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Description of key information

Green liquor is highly alkaline and corrosive substance. Test results on animals is not available. Animal testing is not an appropriate way to clarify repeated dose toxicity of this substance. Read-across from analogous substances/constituents has been used and can contribute to the procedure for hazard identification and DNEL derivation. DNEL levels are derived applying existing data on lowest reliable and relevant test results of critical constituents (hydroxides (OH-) and sulfides (S=)) of GL.  Inhalation route is also regarded as relevant since GL mists and H2S gases are generated during manufacturing, handling and downstream use of GL.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: oral
Data waiving:
exposure considerations
Justification for data waiving:
other:
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LOAEL
80 mg/kg bw/day
Study duration:
subacute
Species:
rat

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: inhalation
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Reason / purpose for cross-reference:
reference to same study
Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Route of administration:
inhalation: gas
Type of inhalation exposure:
nose/head only
Vehicle:
air
Details on inhalation exposure:
see 7.2.2
Details on analytical verification of doses or concentrations:
see 7.2.2
Duration of treatment / exposure:
6 hour per day/70 days
Remarks:
Doses / Concentrations:
10-80 ppm
Basis:
analytical conc.
Details on study design:
see 7.2.2
Observations and examinations performed and frequency:
In this study 10-week-old male CD rats were subchronically exposed to relatively low concentrations of H2S. The exposure-related lesions in the nasal cavity were evaluated. Rats (n = 12/group) were exposed via inhalation to 0, 10, 30, or 80 ppm H2S 6 h/d and 7 d/wk for 10 weeks. Following exposure to 30 and 80 ppm H2S, a significant increase in nasal lesions limited to the olfactory mucosa was observed.

The lesions, which consisted of olfactory neuron loss and basal cell hyperplasia, were multifocal, bilaterally symmetrical, and had a characteristic rostrocaudal distribution pattern. Regions of the nasal cavity affected included the dorsal medial meatus and the dorsal and medial portions of the ethmoid recess.
Dose descriptor:
NOAEC
Effect level:
> 10 ppm
Based on:
test mat.
Sex:
male
Basis for effect level:
other: The no observed adverse effect level for olfactory lesions in this study was 10 ppm. These findings suggest that subchronic inhalation exposure to a relatively low level of H2S (30 ppm) can result in olfactory toxicity in rats.
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEC
14 mg/m³
Study duration:
subacute
Species:
rat

Repeated dose toxicity: inhalation - local effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: inhalation
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Reason / purpose for cross-reference:
reference to same study
Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Route of administration:
inhalation: gas
Type of inhalation exposure:
nose/head only
Vehicle:
air
Details on inhalation exposure:
see 7.2.2
Details on analytical verification of doses or concentrations:
see 7.2.2
Duration of treatment / exposure:
6 hour per day/70 days
Remarks:
Doses / Concentrations:
10-80 ppm
Basis:
analytical conc.
Details on study design:
see 7.2.2
Observations and examinations performed and frequency:
In this study 10-week-old male CD rats were subchronically exposed to relatively low concentrations of H2S. The exposure-related lesions in the nasal cavity were evaluated. Rats (n = 12/group) were exposed via inhalation to 0, 10, 30, or 80 ppm H2S 6 h/d and 7 d/wk for 10 weeks. Following exposure to 30 and 80 ppm H2S, a significant increase in nasal lesions limited to the olfactory mucosa was observed.

The lesions, which consisted of olfactory neuron loss and basal cell hyperplasia, were multifocal, bilaterally symmetrical, and had a characteristic rostrocaudal distribution pattern. Regions of the nasal cavity affected included the dorsal medial meatus and the dorsal and medial portions of the ethmoid recess.
Dose descriptor:
NOAEC
Effect level:
> 10 ppm
Based on:
test mat.
Sex:
male
Basis for effect level:
other: The no observed adverse effect level for olfactory lesions in this study was 10 ppm. These findings suggest that subchronic inhalation exposure to a relatively low level of H2S (30 ppm) can result in olfactory toxicity in rats.
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
adverse effect observed

Additional information

Green liquor contains several constituents that have been in industrial use during decades. For this reason numerous studies can be found characterizing health effects of these compounds in humans. However, only few oral repeated dose toxicological studies on GL constituents are available from animal experiments due to compounds alkaline nature, and these reports are rather old and not performed according to the recent guidelines.DNEL levels are derived applying existing data on lowest reliable and relevant test results of critical constituents (OH-and S2-) of GL. Inhalation route is also regarded relevant since GL mists and H2S gases are generated during manufacturing, handling and downstream use of GL.

