L-valine

Endpoint summary

Description of key information

L-valine did not cause any mortality in an acute oral toxicity study according to OECD 423. LD50 derived from this limit test was > 2000 mg/kg bw. In another study for acute oral toxicity LD 50 was determined to be > 16 g/kg bw.. No acute toxicity occured in a limit test according to OECD 403 for the inhalation route at a concentration of 5.26 mg/m³. The acute dermal study was waived based on the above results as well as the physico-chemical and toxikokinetic properties.

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:

2005-10-05 to 2005-07-05

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP guideline study

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

other: Wistar outbred rat; Crl:(W1) WU BR

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River, Germany
- Age at study initiation: 8 - 9 weeks
- Weight at study initiation: 152 - 169 g
- Fasting period before study: overnight
- Housing: Maximum of 6 animals per macrolon cage
- Diet (e.g. ad libitum): Ad libitum approx. 4 h after dosing
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: 6 days

ENVIRONMENTAL CONDITIONS
according to guideline

IN-LIFE DATES: From: 2005-06-01 To:2005-06-21

Route of administration:

oral: gavage

Vehicle:

maize oil

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 200 mg/ml
- Amount of vehicle (if gavage):1.5 to 1.7 ml

MAXIMUM DOSE VOLUME APPLIED: 1.7 ml

Doses:

2000 mg/kg b.w.

No. of animals per sex per dose:

6

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Before dosing, day 3, day 7, day 14
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortality observed.

Clinical signs:

other: No clinical signs observed.

Gross pathology:

No distinct treatment-related gross alterations

Interpretation of results:

practically nontoxic

Remarks:

Migrated information Criteria used for interpretation of results: OECD GHS

Conclusions:

L-valine did not cause any mortality in an acute oral toxicity study according to OECD 423. LD50 derived from this limit test was > 2000 mg/kg bw.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 100 mg/kg bw

Quality of whole database:

GLP guideline study Klimisch Code 1

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2005-03-16 to 2005-10-04

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Deviations:

no

Remarks:

Some minor deviations which do not influence integrity and validity of the study and its results.

Qualifier:

according to guideline

Guideline:

EU Method B.2 (Acute Toxicity (Inhalation))

Deviations:

no

Remarks:

Some minor deviations which do not influence integrity and validity of the study and its results.

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:

TEST ANIMALS
- Source: Charles River, Sulzfeld, Germany
- Age at study initiation: 10 - 11 weeks
- Weight at study initiation: mean males 303 g, mean females 194 g
- Fasting period before study: none
- Housing: Macrolon cages with a stainless steel wire lid and wood shavings (Espen E-00 1; ABEDD, Köflach, Austria) as bedding material. The animals were housed five males or five females to a cage.
- Diet (e.g. ad libitum): ad libitum except during exposure (no access to food)
- Water (e.g. ad libitum): ad libitum except during exposure (no access to water)
- Acclimation period:5 weeks

ENVIRONMENTAL CONDITIONS
According to guideline

IN-LIFE DATES: From: 2005-05-18 To:2005-07-05

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

nose only

Vehicle:

clean air

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: ADG Developments Ltd., Codicote, Hitchin, Herts, SG4 8UB, UK
- Exposure chamber volume: 50 l
- Method of holding animals in test chamber: The animals were secured in plastic animal holders (Battelle ), positioned radially through the outer cylinder around the central column.
- Source and rate of air: Fresh, cleaned ambient air. 90.45 L/min.
- Method of conditioning air: The test atmosphere was generated by passing the milled test material to an eductor (Fox mini type 060, Fox Valve Development corp., Dover, NJ, USA) using a dry material feeder (Gericke GMD 60, Gericke AG, Regensburg, Switzerland). The eductor was placed at the top inlet of the exposure unit and was operated with humidified compressed air controlled by a pressure reducing valve at a constant pressure of 1.0 bar.
- System of generating particulates/aerosols: The milled test material was delivered in a slip stream of humidified ambient air.
- Method of particle size determination: Particle size distribution measurements were carried out once during preliminary testing and once during exposure using a 10-stage cascade impactor (Andersen, Atlanta, USA). The Mass Median Aerodynamic Diameter (MMAD) and the geometric standard deviation (gsd) were calculated.
- Treatment of exhaust air: The test atrmosphere was exhausted at the bottom of the test unit
- Temperature, humidity, pressure in air chamber: The mean temperature during exposure was 21.8 ± 0.2°C and the mean relative humidity was 49 ± 1% (range 48 - 50%). The oxygen concentration in the inhalation unit during exposure was 20.9%. The mean air flow through the exposure unit was 90.45 Llmin.

