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Toxicological information

Acute Toxicity: inhalation

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Administrative data

Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2008-03-12 to 2008-04-02
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study; GLP, no deviations

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2008
Report Date:
2008

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.2 (Acute Toxicity (Inhalation))
Version / remarks:
1992
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 870.1300 (Acute inhalation toxicity)
Deviations:
not specified
GLP compliance:
yes (incl. certificate)
Test type:
standard acute method
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): 3-mercaptopropionic acid
- Physical state: liquid
- Analytical purity: 99.8% (GC)
- Purity test date: 2008-02-21
- Lot/batch No.: 22333
- Expiration date of the lot/batch: 2009-02-19
- Stability under test conditions: analytically verified
- Storage condition of test material: Room temperature / darkness / dry (head-space purge with N2).

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Harlan-Winkelmann GmbH, Borchen (Germany),
- Age at study initiation: about 2 months
- Weight at study initiation: 182-199 g (m), 172-194 g (f)
- Fasting period before study: no
- Housing: During the acclimatization and study periods the animals were housed singly in conventional Makrolon Type IllH cages
- Diet (ad libitum): KLIBA 3883 pellets maintenance diet for rats and mice; PROVlMl KLIBA SA, 4303 Kaiseraugst, Switzerland
- Water: ad libitum
- Acclimation period: at least 5 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +- 2 °C
- Humidity (%): 20-80
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12


IN-LIFE DATES: From: March 12, 2008 to April 02, 2008

Administration / exposure

Route of administration:
inhalation: aerosol
Type of inhalation exposure:
nose only
Vehicle:
other: unchanged (no vehicle)
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Plexiglas exposure tubes applying a directed-flow nose-only exposure principle.
- Exposure chamber volume: 3.8 L
- Method of holding animals in test chamber: plexiglass tubes
- Source and rate of air: Compressed air was supplied by Boge compressors
- Method of conditioning air: Air was conditioned (i.e. freed from water, dust, and oil) automatically by a VIA compressed air dryer.
- System of generating particulates/aerosols: Under dynamic conditions the neat test article was atomized into a baffle (pre-separator) from which the substance was conveyed into the intake of the cylindrical inhalation chamber. Atomization was achieved by using two types of binary nozzles with conditioned compressed air (15 L/min; dispersion pressure approximately 600 kPa). The test substance was fed into the nozzle by a calibrated digital pump (Harvard PHD 2000).
- Method of particle size determination: The particle-size distribution was analyzed using a BERNER-TYPE AERAS low-pressure critical orifice cascade impactor
- Temperature, humidity, pressure in air chamber: < 5%

TEST ATMOSPHERE
- Brief description of analytical method used: The test-substance concentration sampled by gravimetric analysis was eluted from the filter and then determined by HPLC. A sampling train was used to analyze volatilized test article in addition. No test article was found in the gass bubbler.
- Samples taken from breathing zone: yes
Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
4 h
Concentrations:
860, 1350, and 2053 mg/m³ (0.86, 1.35, and 2.053 mg/L)
No. of animals per sex per dose:
5
Control animals:
yes
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: The appearance and behavior of each rat were examined carefully several times on the day of exposure and at least once daily thereafter. Body weights were measured before exposure, on days 1, 3 and 7, and weekly thereafter. Individual weights are also recorded at death, if applicable.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, organ weights, histopathology, other: rectal temperatures
Statistics:
Necropsy: pair-wise Fisher test after the R X C chi-squared test.
Body weights: one-way ANOVA
LC50: maximum-likelihood method (Bliss)

Results and discussion

Effect levels
Sex:
male/female
Dose descriptor:
LC50
Effect level:
1 818 mg/m³ air
Exp. duration:
4 h
Mortality:
see Table 2
Clinical signs:
other: All exposure concentrations caused pronounced irritant effects in the upper respiratory tract (nose) and central nervous effects.  The following clinical signs were observed: bradypnea, irregular breathing patterns, tachypnea, labored breathing patterns, 
Body weight:
Comparisons between the control and the exposure groups revealed consistent, concentration-dependent decrease in body weights.
Gross pathology:
Animals sacrificed at the end of the observation period: The macroscopic findings were essentially indistinguishable amongst exposure and control groups. However, some rats showed evidence of inflammatory responses of the nose
Animals succumbing during the observation period: Eyes: opacity; nose: yellowishgreen discoloration, mucosa reddened; lung: less collapsed, light discoloration, dark red foci; stomach: bloated, glandular stomach: mucosa with light-red areas; small intestine: bloated, dark-red mucous content, mucosa reddened; liver, kidneys, and spleen: light discoloration.
Other findings:
Rectal temperatures were significantly decreased in both sexes at 750 ppm (p< 0.05) and in both sexes at 1200 and 2000 ppm (p<0.01).

