Ammonium hydrogensulphite

Endpoint summary

Description of key information

Based on the described read-across methodology information from sodium sulfite (CAS 7757-83-7), sodium metabisulfite (CAS 7681 -57 -4) and potassium metabisulfite (CAS 16731 -55 -8) were used to determine acute toxicity values (oral, dermal and inhalative) for ammonium hydrogensulfite.
Please see `discussion` below.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: oral

Type of information:

read-across based on grouping of substances (category approach)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Remarks:

Minor deviations with no effect on the results: - The purity and stability were missing. - The number of animals showing signs of toxicity was missing. -The method for LD50 calculation was not stated.

Justification for type of information:

see attachment “Read-across concept – Human Health/Environment - Category approach for Inorganic sulfites/thiosulfates/dithionite" in section 13.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Version / remarks:

1981-05-12

Deviations:

yes

Remarks:

, see "Rationale for reliability"

GLP compliance:

not specified

Test type:

standard acute method

Limit test:

no

Specific details on test material used for the study:

not specified

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Wiga, Sulzfeld
- Age at study initiation: ca. 12 weeks
- Weight at study initiation: mean weight males : 210 g (Individual weights of males: 230 g, 180 g, and 220 g); mean weights females: 190 g ( individual weights of females: 180 g, 180 g, and 210 g)
- Fasting period before study: The animals were given no food for 16 hours before administration, but water was available ad libitum.
- Housing: Animals were housed in groups of 5. They were housed in V-II-A- stainless steel wire mesh cages, Type DK-III (supplied by Becker & Co., Castrop-Rauxel); Animals of comparable weights (+/- 10 g) in one cage.
- Diet: ssniff R; Firma ssniff, Versuchstierdiaeten; 4470 Soest
- Water (ad libitum): Fully demineralized water each workday; tap water on public holidays
- Acclimation period: Acclimatization in the animal care unit for at least one week.

ENVIRONMENTAL CONDITIONS
- Temperature: 20-26°C
- Relative humidity: 45-75 %
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 31.6 % (Dosis: 3160 mg/kg), 26.1 % (Dosis: 2610), and 21.5 % (Dosis: 2150 mg/kg)
- Justification for choice of vehicle:: Aqueous preparation corresponding to the physiological medium.

MAXIMUM DOSE VOLUME APPLIED: 10 ml/kg

Doses:

2150, 2610, 3160 mg/kg

No. of animals per sex per dose:

5 males / 5 females

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Groups were weighed before administration, and on days 3, 7, and 13 after application. Recording of signs and symptoms <15 min, 15 min, 30 min, 1 h, 2 h, 4 h and 5 h after test substance administration and then once each workday. Check for moribund and dead animals twice each workday and once daily on public holidays.
- Necropsy of survivors performed: yes
- Pathology: Withdrawal of food 16 hours before sacrifice with CO2; then necropsy with gross-pathological examination. All animals that die are necropsied as early as possible.

Statistics:

No data

Sex:

male/female

Dose descriptor:

LD50

Effect level:

ca. 2 610 mg/kg bw

Based on:

test mat.

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 150 - < 2 610 mg/kg bw

Based on:

test mat.

Remarks on result:

other: 5 % level of significance

Sex:

male

Dose descriptor:

LD50

Effect level:

ca. 2 746 mg/kg bw

Based on:

test mat.

Remarks on result:

other: Value obtain through interpolation.

Mortality:

Please refer to table below ("Any other infromation on results incl. tables")

Clinical signs:

other: The following symptoms were observed: MALES 3160 mg/kg: - Dyspnoea: 15 minutes - 3 days - Apathy: 30 minutes - 3 days - Abnormal position: 4 hours - Staggering: 30 minutes - 3 days - Tremor: 4 hours - 3 days - Tremble: 4 hours - 3 days - Jumping convuls

Gross pathology:

MALE ANIMALS:
Animal that died:
3160 mg/kg: dilated intensely reddened mucosa, filled with blood-colored liquid; small intestine: atonic, intensely reddened mucosa, blood-red liquid content.
2160 mg/kg: congestive hyperemia; stomach: in the glandular stomach reddened mucosa, filled with liquid; intestine: atonic, intensely filled with liquid.
Sacrificed animals: no findings

FEMALE ANIMALS:
Animal that died:
3160 mg/kg: dilated intensely reddened mucosa, filled with blood-colored liquid; small intestine: atonic, intensely reddened mucosa, blood-red liquidcontent.
2160 mg/kg: congestive hyperemia; stomach; in the glanduar stomach reddened mucosa, filled with liquid; intestine: atonic, intensely filled with liquid.
Sacrificed animals: no findings

Other findings:

No data

Body weights (mean weights in g):

Male animals		Start of the study	After 3 days	After 7 days	After 13 days
	3160 mg/kg	230	178
	2610 mg/kg	180	212	248	292
	2150 mg/kg	220	260	295	321
Female animals		Start of the study	After 3 days	After 7 days	After 13 days
	3160 mg/kg	180
	2610 mg/kg	180
	2150 mg/kg	210	232	240	245

Mortality:

Male animals		3160 mg/kg	2610 mg/kg	2150 mg/kg
Dead animals after	1 hour	0/5	0/5	0/5
	1 day	4/5	1/5	0/5
	2 days	4/5	1/5	0/5
	7 days	5/5	1/5	0/5
	14 days	5/5	1/5	0/5
Female animals		3160 mg/kg	2610 mg/kg	2150 mg/kg
Dead animals after	1 hour	0/5	0/5	0/5
	1 days	5/5	5/5	0/5
	2 days	5/5	5/5	0/5
	7 days	5/5	5/5	0/5
	14 days	5/5	5/5	0/5

Interpretation of results:

GHS criteria not met

Conclusions:

According to the EC Regulation No. 1272/2008 and subsequent regulations, the test item is not classified as acute toxic via the oral route.

