Metam-sodium

Endpoint summary

Description of key information

Acute oral toxicity: 

Acute oral toxicity dose (LD50) of Metam-sodium (CAS no: 137-42-8) was considered based on different experimental studies conducted on rats, rabbits, mice and guinea pigs. The LD50 value was considered to be 896 mg/kg bw in Male and female rats; 870 mg/kg bw in Male rats and 924 mg/kg bw in Female rats. The study concluded that the LD50 value is between 300-2000 mg/kg bw. Thus, comparing this value with the criteria of CLP regulation, Metam-sodium (CAS no: 137-42-8) can be classified as “Category 4” for acute oral toxicity.

Acute Inhalation toxicity: 

Acute Inhalation toxicity dose (LC50) for Metam-sodium (CAS no: 137-42-8) was considered based on different experimental studies conducted on rats. The LC50 value was considered to be > 6.8 mg/L (>6800 mg/m3). The study concluded that the LC50 value is >5 mg/L air. Thus, comparing this value with the criteria of CLP regulation, Metam-sodium cannot be classified for acute Inhalation toxicity.

Acute Dermal toxicity: 

Acute Dermal toxicity dose (LD50) for Metam-sodium (CAS no: 137-42-8) was considered based on different experimental studies on rats and rabbits for acute dermal toxicity. The LD50 value was considered to be 3074 mg/kg bw. The study concluded that the LD50 value is >2000 mg/kg bw. Thus, comparing this value with the criteria of CLP regulation, Metam-sodium cannot be classified for acute dermal toxicity

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:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Justification for type of information:

Data is from handbook.

Qualifier:

according to guideline

Guideline:

other: As mentioned below

Principles of method if other than guideline:

Acute oral toxicity of Metam-sodium (CAS no: 137-42-8) in rat.

GLP compliance:

not specified

Test type:

other: not specified

Limit test:

no

Specific details on test material used for the study:

- IUPAC Name: Metam-sodium
- InChI: 1S/C2H5NS2.Na/c1-3-2(4)5;/h1H3,(H2,3,4,5);/q;+1/p-1
- Smiles: C(=S)(NC)[S-].[Na+]
- Molecular formula :C2H4NNaS2
- Molecular weight:129.1826 g/mol
- Substance type:Organic

Species:

rat

Strain:

other: CD rats

Sex:

male/female

Details on test animals or test system and environmental conditions:

not specified

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

not specified

Doses:

640, 800, 1000 or 1600 mg/kg bw

No. of animals per sex per dose:

Total = 40 (Sex/dose)

Control animals:

not specified

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: The animals were observed for mortality and clinical signs.
- Necropsy of survivors performed: yes

Statistics:

The data obtained did not permit the fitting of a probit line using the standard method. However, it was possible to fit a line if a fixed slope was assumed and a value of 8.333 was used.

Preliminary study:

A preliminary test was carried out by dosing 2 rats/sex at 1000 mg/kg bw and the acute median lethal dose of metam sodium was in the region of 1000 mg/kg be for males and >1000 mg/kg bw for female rats.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

896 mg/kg bw

Based on:

test mat.

95% CL:

779 - 1 031

Remarks on result:

other: 50% mortality was observed

Sex:

male

Dose descriptor:

LD50

Effect level:

870 mg/kg bw

Based on:

test mat.

95% CL:

715 - 1 059

Remarks on result:

other: 50% mortality was observed

Sex:

female

Dose descriptor:

LD50

Effect level:

924 mg/kg bw

Based on:

test mat.

95% CL:

758 - 1 130

Remarks on result:

other: 50% mortality was observed

Mortality:

50% mortality was observed as below –
Male and female rats combined 896 mg/kg bw, with 95% confidence limit of 779-1031 mg/kg bw.
Males only: 870 mg/kg bw, with 95% confidence limit of 715-1059 mg/kg bw.
Females only: 924 mg/kg bw, with 95% confidence limit of 758-1130 mg/kg bw.

Clinical signs:

other: All animals had piloerection, hunched posture, abnormal gait, lethargy, decreased respiratory rate, ptosis, pallor of the extremities, increased salivation. Clonic convulsions and prostration affected animals at 1000 and 1600 mg/kg bw.

Gross pathology:

No macroscopic abnormalities were seen.