Any other information on results incl. tables

Table 1: Test atmosphere characteristics

Group 

1

2

3

4

Target conc [mg/m³] 

control

750

1200

2000

Nominal conc [mg/m³] 

--

978

1806

3283

Analytical conc [mg/m³]

--

703

1258

1904

 MMAD [µm]

--

2.66

2.51

2.54

 GSD

--

1.92

1.83

1.82

 Aerosol mass < 3 µm [%]

--

57.6

61.7

61.2

 

Analytical as well as real-time aerosol monitoring of the aerosol test atmosphere from the breathing zone indicated
that the exposure conditions were temporally stable over the 4 hour exposure period.  The respirability of the aerosol
generated was verified (MMAD was < 4 µm; MMAD 2.5-2.7 µm; GSD 1.9).
All concentration data represented actual concentrations of the test substance in the rats' breathing zone. 

Table 2: Summary of acute inhalation toxicity

Group / sex

Target conc [mg/m³]

Toxicological Resulta

Onset and Duration of Signs

Onset and Duration of Mortality

Rectal Temperature

1 / m

0

0 / 0 / 5

38.1

2 / m

750

0 / 5 / 5

0d - 14d

33.1*

3 / m

1200

1 / 4 / 5

0d - 6d

0d

28.9**

4 / m

2000

2 / 4 / 5

0d - 7d

0d, 1d

27.4**

1 / f

0

0 / 0 / 5

38.2

2 / f

750

0 / 5 / 5

0d - 7d

34.7*

3 / f

1200

0 / 5 / 5

0d - 14d

32.9**

4 / f

2000

5 / 3 / 5

0d

0d, 1d

26.4**

m = males, f = females, * = p 0.05, ** = p 0.01

aValues given in the 'Toxicological results' column are:

1st = number of dead animals.

2nd=number of animals with signs after cessation of exposure.

3rd = number of animals exposed.

Applicant's summary and conclusion

Interpretation of results:
harmful
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
LC50 Inhalation (liquid aerosol, 4 h, m+f): approximately 1818 mg/m³
NO(A)EC: males and females: < 860 mg/m³
EU-Classification: Xn, R20-37
GHS-Classification: Acute Inhalation Category 4
Executive summary:

A study on the acute inhalation toxicity of 3-Mercaptopropionic acid (henceforward referred to as test substance) on rats has been conducted in accordance with OECD Guideline No. 403. Test procedures were adapted so as to comply also with the EU Directive 92/69/EEC, OPPTS 870.1300, and Japan MAFF, Notification No. 12 Nousan-8147. Three groups of rats were nose-only exposed to actual liquid aerosol in concentrations of 860, 1350, and 2053 mg/m³ air. The results can be summarized as follows:

LC50 (m+f) = 1.818 mg/L, NOAEC (m+f) < 0.860 mg/L

Mortality occurred in few rats at 1350 mg/m³ and above. All exposure concentrations caused pronounced irritant effects in the upper respiratory tract (nose) and central nervous effects. The following clinical signs were observed: bradypnea, irregular breathing patterns, tachypnea, labored breathing patterns, dyspnea, vocalization, breathing sounds, high-legged gait, salivation, nasal discharge (serous), nose: reddened, nose: swollen, nostrils/muzzle: red encrustations, nose: necrosis, piloerection, hair-coat ungroomed, behavioral changes (transient), exaggerated

response, fasciculations, convulsions (tonic), jerks, tremor, motility increased, motility reduced, limp, apathy, flaccidity (hindlegs), prostration, exophthalmia, miosis, chromodacryorrhea, cornea: opalescence, lens: opalescence, eyelids: red encrustations, cyanosis, emaciation, abdominal enlargement, hypothermia, decreased reflexes, and decreased body weights.

Internationally recognised recommendations such as of SOT (1992) were fulfilled, in regard to the respirability of the aerosol generated, i.e. the MMAD was <4 µm (MMAD 2.5-2.7 µm, GSD 1.9). NO(A)EC Males & females: <860 mg/m³ air

In summary, the aerosolized test substance (liquid aerosol of undiluted test article) proved to have a moderate to low acute inhalation toxicity in rats.