Reference 2

Endpoint:

acute toxicity: oral

Type of information:

read-across based on grouping of substances (category approach)

Adequacy of study:

key study

Study period:

1987-08-05 to 1987-09-04

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Remarks:

Stability of the test material was missing.

Justification for type of information:

see attachment “Read-across concept – Human Health/Environment - Category approach for Inorganic sulfites/thiosulfates/dithionite" in section 13.

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Version / remarks:

1987-02-24

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Limit test:

no

Specific details on test material used for the study:

- Storage condition of test material: In the dark in a fume hood at 22°C

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: HOECHST AG, Kastenfrund, SPF-Breed
- Age at study initiation: Males: ca. 7 weeks; females: ca.8 weeks
- Weight at study initiation: Males (n = 15): Mean weight: 195 g +/- 13 g (max. 215 g, min. 179 g); females (n = 15): Mean weight: 178 g +/- 5 g (max. 185 g, min. 168 g)
- Fasting period before study: Ca. 16 hours before administration and 3-4 hours after administration.
- Housing: Animals were housed in groups of five in Makroloncages (Type 4) on granulat of softwood.
- Diet (ad libitum): Rat diet Altromin 1324 (Altromin-GmbH, Lage/Lippe)
- Water (ad libitum): Tap water in plastic drinking bottles
- Acclimation period: At least 5 days

ENVIRONMENTAL CONDITIONS - fully airconitioned rooms
- Temperature:: 22+/- 3°C
- Relative humidity: 50% +/- 20%
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

water

Remarks:

deionised water

Details on oral exposure:

RANGE-FINDING STUDY:
Doses of the main study were selected based on a range-finding studies. The following doses were tested in one male and one female: 500, 1000, and 2000 mg/kg bw in deionised water (25% Concentration).
The following findings were made:
Both male and female died 120 minutes after the administration of 2000 mg/kg bw.
On the application day the animals showed reduced spontaneous activity, crouching, drawn in flanks, long-legged gait and irregular breatching. The symptoms of surviving animals were reversible from Day 1 on.
The animals, which died during the study had reddened mucous coat of the stomach as well as haematoma in the gastro-intestinal tract. The macroscopically examined animals, which were killed at the end of the study showed no changes.

MAXIMUM DOSE VOLUME APPLIED: 10 ml/kg bw.

DOSAGE PREPARATION: Sodium disulfite was dissolved in deionised water.
Concentrations:
8.0% (w/v) (Dose: 800 mg/kg bw.)
12.5% (w/v) (Dose: 1250 mg/kg bw.)
16.0% (w/v) (Dose: 1600 mg/kg bw.)
20.0% (w/v) (Dose: 2000 mg/kg bw.)

Doses:

Males: 1250, 1600, and 2000 mg/kg bw
Females: 800, 1250, and 1600 mg/kg bw

No. of animals per sex per dose:

Males: 5 per dose
Females: 5 per dose

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: The body weight of the animals were recorded weekly. The clinical signs and mortality were observed at least 10 and 30 minutes after administration, and 1, 2, 4 and 6 hours after administration. Afterwards the clinical signs and mortality were observed daily.
- Necropsy of survivors performed: Yes
The animals, which died during the study, were dissected and macrosopically examined. The animals, which survived until the end of the observation period, were killed with carbon dioxide. They were also dissected and macroscopically examined.
- Examinations performed: The symptoms and the mortality were recorded.

Statistics:

The LD50, the confidence interval, and the equation of the grade of the probit were calculated from the observed death rates using a probit analysis.

Sex:

female

Dose descriptor:

LD50

Effect level:

1 420 mg/kg bw

Based on:

test mat.

95% CL:

>= 1 040 - <= 2 110

Remarks on result:

other: Confidence interval: P = 0.05

Sex:

male

Dose descriptor:

LD50

Effect level:

1 630 mg/kg bw

Based on:

test mat.

95% CL:

>= 1 210 - <= 2 260

Remarks on result:

other: Confidence interval: P = 0.05

Sex:

male/female

Dose descriptor:

LD50

Effect level:

1 540 mg/kg bw

Based on:

test mat.