Other findings:

not specified

Table - Mortality:

Dose (mg/kg bw)	Death		Day or hours after dosing
	M	F	M	F
640	0	0
800	1	0	Day 2
1000	5	5	4 day 4, 1 after 5 h	4 day 2, 1 after 5 h
1600	5	5	4 after 4 h; 1 after 1 h	3 after 4 h; 2 after 5 h

 

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

The acute oral LD50 value was considered as follows –
Male and female rats - 896 mg/kg bw, with 95% confidence limit of 779-1031 mg/kg bw; Male rats - 870 mg/kg bw, with 95% confidence limit of 715-1059 mg/kg bw; and Female rats - 924 mg/kg bw, with 95% confidence limit of 758-1130 mg/kg bw, when male and female CD rats were treated with Metam-sodium (CAS no: 137-42-8) via oral route.

Executive summary:

Acute oral toxicity study of Metam-sodium (CAS no: 137-42-8)was conducted in 40 male and female CD rats at the concentration of 640, 800, 1000 or 1600 mg/kg bw. All animals received metam sodium (510 g/L) via oral gavage route. A preliminary test was carried out by dosing 2 rats/sex at 1000 mg/kg bw and the acute median lethal dose of metam sodium was in the region of 1000 mg/kg be for males and >1000 mg/kg bw for female rats. The data obtained did not permit the fitting of a probit line using the standard method. However, it was possible to fit a line if a fixed slope was assumed and a value of 8.333 was used.The animals were observed for mortality and clinical signs for 14 days. Necropsy was performed. 50% mortality was observed as– Male and female rats combined 896 mg/kg bw; Males only: 870 mg/kg bw; Females only: 924 mg/kg bw. All animals had piloerection, hunched posture, abnormal gait, lethargy, decreased respiratory rate, ptosis, pallor of the extremities, increased salivation. Clonic convulsions and prostration affected animals at 1000 and 1600 mg/kg bw. Body weight was not affected in surviving male animals; surviving females of the group 800 mg/kg bw had decreased body weight. No macroscopic abnormalities were seen. Therefore, LD50 was considered to be 896 mg/kg bw in Male and female rats; 870 mg/kg bw in Male rats and 924 mg/kg bw in Female rats, when male and female CD rats were treated with Metam-sodium (CAS no: 137-42-8) via oral route.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

896 mg/kg bw

Quality of whole database:

Data is Klimisch 2 and from handbook.

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Justification for type of information:

Data is from authoritative database.

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Principles of method if other than guideline:

Acute inhalation toxicity of Metam-sodium (CAS no: 137-42-8) in rat.

GLP compliance:

not specified

Test type:

other: not specified

Limit test:

no

Specific details on test material used for the study:

- IUPAC Name: Metam-sodium
- InChI: 1S/C2H5NS2.Na/c1-3-2(4)5;/h1H3,(H2,3,4,5);/q;+1/p-1
- Smiles: C(=S)(NC)[S-].[Na+]
- Molecular formula :C2H4NNaS2
- Molecular weight:129.1826 g/mol
- Substance type:Organic

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

not specified

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

nose/head only

Vehicle:

other: aqueous formulation containing 42.2% methylcarbamodithionic acid monosodium salt

Mass median aerodynamic diameter (MMAD):

2.6 µm

Remark on MMAD/GSD:

not specified

Details on inhalation exposure:

not specified

Analytical verification of test atmosphere concentrations:

not specified

Duration of exposure:

4 h

Remarks on duration:

not specified

Concentrations:

6.8 mg/L (6800 mg/m3)

No. of animals per sex per dose:

5 rats/sex/dose

Control animals:

not specified

Details on study design:

- Duration of observation period following administration: 7 days
- Frequency of observations and weighing: Animals were observed for mortality, clinical signs and body weight change.

Statistics:

not specified

Preliminary study:

not specified

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 6.8 mg/L air

Based on:

test mat.

Exp. duration:

4 h

Remarks on result:

other: No mortality was observed

Mortality:

No mortality was observed at 6.8 mg/L air (6800 mg/m3)

Clinical signs:

other: Clinical signs during exposure animals attempt to escape. Reddish discharge from the nose and discharge from eyes were noted. After inhalation, hair in the genital area was covered with reddish crusts as well as part of the nose covered with reddish crust

Body weight:

Body weight gain of male rats was retarded in the first week of observation period but recovered in the second week. Body weight gain of females remained slightly retarded over the total observation period.

