC50 would be greater than 10 -50 mg/l.

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Based on the assumptions for the extrapolation from the acute oral toxicity data, the 4 -h LC50 would be greater than 10-50 mg/l.

Executive summary:

From the available data on two acute oral toxicity studies, it is concluded that the oral LD50 for the substance is greater than 2000 mg/kg bw (study 1: no mortality was observed) and greater from 10000 mg/kg bw (study 2: mortality was observed). As recommended in the corresponding guidelines, where data from the oral route is being used as the starting point, if no data are available on oral bioavailability, it is appropriate to assume that 100% of an orally administered dose is systemically available. Since no data is available on inhalation absorption, the most precautionary default would be to assume 100% absorption by this route.

Based on this acute oral toxicity data, an oral NOAEL may be identified as greater than 10000 mg/kg bw. This NOAEL can be modified into an inhalation NOAEL using a route-to-route extrapolation based on the assumptions stated above. Taking into account an exposure of 4 hours for the acute inhalation toxicity study, the value of the oral LD50 is divided by the default physiological parameter under the allometric scaling principle which is approximately 0.2 m3/kg bw for rats. This extrapolation leads to a value of 10 mg/l (study 1) and 50 mg/l (study 2). Therefore, the 4 -h LC50 would be greater than 10 -50 mg/l.

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LC50

Value:

50 mg/m³ air

Quality of whole database:

The study has a Klimish score 2 and is adequate for assessment.

Reference

Endpoint:: acute toxicity: dermal
Type of information:: other: extrapolation from results obtained by the oral route
Adequacy of study:: key study
Reliability:: 2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:: other: Extrapolation based on available guidelines on route-to-route extrapolation of toxicity data when assessing health risks of chemicals.
Principles of method if other than guideline:: Extrapolation based on available guidelines on route-to-route extrapolation of toxicity data when assessing health risks of chemicals.
Dose descriptor:: LD50
Effect level:: > 1 000 mg/kg bw
Dose descriptor:: LD50
Effect level:: > 5 000 mg/kg bw
Interpretation of results:: not classified
Remarks:: Migrated information Criteria used for interpretation of results: EU
Conclusions:: Based on the assumptions for the extrapolation from the acute oral toxicity data, the dermal LD50 would be greater than 1000 mg/kg bw (study 1) and greater than 5000 mg/kg bw (study 2).
Executive summary:: From the available data on two acute oral toxicity studies, it is concluded that the oral LD50 for the substance is greater than 2000 mg/kg bw (study 1: no mortality was observed) and greater from 10000 mg/kg bw (study 2: mortality was observed). As recommended in the corresponding guidelines, where data from the oral route is being used as the starting point, if no data are available on oral bioavailability, it is appropriate to assume that 50% of an orally administered dose is systemically available. Since no data is available on skin absorption, the most precautionary default would be to assume 100% absorption by this route although in reality very few substances will cross the skin to this extent. Therefore, based on these assumptions, the dermal LD50 would be greater than 1000 mg/kg bw (study 1) and greater than 5000 mg/kg bw (study 2).

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 001 mg/kg bw

Quality of whole database:

The study has a Klimish score 2 and is adequate for assessment.

Oral acute toxicity:

Key study: Study with 6 female rats (2 groups with 3 female rats per group) in a single dose oral toxicity test at 2000 mg/kg bw.

OECD Test Guideline 423.

The result was as follows: LD50 >2000 mg/kg bw.

Dermal acute toxicity:

Key study: Extrapolation from oral data.

From the available data on two acute oral toxicity studies, it is concluded that the oral LD50 for the substance is greater than 2000 mg/kg bw (study 1: no mortality was observed) and greater from 10000 mg/kg bw (study 2: mortality was observed). As recommended in the corresponding guidelines, where data from the oral route is being used as the starting point, if no data are available on oral bioavailability, it is appropriate to assume that 50% of an orally administered dose is systemically available. Since no data is available on skin absorption, the most precautionary default would be to assume 100% absorption by this route although in reality very few substances will cross the skin to this extent. Therefore, based on these assumptions, the dermal LD50 would be greater than 1000 mg/kg bw (study 1) and greater than 5000 mg/kg bw (study 2).

Inhalation acute toxicity:

Key study: Extrapolation from oral data.

From the available data on two acute oral toxicity studies, it is concluded that the oral LD50 for the substance is greater than 2000 mg/kg bw (study 1: no mortality was observed) and greater from 10000 mg/kg bw (study 2: mortality was observed). As recommended in the corresponding guidelines, where data from the oral route is being used as the starting point, if no data are available on oral bioavailability, it is appropriate to assume that 100% of an orally administered dose is systemically available. Since no data is available on inhalation absorption, the most precautionary default would be to assume 100% absorption by this route.

Based on this acute oral toxicity data, an oral NOAEL may be identified as greater than 10000 mg/kg bw. This NOAEL can be modified into an inhalation NOAEL using a route-to-route extrapolation based on the assumptions stated above. Taking into account an exposure of 4 hours for the acute inhalation toxicity study, the value of the oral LD50 is divided by the default physiological parameter under the allometric scaling principle which is approximately 0.2 m3/kg bw for rats. This extrapolation leads to a value of 10 mg/l (study 1) and 50 mg/l (study 2). Therefore, the 4 -h LC50 would be greater than 10 -50 mg/l.

Justification for selection of acute toxicity – oral endpoint

The study is of higher quality.

Justification for selection of acute toxicity – inhalation endpoint

Only one study available.

Justification for selection of acute toxicity – dermal endpoint

Only one study available.

Oral acute toxicity LD50> 2000 mg/kg: not classified.

Dermal acute toxicity LD50> 2000 mg/kg: not classified.

Inhalation acute toxicity LC50 > 10 -50 mg/l: not classified (inhalation of dusts)

Based on the available data, the substance is not classified for acute toxicity according to CLP Regulation (EC) No 1272/2008.