95% CL:

>= 1 290 - <= 1 960

Remarks on result:

other: Confidence interval: P = 0.05

Mortality:

The following death rates were observed:
800 mg/kg bw.: Females: 0/5 (0%)
1250 mg/kg bw.: Males: 1/5 (20%; death after 60 minutes of administration); Females: 1/5 (20%; death after 70 minutes of administration)
1600 mg/kg bw.: Males: 2/5 (40%; death after 75 and 180 minutes of administration, respectively); Females: 4/5 (80%, death after 60 minutes of administration)
2000 mg/kg bw.: Males: 4/5 (80%; death after 70 minutes of administration)

Clinical signs:

other: The following clinical signs were observed in the males and females, respectively: reduced spontaneous activity, crouching, flanks drawn-in, ruffled fur, irregular breathing, and long-legged gait. In addition, latero-abdominal position, constricted palpeb

Gross pathology:

The macroscopically examination of the males and females, which died during the study, showed the following:
- gastro-intestinal tract filled with blood (Males in the 1250, 1600 and 2000 mg/kg bw. dose; females: 1250 and 1600 mg/kg bw. dose)
- Mucous coat of the stomach reddened (Males in the 1250 and 2000 mg/kg bw. dose; females: 1250 and 1600 mg/kg bw. dose)
- Liver dark discoloured (Males in the 1250, 1600 and 2000 mg/kg bw. dose; females: 1600 mg/kg bw. dose)
- Marked liver lobules (Females: 1600 mg/kg bw. dose
The animals, which were killed at the end of the observation period, were free of macroscopical changes.

The following clinical signs were observed.

Clinical sigs of the males:

1250 mg/kg bw.:

- Reduced spontaneous activity: One male after at least 30 minutes and four males after 1 hour of administration until Day 1 after administration.

- Long-legged gait: Four males at least 30 minutes after administration until Day 1 after administration.

- Crouching: Four males at least 30 minutes after administration until Day 1 after administration.

- Irregular breathing: Four males 1 hour after administration until Day 1 after administration.

- Ruffled fur: Two males 2 hours after administration.

1600 mg/kg bw.:

- Reduced spontaneous activity: Five males after at least 30 minutes, four males after 1 hour and three males after 2 hour of administration until Day 1 after administration.

- Long-legged gait: Two males at least 30 minutes and three males 1 hour after administration until Day 1 after administration.

- Crouching: Five males at least 30 minutes, four males 1 hour and 3 males 2 hours after administration until Day 1 after administration.

- Irregular breathing: Four males 1 hour after administration until 2 hours after administration.

- Ruffled fur: Two males 2 hours after administration.

- Flank drawn-in: 3 males after at least 30 minutes after administration until Day 1 after administration.

- Constricted palpebral fissure: 1 male after 1 hour of administration until 2 hours after administration

- Abdominal or lateral position: 1 male at 2 hours after administration

-Drowsiness: 1 male at 2 hours after administration

2000 mg/kg bw.:

- Reduced spontaneous activity: Five males after at least 30 minutes, one male after 1 hour of administration until 4 hours after administration.

- Crouching: Four males at least 30 minutes, and one male 1 hour after administration until 4 hours after administration.

- Irregular breathing: Four males at least 30 minutes, five males 1 hour, and onemale 2 hours after administration until 4 hours after administration.

- Ruffled fur: One male 4 hours after administration.

- Flank drawn-in: Four males after at least 30 minutes and one male 1 hour after administration until Day 1 after administration.

- Constricted palpebral fissure: 1 male at least 30 miuntes after administration until 1 hour after administration

- Abdominal or lateral position: Four males at 1 hour after administration

-Drowsiness: Four males at 4 hours after administration

Clinical sigs of the females:

800 mg/kg bw.:

- Reduced spontaneous activity: five females after 1 hour of administration until Day 1 after administration.

1250 mg/kg bw.:

- Reduced spontaneous activity: Five females after at least 30 minutes and four females after 1 hour of administration until Day 1 after administration.

- Crouching: Two females after at least 30 minutes and four females after 1 hour of administration until Day 1 after administration.

- Flank drawn-in: Two females after at least 30 minutes and four females after 1 hour of administration until Day 1 after administration.

- Irregular breathing: Two females after at least 30 minutes and four females after 1 hour of administration until Day 1 after administration.

- Ruffled fur: One female after 2 hours of administration until 4 hours after administration.

1600 mg/kg bw.:

- Reduced spontaneous activity: One female after at least 30 minutes of administration until Day 1 after administration.

- Long-legged gait: Five females at least 30 minutes and 1 female after 1 hour of administration until Day 1 after administration.

- Crouching: One females after at least 30 minutes of administration until Day 1 after administration.

- Flank drawn-in: One females after at least 30 minutes of administration until Day 1 after administration.

- Irregular breathing: One females after 2 hours of administration until Day 1 after administration.

- Ruffled fur: One females after 2 hours of administration until Day 1 after administration.

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

According to the EC Regulation No. 1272/2008 and subsequent regulations, the test item is classified as Category 4.

Reference 3

Endpoint:

acute toxicity: oral

Type of information:

read-across based on grouping of substances (category approach)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Remarks:

Minor deviations without an effect on the results: - The purity and stability are missing. -According to the guideline, the observation period should be at least 14 days. In this study the animals were only observed for 7 days. This was not regarded to influence the results, since no animals died after 24 hours. - According to the guideline, the animals should be acclimatised to the laboratory condition for at least 5 days. This information was missing from the report. - According to the guideline, the volume administered to the animals should not exceed 2ml/100 g. In this report the volume administered was not stated. - The housing and environmental conditions were not stated, which according to the guideline should be included. - According to the guideline, animals should be fasted prior to administration of the test material. It was not stated in the report if the animals were deprived of food before test item administration. - According to the guideline the animals should be observed at least once a day and the body weight determined before administration, weekly thereafter and at death. The animals were not observed daily and the body weight was only determined before administration.