Gross pathology:

No organ abnormalities were detected.

Other findings:

not specified

Interpretation of results:

other: Not classified

Conclusions:

The acute inhalation LC50 value was considered to be > 6.8 mg/L (>6800 mg/m3), when 10 Wistar rats were treated with Metam-sodium (CAS no: 137-42-8) via inhalation route by aerosol for 4 hours exposure.

Executive summary:

Acute inhalation toxicity study of Metam-sodium (CAS no: 137-42-8)was conducted according to OECD Guide–line 403 "Acute Inhalation Toxicity"in 10 Wistar rats at the concentration of 6.8 mg/L (6800 mg/m3). The rats were exposed to metam sodium (batch n° ZH 130 585, 42.2% aqueous solution) by head-nose to an aerosol air mixture for 4 hours (MMAD 50% = 2.6 μm; 90.1% was respirable). Animals were observed for mortality, clinical signs and body weight change for 7 days. No mortality was observed at 6.8 mg/L air (6800 mg/m3). Clinical signs during exposure animals attempt to escape. Reddish discharge from the nose and discharge from eyes were noted. After inhalation, hair in the genital area was covered with reddish crusts as well as part of the nose covered with reddish crusts. Stepping gait was slightly high and respiration was slightly sound. The poisoning symptoms confirmed the pronounced irritation described above (fully reversible within 7 days). Body weight gain of male rats was retarded in the first week of observation period but recovered in the second week. Body weight gain of females remained slightly retarded over the total observation period. No organ abnormalities were detected. Therefore, LC50 value was considered to be > 6.8 mg/L (>6800 mg/m3), when 10 Wistar rats were treated with Metam-sodium (CAS no: 137-42-8) via inhalation route by aerosol for 4 hours exposure.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LC50

Value:

6 800 mg/m³ air

Quality of whole database:

Data is Klimisch 2 and from authoritative database.

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Justification for type of information:

Data is from authoritative database.

Qualifier:

according to guideline

Guideline:

other: As mentioned below

Principles of method if other than guideline:

Acute dermal toxicity of Metam-sodium (CAS no: 137-42-8) in rabbit.

GLP compliance:

not specified

Test type:

other: not specified

Limit test:

no

Specific details on test material used for the study:

- IUPAC Name: Metam-sodium
- InChI: 1S/C2H5NS2.Na/c1-3-2(4)5;/h1H3,(H2,3,4,5);/q;+1/p-1
- Smiles: C(=S)(NC)[S-].[Na+]
- Molecular formula :C2H4NNaS2
- Molecular weight:129.1826 g/mol
- Substance type:Organic

Species:

rabbit

Strain:

not specified

Sex:

not specified

Details on test animals or test system and environmental conditions:

not specified

Type of coverage:

other: Dermal

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

not specified

Duration of exposure:

not specified

Doses:

3074 mg/kg bw

No. of animals per sex per dose:

not specified

Control animals:

not specified

Details on study design:

not specified

Statistics:

not specified

Preliminary study:

not specified

Sex:

not specified

Dose descriptor:

LD50

Effect level:

3 074 mg/kg bw

Based on:

test mat.

Remarks on result:

other: 50% mortality was observed

Mortality:

50% mortality was observed at 3074 mg/kg bw

Clinical signs:

other: not specified

Gross pathology:

not specified

Other findings:

not specified

Interpretation of results:

other: Not classified

Conclusions:

The acute dermal LD50 value was considered to be 3074 mg/kg bw, when rabbits were treated with Metam-sodium (CAS no: 137-42-8) by dermal application.

Executive summary:

Acute dermal toxicity study of Metam-sodium (CAS no: 137-42-8)was conducted in rabbits at the concentration of 3074mg/kg bw . 50% mortality was observed at 3074mg/kg bw. Therefore, LD50 value was considered to be 3074mg/kg bw, when rabbits were treated with Metam-sodium (CAS no: 137-42-8) by dermal application. 

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

3 074 mg/kg bw

Quality of whole database:

Data is Klimisch 2 and from authoritative database.