TEST ATMOSPHERE
- Brief description of analytical method used:
Gravimetric analysis six times during exposure. The test atmosphere was sampled in the breathing zone of the animals. Representative test atmosphere samples were obtained by passing measured amounts of test atmosphere at a sampling flow of 5 L/min through glass fibre which weere weighed before sampling and after loading.
- Samples taken from breathing zone: yes

VEHICLE
- Composition of vehicle (if applicable): clean air
- Concentration of test material in vehicle (if applicable): 5 g/m³
- Justification of choice of vehicle: normal brating conditions


TEST ATMOSPHERE (if not tabulated)
- Particle size distribution: 1 - 4µm
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): During exposure, about 87% of the mass of the aerosol present at the animals' breathing zone was contained in particles with an aerodynamic diameter equal to or smaller than 7.5 µm. The MMAD during exposure was estimated tobe 3.8 µm. The distribution of particle sizes had an estimated gsd of 2.1.

Analytical verification of test atmosphere concentrations:

yes

Remarks:

Determined by gravimetric analysis 6 times during exposure

Duration of exposure:

4 h

Concentrations:

5.26 g/m³

No. of animals per sex per dose:

5 male, 5 female

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: At least once a day
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs just before exposure, shortly after exposire and at least daily during the 14-day observation period. Body weight just before exposure and on day 7 as well as day 14. Gross pathological changes with particuliar reference to any changes in the respiratory tract.

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 5 260 mg/m³ air (analytical)

Based on:

test mat.

Exp. duration:

4 h

Mortality:

No mortality

Clinical signs:

other: Slightly decreased breathing rate was observed in all animals throughout the entire exposure period. An hour after exposure, slight irregular breathing and slight or moderate blepharospasm were observed in all animals, accompanied in one male (animal no.

Body weight:

Overall body weight gain in male and female animals was observed.
Mean values for males:
Day 0 302.8 g (sd 8.3. g), day 7 317.5 g (sd 7.8 g), day 14 336.4g (sd 12.1 g)
Mean values for female:
Day 0 193.5 g (sd 4.8 g), day 7 200.2 g (sd 6.3 g), day 14 207.0 g (sd 6.6 g)

Gross pathology:

Macroscopic examination at necropsy did not reveal treatment-related gross changes.

Other findings:

A sparsely haired skin was seen in one female, but this finding was not considered to be related to treatment.

Interpretation of results:

practically nontoxic

Remarks:

Migrated information Criteria used for interpretation of results: OECD GHS

Conclusions:

The 4-h LC50 value of L-valine in rats was > 5.26 g/m³ for both sexes.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LC50

Value:

5.26 mg/m³ air

Quality of whole database:

GLP guideline study Klimisch Code 1

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Data waiving:

other justification

Justification for data waiving:

other:

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

L-valine did not cause any mortality in an acute oral toxicity study according to OECD 423. LD50 derived from this limit test was > 2000 mg/kg bw. This GLP guideline study is considered most reliable according to the Klimisch classification system (Klimisch 1). In another study for acute oral toxicity LD 50 was determined to be > 16 g/kg bw. This study was performed prior to the implementation of GLP and availibility of an OECD guideline or any other international test guideline; thus its reliability is Klimisch 2. However, the findings indicates that the acute oral LD50 of L-valine is considerably higher than 2000 mg/kg bw. For CSA the effect level for acute toxicity, oral, was indicted to be 2100 mg/kg in order to on one hand apply a very conservative approach and on the other hand to be above the threshold value of 2000 mg/kg of acute toxicity, Cat. 4 CLP.

No acute toxicity occured in a limit test according to OECD 403 for the inhalation route at a concentration of 5.26 mg/m³. The LC50 was derived to be > 5.26 mg/m³. For technical reasons the test substance was applied as an aerosol in the test apparatus. Exposure at the work place is much more as a dust.

Of particular importance in classifying for inhalation toxicity is the use of well articulated values in the high toxicity categories for dusts and mists. Inhaled particles between 1 and 4 microns mean mass aerodynamic diameter (MMAD) will deposit in all regions of the rat respiratory tract. This particle size range corresponds to a maximum dose of about 2 mg/l. In order to achieve applicability of animal experiments to human exposure, dusts and mists would ideally be tested in this range in rats. This is the reason why the test substance was milled several times in order to achieve a low MMAD, which was measured to be ca. 3.8 µm. The acute toxicity hazard categories and acute toxicity estimates for dust apply as the basis for (non-)classification.

Justification for selection of acute toxicity – oral endpoint

Key study

Justification for selection of acute toxicity – inhalation endpoint

Key study

Justification for classification or non-classification

Based on the data available no classification for acute toxicity (oral toxicity, dermal toxicity, inhalation toxicity) is required.