Justification for type of information:

see attachment “Read-across concept – Human Health/Environment - Category approach for Inorganic sulfites/thiosulfates/dithionite" in section 13.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Version / remarks:

1981-05-12

Deviations:

yes

Remarks:

, see "rationale for reliablity"

GLP compliance:

no

Test type:

standard acute method

Limit test:

no

Specific details on test material used for the study:

not specified

Species:

rat

Strain:

other: Gassner

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: mean 170 g (male), 166.0 g (female)

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 2%, 16%, 20%, 25%, 30%

DOSAGE PREPARATION (if unusual): 90 min prior to dosing
No further information on the oral exposure was stated.

Doses:

200, 1600, 2000, 2250, 2500, 3200, 6400 mg/kg bw (2 %, 16 %, 20 % 25 %, 25 %, 30 % and 30 % respectively)

No. of animals per sex per dose:

5 males / 5 females

Control animals:

not specified

Details on study design:

- Duration of observation period following administration: 7 days
- Necropsy of survivors performed: yes
- Other examinations performed: Clinical signs, body weight (determined before the study started), and gross pathology

Statistics:

not stated

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: The LD50 was determined after an observation period of 7 days.

Mortality:

6400 mg/kg bw: 5/5 males within 1 h; 5/5 females within 1 hour
3200 mg/kg bw: 1/5 male within 1 h, 4/5 males within 24 h; 3/5 females within 1 h, 5/5 females within 24 h
2500 mg/kg bw: 2/5 males within 24 h; 3/5 females within 1 h, 5/5 females within 24 h
2250 mg/kg bw: 0/5 males; 3/5 females within 24 h
200 - 2000 mg/kg bw: 0/5 males; 0/5 females
Overall, when animals died they died within 24 hours.

Clinical signs:

other: The following clinical signs were observed immediately after the beginning of the study up to 20 minutes thereafter: 6400 mg/kg bw: staggering, abdominal position, accelerated respiration,convulsions (Animals died within 15 minutes) 3200 mg/kg bw: stagge

Gross pathology:

6400 mg/kg: Heart: acute cardiac dilation; stomach: filled with thin fluid content, ecchymosis, duodenum is diffused reddened
3200 mg/kg: Heart: acute cardiac dilation, venous congestical hyperemia ; stomach: filled with thin fluid content, ecchymosis, duodenum is diffused reddened; Intestine: light diarrhoeic content; liver: relatively dark; kidneys: lighten kidneys
2500 mg/kg: Heart: acute cardiac dilation, venous congestical hyperemia; stomach: filled with thin fluid content, light diffused reddening, some animals had a bloody mucosa with bloody content; Intestine: moderate diarrhoeic content
2250 mg/kg: Heart: acute cardiac dilation, venous congestical hyperemia; stomach: extented, fluid content, diffused reddened, vessels heavy injected; intestine: slight diarrhoeic content; kidney: bloody imbibition
2000 mg/kg: No gross pathology found
1600 mg/kg: No gross pathology found
200 mg/kg: No gross pathology found

Other findings:

not stated

Interpretation of results:

GHS criteria not met

Conclusions:

A LD50 >2000 mg/kg bw was found determined for male and female rats after an observation time of 7 days.
According to the EC Regulation No. 1272/2008 and subsequent regulations, the test item is not classified as acute toxic via the oral route.

Executive summary:

Based on the nearly similar SO2 contents (wt%) of sodium hydrogensulfite (61 wt% SO2) and potassium metabisulfite (58 wt% SO2), it can be assumed that the LD50 value for the substance sodium hydrogensulfite is >2000 mg/kg bw, based on the data given.

Nevertheless, the substance sodium hydrogensulfite is classified according to Regulation (EC) No 1272/2008 ( Acute Tox. 4, H302).

Reference 4

Endpoint:

acute toxicity: oral

Type of information:

read-across based on grouping of substances (category approach)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Remarks:

Minor deviations without an effect on the results: Not stated: - purity and stability - Observation period 7 days - Acclimatisation period - Volume administered - Housing and environmental conditions - Fasting period In addition: - The animals were not observed daily and the body weight was only determined before administration.

Justification for type of information:

see attachment “Read-across concept – Human Health/Environment - Category approach for Inorganic sulfites/thiosulfates/dithionite" in section 13.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Version / remarks:

1981-05-12

Deviations:

yes

Remarks:

, see "Rationale for reliability"

GLP compliance:

no

Test type:

standard acute method

Limit test:

no

Specific details on test material used for the study:

not specified

Species:

rat

Strain:

not specified

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Gassner
- Weight at study initiation: mean weight males: 170.0 g (range of weight: 147 - 188 g); mean weight females: 164.2 g (range of weight: 148 - 178 g)

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 2%, 16%, 30%
DOSAGE PREPARATION (if unusual): The dosage were prepared 90 min prior to dosing.

Doses:

200, 1600, 3200, 6400 mg/kg bw

No. of animals per sex per dose:

5 males / 5 females

Control animals:

not specified

Details on study design:

- Duration of observation period following administration: 7 days
- Necropsy of survivors performed: yes
- Examinations performed: Clinical signs and gross pathology were recorded. Body weight was determined at the beginning of the study.