 

A residual alkali concentration (mainly composed by hydroxides) for GL varies from 3% to 6 %. The most outstanding effect of NaOH is its local irritation and corrosion. Repeated oral dosing of 80 mg/kg NaOH (5 ml of 0.1N NaOH/weekly for 12 weeks) to male rats resulted in intestinal metaplasia in the glandular stomach at week 58 (Kojima et al., 1987). Repeated exposure of aerosols generated from a 40% NaOH solution killed all rats within a month, mostly from bronchopneumonia. With 20% NaOH, the septa were emphymatously dilated and cracked, the bronchi were dilated and their epithelial cover was thin and frequently desquamated, and a light round cell infiltration of the submucus membrane tissue occurred. In the group exposed to aerosols from 5% NaOH, rats had dilation of the bronchi and a slight degeneration of the mucus membrane and thickened strata of the lymphadenoid tissue surrounding the bronchi (NIOSH, 1975).Occupational exposure data for inhalation route for hydroxides has been analysed and reported. Case reports show irreversible obstructive lung disease following chronic occupational exposure to sodium hydroxide (Rubin et al., 1992 in OEHHA 2008). According animal studies oral LOAEL for repeated NaOH administration is 80 mg/kg NaOH (5 ml of 0.1N NaOH/weekly for 12 weeks), and for inhalation exposure LOAEL is 5% (2 daily periods of 30 min for 2.5 months).

Sulfides present in GL are able to constitute harmful hydrogen sulfides when entering the gastrointestinal tract. Sulfides have high oral acute toxicity, but reliable studies concerning repeated oral toxicity are lacking. A lot of information on chronic inhalation exposure to hydrogen sulfide in humans is also available in epidemiological studies. However, exposure levels for hydrogen sulfide are not possible to evaluate based on these studies, and NOAEL or LOAEL values could be derived for humans.However, numerous inhalation studies on hydrogen sulfide in animals are available and NOAEL values have been evaluated. Two very similar studies with medium-term inhalation exposure to hydrogen sulfide were performed in rats (Brenneman et al., 2000) and mice (CIIT, 1983a).The most sensitive target organ in these studies was the nasal olfactory mucosa. Other organs, including brain, kidney, spleen, liver, heart, and ovaries/testes, did not show histopathological lesions or changes. Eye irritation was not noted. The NOAEL for olfactory lesions in rats was 14 mg/m3(10 ppm; 10 weeks) and in mice was 43 mg/m3(30ppm, 90 days). Brenneman et al. (2002) in shorter, 5 day, inhalation study (3h/day) resulted NOAEL 43 mg/m3(30 ppm) and LOAEL 112 mg/m3(80 ppm).

 

Oxidized sulfur constituents are also present in GL at moderate level. Toxicity of sulfates, tiosulphates and sulphites is significantly lower if compared to sulfides.Two repeated oral dose experiment were done using rats and 2% sodium sulfate in their diet (Blunck and Crowther, 1975 and Moinuddin & Wing-tstit Lee, 1960) . No adverse effects were detected, thus the NOAEL for sulfates based on these studies is 2000 mg /kg/day. Repeated oral dose toxicity for disodium disulfite (Na2SO3)was also performed with Wistar rats (Tilet al.,1972).[j1] Twenty animals/dose/sex received a diet containing 0, 0.125, 0.25, 0.5, 1.0 or 2.0 % of disodium disulfite (i.e. actual doses of ca. 48, 106, 217, 454, and 942 mg/kg/day) for 104 weeks. The only major finding in this study was local irritation in the stomach. No signs of systemic toxicity were observed in this study, and therefore, the NOAEL for systemic toxicity was the highest dose tested (942 mg/kg/day). No human reports are located for repeated oral toxicity. As a conclusion the repeated oral toxicity foroxidized sulfur constituents is very low.

