diethyl pyridine-2,4-dicarboxylate

Endpoint summary

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:

3.9.2002 - 30.1.2003

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Study has been performed under GLP and according to OECD guidelines.

Qualifier:

according to guideline

Guideline:

OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)

Deviations:

no

Qualifier:

according to guideline

Guideline:

other: EC Directive No. 92/69/EEC, B.1 bis, 31st July 1992

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

fixed dose procedure

Limit test:

yes

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

Animals:- Species, strain: rat, Sprague-Dawley Rj: SD (IOPS Han).- Breeder: Janvier, Le Genest-Saint-Isle, France.- Number and sex: two females for the sighting test and one group of ten animals (five males and five females) for the main experiment.- Age/weight: on the day of treatment, the animals were approximately 6 weeks old. In the main experiment, they had a mean body weight ± standard deviation of 186 ± 5 g for the males and 164 ± 10 g for the females. Females were nulliparous and non pregnant.- Fasting period before study: fasted for an overnight period of approximately 18 hours before dosing, but had free access to water- Diet (e.g. ad libitum): free access to A04 C pelleted diet- Water (e.g. ad libitum): ad libitum- Housing: polycarbonate cage, max 7 animals per 48 x 27 x 20 cm- Acclimation: at least 5 days before the beginning of the study.- Identification: individually by earnotches.Environmental conditions:- temperature: 22 ± 2°C- relative humidity: 30 to 70%- light/dark cycle: 12 h/12 h- ventilation: approximately 12 cycles/hour of filtered, non-recycled air.

Route of administration:

oral: gavage

Vehicle:

other: 0.5% suspension of methylcellulose

Details on oral exposure:

VEHICLE- Concentration in vehicle: 200 mg/mL- Amount of vehicle (if gavage): 10 mL- Justification for choice of vehicle: not reportedMAXIMUM DOSE VOLUME APPLIED: 10 mL/kgDOSAGE PREPARATION (if unusual): On the day of treatment, the test item was ground using a mortar and pestle, then was prepared at the chosen concentration in the vehicle.

Doses:

Sighting test: 500, 2000 mg/kg Main test: 2000 mg/kg

No. of animals per sex per dose:

Sighting test: 1 female per doseMain test: one group of ten animals (five males and five females).

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days (main test), 7 days (sighting test)- Frequency of observations and weighing: day 1, day 8, day 15- Necropsy of survivors performed: yes- Examinations performed: Mortality, clinical signs, body weight, macroscopic necropsy examination

Preliminary study:

No clinical signs and no mortality were observed at the 500 mg/kg dose-level. Dyspnea and piloerection were observed on day 1 in the animal given 2000 mg/kg.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

no death

Clinical signs:

At the 2000 mg/kg dose-level, except for piloerection noted on day 1 in all animals, no clinical signs were recorded during the study.

Body weight:

The body weight gain of the animals was not affected by treatment with the test item.

Gross pathology:

Macroscopic examination of the main organs of the animals revealed no apparent abnormalities.

Interpretation of results:

not classified

Remarks:

Migrated informationCriteria used for interpretation of results: EU

Conclusions:

Under the experimental conditions, no deaths were observed at 2000 mg/kg. The test item can be considered as devoid of significant acute oral toxicity.

Executive summary:

The acute oral toxicity of the test item MEXORYL SBU was evaluated in rats according to OECD 420. The study was conducted in compliance with the principles of Good Laboratory Practice Regulations.

A preliminary test was conducted at 500 mg/kg and 2000 mg/kg with one female rat each. In the main test, the test item was administered by oral route (gavage) to one group of ten fasted Sprague-Dawley rats (five males and five females). The test item was prepared in 0.5% methylcellulose and administered to the animals at the dose of 2000 mg/kg. Clinical signs and mortality were checked for a period of 14 days following the single administration of the test item. The animals were checked for body weight gain and were subjected to necropsy.

In the sighting test, no clinical signs and no mortality were observed at the 500 mg/kg dose-level. Dyspnea and piloerection were observed on day 1 in the animal given 2000 mg/kg. In the main test, at the 2000 mg/kg dose-level, except for piloerection noted on day 1 in all animals, no clinical signs and no death were recorded during the study. The body weight gain of the animals was not affected by treatment with the test item. At necropsy, no apparent abnormalities were observed.

Under the experimental conditions, no deaths were observed at 2000 mg/kg and the test item was considered as devoid of significant acute oral toxicity. According to the classification criteria laid down in Council Directive 67/548/EEC (and subsequent adaptations), concerning the potential toxicity by oral route, the test item should not be classified.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

mg/kg bw

Quality of whole database:

reliability 1

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:

calculation (if not (Q)SAR)

Remarks:

Migrated phrase: estimated by calculation

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: extrapolated value of dermal LD50 according to acute oral study data and weight of evidence approach

Reason / purpose for cross-reference:

other:

Qualifier:

according to guideline

Guideline:

other: OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)

Test type:

other: extrapolation from acute oral toxicity study

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other:

Remarks:

extrapolation from acute oral toxicity study

A Weight of Evidence Approach (WoE) using a route to route extrapolation can be considered as sufficiently robust to determine the acute dermal toxic potential of Mexoryl SBU. The WoE complies with the REACH regulation to avoid animal testing.

Data are available from acute oral toxicity study on Rat, skin irritation study on rabbit and repeated dose toxicity study by dermal route on rat can be used in order to make a route to route extrapolation to estimate the dermal LD50.

A 2-week toxicity study was performed by dermal route in rats at 500, 750, and 1000 mg/kg/day.