Statistics:

No data

Sex:

male/female

Dose descriptor:

LD50

Effect level:

ca. 3 200 mg/kg bw

Based on:

test mat.

Remarks on result:

other: The observation time was 7 days. No animal died after 24 hours.

Mortality:

6400 mg/kg bw: 5/5 males within 15 min; 5/5 females within 15 min
3200 mg/kg bw: 1/5 male within 24 h; 3/5 females within 1 h; 4/5 females within 24 h
1600 mg/kg bw: 1/5 female within 1 h; all males survived
200 mg/kg bw: All males and females survived.

Clinical signs:

other: 6400 mg/kg bw: Immediatley after application accelerated respiration, dyspnea, staggering, lateral position, convulsions; All animals died within 15 min 3200 mg/kg bw: Ca. 5 minutes after application females showed accelerated respiration and lateral posi

Gross pathology:

6400 mg/kg bw (gross pathological findings of males and females which died during the observation period):
- Heart: Acute dilation of right/left ventrical, general hyperemia
- Stomach: Atonia, liquid content
- Intestine: Diarrhetic content

3200 mg/kg bw (gross pathological findings of male and females which died during the observation period):
No findings

1600 mg/kg bw (gross pathological findings of female which died during the observation period):
- Heart: acute dilation of right ventrical, venous hyperemia
- Stomach: liquid content
- Intestine: atonia, diarrhetic content

3200 mg/kg bw (gross pathological findings of males and female which survived until the end of the observation period:
No findings were made.

1600 mg/kg bw (gross pathological findings of males and females which survived until the end of the observation period:
No findings were made.

Other findings:

No data

Interpretation of results:

GHS criteria not met

Conclusions:

The LD50 (female and male rats): ca. 3200 mg/kg bw.
According to the EC Regulation No. 1272/2008 and subsequent regulations, the test item is not classified as acute toxic via the oral route.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

read-across based on grouping of substances (category approach)

Adequacy of study:

key study

Study period:

1981-10-22 to 1981-11-05

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Remarks:

Minor deviations without an effect on the results: - According to the guideline, the air flow, humidity and temperature should be measured, which was not done in this study. It is considered as important to state the humidity, since humidity could have an influence on the substance administration. - There was no statement about an acclimatisation period, which according to the guideline shoud be at least five days. - It was not stated, if the exposure period was conducted after a period of equilibration of the chamber concentration. According to the guideline, the 4 hour exposure period should start after the equilibration of the chamber concentration. - It was not explicitly stated if the respiratory tract was investigated during the pathological examination. According to the guideline consideration should be given to performing a gross necropsy of animals where indicated by the nature of the toxic effects observed with particular reference to any changes in the respiratory tract. - According to the guideline, it should be stated how the exhausted air was treated, which was not stated in this report.

Justification for type of information:

see attachment “Read-across concept – Human Health/Environment - Category approach for Inorganic sulfites/thiosulfates/dithionite" in section 13.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Version / remarks:

1981-05-12

Deviations:

yes

Remarks:

, see "Rationale for reliability"

GLP compliance:

no

Test type:

standard acute method

Limit test:

yes

Specific details on test material used for the study:

not specified

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: WIGA Versuchstierzuchtanstalt, Sulzfeld,
- Age at study initiation: ca. 8 - 10 weeks
- Weight at study initiation: Mean body weight males (test group): 303 ± 18 g; Mean body weight females (test group): 234 ± 12 g; Mean body weight males (control group): 307 g; Mean body weight females (control group): 235 g
- Housing: They were housed in groups of five in cages of Becker, type D III, without bedding. The animals were accommodated in fully air-conditioned rooms.
- Diet (ad libitum): SSNIFF R complete diet for rats and mice, manufacturer: SSNIFF-Versuchstierdiaeten GmbH, Soest, FRG
- Water (ad libitum): Tap water

ENVIRONMENTAL CONDITIONS
- Temperature: 22 ± 2°C
- Humidity: 55 ± 5%
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

other: inhalation: dust/aerosol test

Type of inhalation exposure:

nose/head only

Vehicle:

air

Mass median aerodynamic diameter (MMAD):

3 µm

Geometric standard deviation (GSD):

2.7

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Head-nose inhalation system INA 20 (glass/steel construction, BASF Aktiengesellschaft, V ~ 55 l); The animals are restrained in tubes and their snouts project into the inhalation chamber.

- System of generating particulates/aerosols: A mixture of dust and air was generated by means of a vibration aerosol generator. By means of a dust generator the substance to be tested was generated into a dust aerosol, which was passed into the inhalation system. The concentration was adjusted by varying the amplitude and frequency of the vibrator. The rate of flow was adjusted as follows: 1500 l/h of compressed air through the vibrator.By means of an exhaust air system the pressure ratios in the inhalation chamber were adjusted in such a way that the amount of fresh air was about 10% higher (excess pressure). This ensured that the mixture of test substance and air was not diluted by laboratory air in the breathing zones of the animals.