Additional information

Acute oral toxicity:

In different experimental studies, Metam-sodium (CAS no: 137-42-8) has been investigated for acute oral toxicity to a greater or lesser extent. Often are the studies based on in-vivo experiments in rodents, i.e. most commonly in rats, rabbits, mice and guinea pigs for Metam-sodium (CAS no: 137-42-8). The studies are summarized as below –

The experimental study for the target chemical Metam-sodium (CAS no: 137-42-8) was conducted by Robert Krieger (Hayes' Handbook of Pesticide Toxicology (Third Edition), 2010, Pages 2293–2306), Wypych et al.(Databook of Biocides, 2015), Wypychet al.(Databook of Preservatives, 2015), European Food Safety Authority (EFSA, Scientific Report (2008) 203, 1-97), US EPA-Pesticides (Metam-sodium, US EPA ARCHIVE DOCUMENT, US EPA, 1994), US EPA-Pesticides (Metam-sodium, US EPA; Office of Pesticide Programs, 1993) and European Food Safety Authority (EFSA, Draft Assessment Report (Metam-sodium) - Volume 3, Annex B, part 2, B.6, October 2007). The acute oral toxicity study was conducted in 40 male and female CD rats at the concentration of 640, 800, 1000 or 1600 mg/kg bw. All animals received metam sodium (510 g/L) via oral gavage route. A preliminary test was carried out by dosing 2 rats/sex at 1000 mg/kg bw and the acute median lethal dose of metam sodium was in the region of 1000 mg/kg be for males and >1000 mg/kg bw for female rats. The data obtained did not permit the fitting of a probit line using the standard method. However, it was possible to fit a line if a fixed slope was assumed and a value of 8.333 was used. The animals were observed for mortality and clinical signs for 14 days. Necropsy was performed. 50% mortality was observed as– Male and female rats combined 896 mg/kg bw; Males only: 870 mg/kg bw; Females only: 924 mg/kg bw. All animals had piloerection, hunched posture, abnormal gait, lethargy, decreased respiratory rate, ptosis, pallor of the extremities, increased salivation. Clonic convulsions and prostration affected animals at 1000 and 1600 mg/kg bw. Body weight was not affected in surviving male animals; surviving females of the group 800 mg/kg bw had decreased body weight. No macroscopic abnormalities were seen. Therefore, LD50 was considered to be 896 mg/kg bw in Male and female rats; 870 mg/kg bw in Male rats and 924 mg/kg bw in Female rats, when male and female CD rats were treated with Metam-sodium (CAS no: 137-42-8) via oral route.

In another experimental study supported by U.S. National Library of Medicine (ChemIDplus, 2017), IFA GESTIS (GESTIS SUBSTANCE Database, 2017), RTECS (registry of toxic effect of chemical substance data base, 2017) and Chemical Review Section, National Registration Authority (The National Registration Authority for Agricultural and Veterinary Chemicals (NRA), NRA Special Review Series 97. 2, 1997), for the target chemical Metam-sodium (CAS no: 137-42-8) in male and female rats at the concentration of 450 mg/kg bw . 50% mortality was observed at 450 mg/kg bw. Therefore, LD50 value was considered to be 450 mg/kg bw, when male and female rats were treated with Metam-sodium (CAS no: 137-42-8) via oral route. 

This study is supported with the study conducted by Richard J. Lewis (Sax's Dangerous Properties of Industrial Materials, 12th Edition, 5 Volume Set, 2012), U.S. National

Library of Medicine (HSDB - Hazardous Substances Data Bank, 2017), Timothyet al.(Pesticide Toxicology and International Regulation Volume 1 of Current Toxicology, 2004), G. W. A. Milne (Gardner's Commercially Important Chemicals: Synonyms, Trade Names, and Properties, 2005) and Shmuel Yannai (Dictionary of Food Compounds with CD-ROM, Second Edition, 2012) for the target chemical Metam-sodium (CAS no: 137-42-8) in male and female rats at the concentration of 1700 and 1800 mg/kg bw . 50% mortality was observed at 1800 mg/kg bw in male rats; and 1700 mg/kg bw in female rats. Therefore, LD50 value was considered to be 1800 mg/kg bw in male rats; and 1700 mg/kg bw in female rats, when male and female rats were treated with Metam-sodium (CAS no: 137-42-8) via oral route.