The test substance Mexoryl SBU were applied for 6-hour in a non-occlusive pad (rinsing after 6 hours), with a protective collar (to avoid any ingestion), always on the same area corresponding to 10 % body surface. Scabs were observed at the application site at the dose levels of 750 and 1000 mg/kg/day and dose-related erythema were noted from Day 4 of the study at all the tested doses.

No mortality were noted after 6h application at 1000 mg/kg bw.

The main concern for the dermal application is the local irritant effect, that could appeared after repeated exposure.

In order to reduce the local effects, the highest tested dose chosen for the 90 days repeated doses toxicity study was 750 mg/kg/day and the test article was applied on alternate sites of application.

This value was the NOAEL for the systemic effect for repeated dose toxicity study.

The dermal LD50 could be extrapolated from oral route and in absence of complete ADME study on the bioavailability of the test substance, it could be considered by default to be maximum, that means about 100% of bioavailability for oral and 32.5% for dermal route.

In conclusion, the LD50 dermal for Mexoryl SBU can be assumed to be > 2000 mg/kg bw

Interpretation of results:

not classified

Remarks:

Migrated informationCriteria used for interpretation of results: EU

Conclusions:

LD50 dermal for Mexoryl SBU can be assumed to be > 2000 mg/kg bw.

Executive summary:

A Weight of Evidence Approach (WoE) using a route to route extrapolation can be considered as sufficiently robust to determine the acute dermal toxic potential of Mexoryl SBU. The WoE complies with the REACH regulation to avoid animal testing.

Data are available from acute oral toxicity study on Rat, skin irritation study on rabbit and repeated dose toxicity study by dermal route on rat can be used in order to make a route to route extrapolation to estimate the dermal LD50.

A 2-week toxicity study was performed by dermal route in rats at 500, 750, and 1000 mg/kg/day.

The test substance Mexoryl SBU were applied for 6-hour in a non-occlusive pad (rinsing after 6 hours), with a protective collar (to avoid any ingestion), always on the same area corresponding to 10 % body surface. Scabs were observed at the application site at the dose levels of 750 and 1000 mg/kg/day and dose-related erythema were noted from Day 4 of the study at all the tested doses.

No mortality were noted after 6h application at 1000 mg/kg bw. The main concern for the dermal application is the local irritant effect.

In order to reduce the local effects, the highest tested dose chosen for the 90 days repeated doses toxicity study was 750 mg/kg/day and the test article was applied on alternate sites of application.

This value was the NOAEL for the systemic effect for repeated dose toxicity study.

The dermal LD50 could be extrapolated from oral route and in absence of complete ADME study on the bioavailability of the test substance, it could be considered by default to be maximum, that means about 100% of bioavailability for oral and 32.5 % for dermal route.

In conclusion, the LD50 dermal for Mexoryl SBU can be assumed to be > 2000 mg/kg bw

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

mg/kg bw

Quality of whole database:

reliability 2

Additional information

A Weight of Evidence Approach (WoE) using a route to route extrapolation can be considered as sufficiently robust to determine the acute dermal toxic potential of Mexoryl SBU.

In the acute oral toxicity study:

The test item was administered by oral route (gavage) to one group of ten fasted Sprague-Dawley rats (five males and five females). The test item was prepared in 0.5% methylcellulose and administered to the animals at the dose of 2000 mg/kg. Clinical signs and mortality were checked for a period of 14 days following the single administration of the test item. The animals were checked for body weight gain and were subjected to necropsy.

At 2000 mg/kg dose-level, except for piloerection noted on day 1 in all animals, no clinical signs and no death were recorded during the study. The body weight gain of the animals was not affected by treatment with the test item. At necropsy, no apparent abnormalities were observed.

Under the experimental conditions, no deaths were observed at 2000 mg/kg and the test item was considered as devoid of significant acute oral toxicity.

The potential of the test item Mexoryl SBU to induce skin irritation was evaluated in rabbits according to OECD TG 404, and the the test item was shown to be non-irritant when applied topically to rabbits.

A preliminary 2-week toxicity study was performed by dermal route in rats at 500, 750, and 1000 mg/kg/day.

The test substance Mexoryl SBU was applied for 6-hour in a non-occlusive pad (rinsing after 6 hours), with a protective collar (to avoid any ingestion), always on the same area corresponding to 10 % body surface. Scabs were observed at the application site at the dose levels of 750 and 1000 mg/kg/day and dose-related erythema were noted from Day 4 of the study at all the tested doses.

No mortality were noted after 6h application at 1000 mg/kg bw. The main concern for the dermal application is the local irritant effect, that could appear after repeated exposure.

In order to reduce the local effects, the test article was applied on alternate sites of application and the highest tested dose chosen for the 90-day repeated doses toxicity study was 750 mg/kg/day and this value was the NOAEL for the systemic effect for repeated dose toxicity study.

Accordingly, the dermal LD50 could be extrapolated from oral route. In absence of complete ADME study on the bioavailability of the test substance, the dermal skin absorption was considered from an in vitro skin penetration study performed through human dermatomed skin and rat full thickness skin over a 24 hour exposure period with a formulation containing a nominal 5 % Mexoryl SBU. The dermal absorption rate was 32.5%.

In absence of data for oral route, the oral absorption, considered by default to be maximum, that means about 100% of bioavailability and no default factor will be introduced. Thus the acute toxicity data by oral route can be considered as predictive of the acute toxicity by dermal route.

In conclusion, the LD50 dermal for Mexoryl SBU can be assumed to be > 2000 mg/kg bw.

Justification for selection of acute toxicity – oral endpoint
key study

Justification for selection of acute toxicity – dermal endpoint
key study

Justification for classification or non-classification

According to the Globally Harmonized System of Classification and Labelling of Chemicals and to CLP-Regulation (EC) No. 1272/2008, concerning the potential toxicity by oral and dermal routes, the test item should not be classified.