- Method of particle size determination:
Tools used: Andersen Stack Sampler Mark III Millipore vacuum-compressed air pump XX 60 220 50, nozzle with limited streaming 3l/min, Millipore sampler, inner diameter 6.9 mm, BASF-manometer, stop watch.
Sampling: At the earliest 30 minutes after starting the inhalation exposure 1 sample was drawn (test group).
The impactor was equipped with a glass-fiber collecting plate and a particle filter. The impactor was connected with the pump and the exposure apparatus and a sample of (9 l) was extracted.
The impacotr was disassembled, the collecting plate and particle filter were weighed.
The content of the pre-impactor was determined gravimetrically.

TEST ATMOSPHERE
Tools used:
- Vacuum-compressed air pump (Millipore) XX 60 220 50
- Filtration apparatus with testing probe (Millipore) (Inner diameter: 4 mm)
- Filter: MN 85/90 Bf (d= 4.7 cm)
- Ballance: Cahn 26
Sample drawing:
- Speed of sampling: 1.25 m/s
- Amount of sampling: 1 l
- Position of sampling: close to the animals' nose
- Diameter of testing probe: 4mm
- Frequency of sampling: 1 sample every 30 minutes

- Brief description of analytical method used: Gravimetric determination of the concentration; The preweighted filter was placed in the filtration apparatus. A limited volume of the dust-aerosol was drawn by means of a vacuum-compressed air pump through the filter. The dust concentration was calculated be taking the difference between the preweighted filter and the filter weighed after sampling.
- Samples taken from breathing zone: Yes

TEST ATMOSPHERE
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): MMAD: 3.0 µm (GSD: 2.7 µm)
- Respirable dust: 90.7 %

Analytical verification of test atmosphere concentrations:

yes

Remarks:

gravimetric determination

Duration of exposure:

4 h

Concentrations:

5.5 ± 0.29 mg/L (actual concentration)
Nominal concentration: 27.9 mg/l

No. of animals per sex per dose:

10 males / 10 females (test group)
10 males / 10 females (control group)

Control animals:

yes

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: The body weight of the animals was checked before the beginning of the test, after 7 days and at the end of the observation period. Clinical symptoms were recorded each workday. Mortalities were recorded each day.
- Necropsy of survivors performed: Yes, at the end of the 14-day observation period the animals were sacrificed by CO2 and were subjected to a gross-pathological examination.

Statistics:

The statistical evaluation of the concentration-response relationship was carried out in accordance with the binominal test (Wittig, H.: Mathematische Statistik 1974, pp. 32 - 35) according to tables of the BASF Computer Center.
The particle size was determined in the Department of Toxicology of BASF Aktiengesellschaft in accordance with mathematical and graphical methods of evaluating particle measurements (Silverman, L.: Particle Size Analysis in Industrial Hygiene, 1971, pp. 235-259).

Sex:

male

Dose descriptor:

LC50

Effect level:

> 5.5 mg/L air

Based on:

test mat.

Exp. duration:

4 h

Sex:

female

Dose descriptor:

LC50

Effect level:

> 5.5 mg/L air

Based on:

test mat.

Exp. duration:

4 h

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 5.5 mg/L air

Based on:

test mat.

Exp. duration:

4 h

Remarks on result:

other: Statistical certainty: 99.9%

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 22 mg/L air

Based on:

test mat.

Exp. duration:

1 h

Remarks on result:

other: Recalculated by using the Haber-Rule C X t = k.

Mortality:

No mortality occurred.

Clinical signs:

other: During exposure nothing abnormal was detected. After exposure: substance-contaminated heads, and unstable, staggering gait. After one day nothing abnormal was detected.

Body weight:

The development of the body weight of the males of test group was decelerated compared to the control animals.
The females of the test group showed no notable difference in body weight compared to the females of the control group.

Gross pathology:

Sacrificed animals: Nothing abnormal was detected.

Other findings:

No data

Mean body weights:

	before start of the study		after 7 days		after 14 days
	male rats	female rats	male rats	female rats	male rats	female rats
Group 1	10 animals	10 animals	10 animals	10 animals	10 animals	10 animals
Weight in g	303	234	329	248	351	251
Control	10 animals	10 animals	10 animals	10 animals	10 animals	10 animals
Weight in g	307	235	344	240	372	250

Interpretation of results:

GHS criteria not met

Conclusions:

LC50 (male and female rats; 4 hours) > 5.5 mg/L (actual concentration)
According to the EC Regulation No. 1272/2008 and subsequent regulations, the test item is not classified as acute toxic via the inhalation route.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

read-across based on grouping of substances (category approach)

Adequacy of study:

key study

Study period:

2009-01-27 to 2009-02-11

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Justification for type of information:

see attachment “Read-across concept – Human Health/Environment - Category approach for Inorganic sulfites/thiosulfates/dithionite" in section 13.