In the only reliable short-term repeated inhalation study found, the rats were exposed to well-characterized aerosols of disodium disulfite at levels ranging from 0.1 to about 15 mg/m3for 3 days (Last et al.,1980). Increased rates of glycoprotein secretion were observed for tracheae from rats exposed to 5 or to 15 mg/m3ofNa2SO3aerosol, and thus giving a LOAEL 5 mg/m3(3 days). However, no human reports of the repeated inhalation toxicity for sulfates or sulfites could be found.

 

Carbonates are present in GL a high level (2-8%). However, if administered orally soluble carbonates would be neutralized in the stomach by the low pH of the gastric juice and are not expected to be systemically available. Because of their rapid inactivation, carbonates have relatively low acute toxicity levels according the earlier animal experiments, but are irritant to respiratory tract due their alkaline properties.No animal data are available on repeated dose toxicity studies by oral or dermal routes for sodium carbonate and most of the repeated dose inhalation studies have been reported with insufficient details. In most reliable study, 2% aqueous sodium carbonate aerosol (final conc. 70 mg/m3) for 4 h/day, 5 days/week for 3.5 months to male rats did not change body weight gain, organ weights, body temperature, or several blood parameters. But hyperplasia and desquamination of bronchiolar epithelium, and perivascular oedema in lungs was noticed (Reshetyuk and Shevchenko, 1966). No reliable data on human repeated dosed sodium carbonate via oral, inhalation or dermal, route has been found.

 

GL is aqueous solutions containing a lot of both Na+and K+cations.These cations play an essential role in the human physiology but start to be toxic at plasma levels exceeding 200 – 250 mg/l (K+). Under non-irritating conditions, the cation doses are much lower than those used in acute toxicity studies, and therefore these cations are not relevant from the point of view of the systemic toxicity of GL.

 

GL is not expected to be systemically available in the body under normal handling. If administered orally or by inhalation, generally carbonates and hydroxides are rapidlyneutralized by the low pH of the gastric acid or blood. However, inhalation of sodium carbonate at dose 70 mg/m3resulted in histopathological changes in bronchi and lungs of rats. Similar effects were noticed after aqueous inhalation of 5% NaOH. The most serious effects of GL compounds have been reported with inhaled hydrogensulfide on several tissue systems.

 

As a summary, although repeated dose studies of GL compounds are often old, poorly documented or reliable results are not found e.g. from long-term dermal or oral studies, no further longer animal experiments will be needed. Physiochemical properties of GL, literature on its compounds short term and moderate term effects and test for its irritation and corrosivityshowed that GL is classified as irritating and corrosive agent (Category 1). According OECD guidelines GL is therefore unsuitable for longer animal tests due these reasons. 

 [j1]Til, H.P. , V.J. Feron, A.P. De Groot.The toxicity of sulfite. II. Short and long-term feeding studies in pigs.Fd. Cosmet.

Toxicol. 10, 463-472, 1972

Repeated dose toxicity: via oral route - systemic effects (target organ) digestive: stomach

Repeated dose toxicity: inhalation - systemic effects (target organ) respiratory: nose

Justification for classification or non-classification

Oral: Hydroxides and sulfides are GL components that have highest acute toxicity level. However, limited number of studies is available for these compounds repeated oral toxicity in animals due to high alkalinity and ethical aspects. The most outstanding effect of NaOH is its local irritation and corrosion. Repeated oral dosing of 80 mg/kg NaOH (5 ml of 0.1N NaOH/weekly for 12 weeks) to male rats resulted in intestinal metaplasia in the glandular stomach at week 58 (Kojima et al., 1987). Sulfides have high oral acute toxicity, but reliable studies concerning repeated oral toxicity are lacking. Sodium and hydrogen sulfides have harmonised classification, but no repeated dose STOT classification. Based on available information, no classification for this endpoint is proposed.

 Dermal: No studies are available, the route is of low importance since the substance is corrosive to the skin and low skin penetration of the GL constituents.

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