The above experimental study is supported by the study mentioned in Short-term Toxicity Tests for Non-genotoxic Effects, SCOPE 41, Chapter 20, Pg. 325-338, 1990, by P. Bourdeau et al.for the target chemical Metam-sodium (CAS no: 137-42-8)in rats at the concentration of 700 mg/kg bw. 50% mortality was observed at 700 mg/kg bw. Therefore, LD50 value was considered to be 700 mg/kg bw, when rats were treated with Metam-sodium (CAS no: 137-42-8) via oral route. 

This study is further supported by US EPA; Office of Pesticide Programs (US EPA-Pesticides; Metam-sodium, 1986), for the target chemical Metam-sodium (CAS no: 137-42-8). The study was conducted in groups of 10 male and 10 female Sprague-Dawley rats at the concentration of 2239, 1778, 1413, 1259, 1122, or 891 mg/kg in male and 2239, 1778, 1584, 1500, 1413, or 891 mg/kg in female. A control group of 60 male and 60 female rats were dosed with water. The animals were observed twice daily for mortality, clinical signs and body weight change for 14 days. Mortalities were observed as -At 2239 mg/kg – All animals were died; At 1778 mg/kg – 8/10 males and 10/10 females were died; At 1584 mg/kg – 7/10 females were died; At 1500 mg/kg – 9/10 females were died; At 1413 mg/kg – 6/10 males and 3/10 females were died; At 1122 and 891 mg/kg – No death s occurred. Toxic symptoms included depression, loss of righting reflex, hypersensitivity, ptosis, salivation, piloerection, reddish limbs, swollen eyes, ataxia, stained fur, hunched posture, facial stains, dyspnea, anogenital stains, lacrimation, chromodacryorrhea, excessive urination, and tremors. Gross necropsy revealed redden lungs, clear fluid in thoracic cavity, test material like fluid in the stomach, pale liver, darkened liver, gelatinous appearing intestines, reddish fluid in bladder, pale kidneys, pale intestines, mottled lungs, darkened spleen, reddened stomach mucosa, yellowish-red fluid in intestines, engorged blood vessels on the stomach, solid material in bladder and kidney, enlarged hollowed kidneys, reddened thickened bladder walls, white spots on kidneys, bloated gastrointestinal tract, darkened thymuses, distended stomachs, pale uteri, opaque eyes, and enlarged and darkened adrenals. Therefore LD50 was considered to be1294 mg/kg bw, with 95% confidence limit of 1062-1578 mg/kg bw in male; and 1428 mg/kg bw, with 95% confidence limit of 1352-1508 mg/kg bw in female, when groups of 10 male and 10 female Sprague-Dawley rats were treated with Metam-sodium (CAS no: 137-42-8)by oral gavage route.

All the above experimental studies conducted in rats were supported with the study taken for rabbit. The experimental study mentioned on rabbits was conducted by Richard J. Lewis (Sax's Dangerous Properties of Industrial Materials, 12th Edition, 5 Volume Set, 2012), U.S. National Library of Medicine (ChemIDplus, 2017), U.S. National Library of Medicine (HSDB - Hazardous Substances Data Bank, 2008), RTECS (registry of toxic effect of chemical substance data base, 2017), P. Bourdeau et al.(Short-term Toxicity Tests for Non-genotoxic Effects, SCOPE 41, Chapter 20, Pg. 325-338, 1990) and Chemical Review Section, National Registration Authority (The National Registration Authority for Agricultural and Veterinary Chemicals (NRA), NRA Special Review Series 97. 2, 1997), for the target chemical Metam-sodium (CAS no: 137-42-8).The acute oral toxicity study was conducted in male and female rabbits at the concentration of 320 mg/kg bw . 50% mortality was observed at 320 mg/kg bw. Therefore, LD50 value was considered to be 320 mg/kg bw, when male and female rabbits were treated with Metam-sodium (CAS no: 137-42-8) via oral route.