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Version / remarks:

1987-02-24

Deviations:

yes

Remarks:

, - Solid test substance was applied as a solution; - Humidity range (animal housing): 20- 80 %

GLP compliance:

yes (incl. QA statement)

Remarks:

signed 2008-04-17

Test type:

standard acute method

Limit test:

yes

Specific details on test material used for the study:

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Room temperature; under N2; protect against humidity

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Wiga GmbH, Sandhofer Weg 7, 97633 Sulzfeld, Germany
- Age at study initiation: Young adult animals (male animals approx. 8 weeks, female animals approx. 12 weeks)
- Weight at study initiation: Animals of comparable weight (+/- 20% of the mean weight); mean weights males: 255 g; mean weights females: 218 g
- Housing: The animals were housed individually. The animals were housed in fully air-conditioned rooms. Type of cage: Makrolon cage, type III. Bedding: H 15005-29; Ssniff, Spezialitäten GmbH (Experimental Animal Diets Inc., 59494 Soest, Germany).
- Diet: VRF1(P); SDS Special Diets Services, 67122 Altrip, Germany.
- Water (ad libitum): Tap water
- Acclimation period: At least 5 days before the beginning of the experimental phase; during the acclimatization period, the animals were accustomed to the environmental conditions of the study and to the diet
- Enrichment: NGM E-022; ABEDD®LAB & VET Service GmbH, Hasnerstraße 84/6; 1160 Wien - Austria

ENVIRONMENTAL CONDITIONS
- Temperature: 22 – 26°C
- Relative humidity: 20 – 80%
- Photoperiod (hrs dark / hrs light): 12/12

Type of coverage:

semiocclusive

Vehicle:

water

Details on dermal exposure:

TEST SITE
- Area of exposure: About 24 hours before administration the fur was clipped. Then a single application to the clipped epidermis (dorsal and dorsolateral parts of the trunk) was applied.
- % coverage: At least 10 % of the body surface (about 40 cm^2)
- Type of wrap: Covering of the application site with a semi-occlusive dressing (the bandage consists of four layers absorbent gauze, Ph. Eur. Lohmann GmbH & Co. KG and Fixomull stretch (adhesive fleece), Beiersdorf AG) for 24 hours, afterwards removal of the dressing.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): Rinsing of the application site with warm water.
- Time after start of exposure: 24 hours

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 10 ml/kg (application volume)
- Concentration: 20 g/100 ml
- Constant volume or concentration used: yes, constant volume
- For solids, paste formed: No, a solution was used for application. The test substanc epreparation was produced for the application group shortly before application by stirring with a magnetic stirrer.
VEHICLE: Doubly distilled water

Duration of exposure:

24 hours

Doses:

2000 mg/kg

No. of animals per sex per dose:

5 males / 5 females

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Body weight determination: Individual body weights shortly before administration (day 0), weekly thereafter and on the last day of observation.
- Signs and symptoms: Recording of signs and symptoms several times on the day of application, at least once each workday for the individual animals.
- Scoring of skin findings: Individual readings 30 – 60 minutes after removal of the semi-occlusive dressing (day 1), as a rule weekly thereafter and on the last day of observation.
- Mortality: A check for any dead or moribund animal was made twice each workday and once on weekends and on public holidays, these records are archived by Bioassay.
- Pathology: Necropsy with gross-pathology examination on the last day of the observation period after sacrifice with CO2 in a chamber with increasing concentrations over time.
Assessment of skin reactions: The evaluation of skin reactions was performed according to Draize, J.H. (1959): Appraisal of the safety of chemicals in foods, drugs and cosmetics. The association of food and drug officials of the United States Austin, Texas. Descriptions of any dermal findings not covered by this scale were recorded.

Statistics:

The means and standard deviation were calculated by using MS Excel 2003.

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortality occurred.

Clinical signs:

other: No systemic clinical observations were observed during clinical examination. No local effects were observed.

Gross pathology:

No macroscopic pathologic abnormalities were noted in the animals (5 males and 5 females) examined on the last day of observation.

Other findings:

No data

Interpretation of results:

GHS criteria not met

Conclusions:

LD50 (male and female rats) > 2000 mg/kg bw
According to the EC Regulation No. 1272/2008 and subsequent regulations, the test item is not classified as acute toxic via the dermal route.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Additional information

Read-across concept for sulfites, hydrogensulfites, metabisulfites, dithionites and thiosulfates:

A comprehensive read-across concept has been developed for sulfites, hydrogensulfites and metabisulfites, based on the pH-dependant equilibrium in aqueous solutions which is summarised in the following equations:^[1],[2]

           SO₂+ H₂O <->`H₂SO₃´         H₂SO₃<->H⁺+ HSO₃^-<->2H⁺+SO₃^2-    2HSO₃^-<->H₂O +S₂O₅^2-

Since the nature of the cation (i.e., sodium, potassium, ammonium…) is not assumed to contribute substantially to differences in toxicity and solubility (all compounds are very soluble in water), only the chemical and biological properties of the anion are considered as relevant determinants. Based on the described equilibrium correlations, unrestricted read-across between the groups of sulfites, hydrogensulfites and metabisulfites is considered justified.

 

Additionally, it is known that sodium dithionite disproportionates in water to form sodium hydrogen sulfite and sodium thiosulfate (equation II)^2,[1], so that this substance can also be considered to be covered by the read-across concept described above. Since it can easily be anticipated that the substance is not stable enough under physiological conditions to fulfil the requirements of study guidelines, instead the products of decomposition have to be considered:

 

       2 S₂O₄^2-+ H₂O→2HSO₃^-+ S₂O₃^2-

 

Not fully covered by this read-across concept is the substance class of thiosulfates: although the thiosulfates are also well known to disproportionate in aqueous solution to form polythionic acids and SO₂(HSO₃^-), this requires somewhat different, more acidic conditions. Therefore, read-across to sulfites is primarily restricted to appropriate physiological conditions, i.e. oral administration where the gastric passage with the strongly acidic conditions in the stomach will facilitate the chemical disproportionation described above:

 

       HS₂O₃^-+ H₂S₂O₃→HS₃O₃- + SO₂+ H₂O

 

[1]Hollemann Wiberg, Lehrbuch der Anorganischen Chemie, 101.Auflage

[2]Handbook of Chemistry and Physics, Ed. Lide, DR, 88^thedition, CRC Press

Acute toxicity oral:

In total, four reliable animal studies on acute oral exposure for sulfite substances are available, conducted equivalent or similar to OECD guideline 401. One study (Grundler, 1981) indicates a LD50 value of >2610 mg/kg/bw (male and female rats) for the test item sodium sulfite (CAS 7757 -83 -7). One study performed with potassium metabisulfite (CAS 16731 -55 -8) as test item indicated a LD50 >2000 mg/kg/bw (no clinical symptoms were observed in the concentration range 200 - 2000 mg/kg bw). Two animal study reports on acute oral exposure to sodium metabisulfite (CAS 7681 -57 -4) are available (Hofmann & Jung, 1987 and Zeller&Hofmann, 1974), conducted according to or equivalent/similar to OECD guideline 401. The study of Hofmann & Jung indicated a LD50 >1540 mg/kg/bw. whereas the study performed by Zeller & Hofmann indicated a LD50 value of >3200 mg/kg bw.

 

Acute dermal toxicity:

One study on acute dermal toxicity, performed according to OECD 402 for the test item sodium sulfite (CAS 7757 -83 -7) is available. LD50 value was determined to be greater than 2000 mg/kg/bw (limit test).No systemic clinical observations were observed during clinical examination. No local effects were observed.

 

Acute inhalation toxicity:

One study equivalent or similar to OECD 403 for sodium sulfite (CAS 7757 -83 -7) has been performed which indicated a LC50 >5.5 mg/l (limit test).During exposure nothing abnormal was detected. After exposure: substance-contaminated heads, and unstable, staggering gait. After one day nothing abnormal was detected.

Justification for classification or non-classification

Acute oral toxicity:

The references Grundler (1981) which indicates a LD50 value of > 2610 mg/kg bw (male and female rats), the references Hofmann & Jung (1987) which states a LD50 of 1540 mg /kg bw, and the reference Zeller & Hofmann (1974) where a LD50 of >3200 mg/kg bw was determined as well as the reference Zeller & Hofmann (1974) which indicates a LD50 > 2000 mg /kg bw, are considered as the key studies for acute oral toxicity and will be used for classification.

According to the criteria specified by Directive 67/548/EEC and subsequent regulations, the test item ammonium hydrogensulfite is not classified as acute toxic via the oral route. According to the EC Regulation No. 1272/2008 and subsequent regulations, the test item ammonium hydrogensulfite is not classified as acute toxic via the oral route.

 

Specific target organ toxicant (STOT) – single exposure: oral:

The classification criteria acc. to regulation (EC) 1272/2008 as specific target organ toxicant (STOT) – single exposure, oral are not met since no reversible or irreversible adverse health effects were observed immediately or delayed after exposure and no effects were observed at the guidance value, oral for a Category 1 classification of 300 mg/kg bw and at the guidance value, oral for a Category 2 classification of 2000 mg/kg bw. No classification required.

 

Acute dermal toxicity:

The reference Cords (2009) is considered as the key study for acute dermal toxicity which indicates a LD50 of > 2000 mg/kg bw and will be used for classification.

No systemic clinical signs were observed during clinical examination. No local effects were observed.

According to the criteria specified by Directive 67/548/EEC and subsequent regulations, the test item is not classified as acute toxic via the dermal route. According to the EC Regulation No. 1272/2008 and subsequent regulations, the test item is not classified as acute toxic via the dermal route.

Based on the read-across concept, classification for ammonium hydrogensulfite as acute toxic via dermal route is not anticipated.

 

Acute inhalation toxicity:

The reference Klimisch (1982) that indicates a LC50 value of > 5.5 mg/l is considered as the key study for acute inhalation toxicity and will be used for classification.

According to the criteria specified by Directive 67/548/EEC and subsequent regulations, the test item is not classified as acute toxic via the inhalation route. According to the EC Regulation No. 1272/2008 and subsequent regulations, the test item is not classified as acute toxic via the inhalation route.

Based on the read-across concept, classification for ammonium hydrogensulfite as acute toxic via inhalation route is not anticipated.

 

Specific target organ toxicant (STOT) – single exposure: inhalation:

The classification criteria acc. to regulation (EC) 1272/2008 as specific target organ toxicant (STOT) – single exposure, inhalation dust/mist/fume are not met since no reversible or irreversible adverse health effects were observed immediately or delayed after exposure and no effects were observed at the guidance value, inhalation dust/mist/fume for a Category 1 classification of 1.0 mg/L/4h and at the guidance value, inhalation dust/mist/fume for a Category 2 classification of 5.0 mg/L/4h. Therefore, no classification is required. Finally, any category 3 classification should primarily be based on human data. However, such classification is also not warranted, since only unspecific observations in test animals (mainly rats) were observed at artificially high inhalation exposure levels which are without relevance to current workplace conditions. It can be safely assumed that standard occupational hygiene measures provide a sufficient level of worker protection.