From the above experimental studies conducted on rats and rabbits, other experimental studies are mentioned for mice were contradicted for acute oral toxicity. The studies are as follows –

The experimental study conducted by Richard J. Lewis (Sax's Dangerous Properties of Industrial Materials, 12th Edition, 5 Volume Set, 2012), U.S. National Library of Medicine (ChemIDplus, 2017), U.S. National Library of Medicine (HSDB - Hazardous Substances Data Bank, 2008), RTECS (registry of toxic effect of chemical substance data base, 2017), and Chemical Review Section, National Registration Authority (The National Registration Authority for Agricultural and Veterinary Chemicals (NRA), NRA Special Review Series 97. 2, 1997), for the target chemical Metam-sodium (CAS no: 137-42-8). The acute oral toxicity study was conducted in male and female mice at the concentration of 50 mg/kg bw. 50% mortality was observed at 50 mg/kg bw. Therefore, LD50 value was considered to be 50 mg/kg bw, when male and female mice were treated with Metam-sodium (CAS no: 137-42-8) via oral route.

The above study is supported by P. Bourdeauet al.(Short-term Toxicity Tests for Non-genotoxic Effects, SCOPE 41, Chapter 20, Pg. 325-338, 1990), for the target chemical Metam-sodium (CAS no: 137-42-8). The acute oral toxicity study was conducted in mice at the concentration of 266 mg/kg bw. 50% mortality was observed at 266 mg/kg bw. Therefore, LD50 value was considered to be 266 mg/kg bw, when mice were treated with Metam-sodium (CAS no: 137-42-8) via oral route.

Both the above experimental studies on mice are further supported by Timothy et al.(Pesticide Toxicology and International Regulation Volume 1 of Current Toxicology, 2004), G. W. A. Milne (Gardner's Commercially Important Chemicals: Synonyms, Trade Names, and Properties, 2005) and Chemical Review Section, National Registration Authority (The National Registration Authority for Agricultural and Veterinary Chemicals (NRA), NRA Special Review Series 97. 2, 1997), for the target chemical Metam-sodium (CAS no: 137-42-8).Acute oral toxicity study was conducted in male and female mice at the concentration of 285 mg/kg bw. 50% mortality was observed at 285 mg/kg bw. Therefore, LD50 value was considered to be 285 mg/kg bw, when male and female mice were treated with Metam-sodium (CAS no: 137-42-8) via oral route.

From the above experimental studies conducted on rats and rabbits, other experimental study is mentioned for guinea pigs, which is supported for acute oral toxicity. The study was conducted by Richard J. Lewis (Sax's Dangerous Properties of Industrial Materials, 12th Edition, 5 Volume Set, 2012), U.S. National Library of Medicine (ChemIDplus, 2017), U.S. National Library of Medicine (HSDB - Hazardous Substances Data Bank, 2008), RTECS (registry of toxic effect of chemical substance data base, 2017), P. Bourdeau et al.(Short-term Toxicity Tests for Non-genotoxic Effects, SCOPE 41, Chapter 20, Pg. 325-338, 1990), for the target chemical Metam-sodium (CAS no: 137-42-8) in guinea pigs at the concentration of 815 mg/kg bw . 50% mortality was observed at 815 mg/kg bw. Therefore, LD50 value was considered to be 815 mg/kg bw, when guinea pigs were treated with Metam-sodium (CAS no: 137-42-8) via oral route.

Though the study available for mice concluded that the LD50 value is in the range between 50-300 mg/kg bw, the classification for acute oral toxicity will considered to be “Category 4”, because of less reliability and insufficient data for study available for mice. Thus, based on the above studies on rats, rabbits and guinea pigs for Metam-sodium (CAS no: 137-42-8), it can be concluded that LD50 value is between 300-2000 mg/kg bw. Thus, comparing this value with the criteria of CLP regulation, Metam-sodium can be classified as “Category 4” for acute oral toxicity.

Acute Inhalation Toxicity:

In different experimental studies, Metam-sodium (CAS no: 137-42-8) has been investigated for acute Inhalation toxicity to a greater or lesser extent. Often are the studies based on in-vivo experiments in rodents, i.e. most commonly in rats for Metam-sodium. The studies are summarized as below –

The experimental study was conducted by IFA GESTIS (GESTIS SUBSTANCE Database, 2017), U.S. National Library of Medicine (HSDB - Hazardous Substances Data Bank, 2008), EUROPEAN COMMISSION – European Chemicals Bureau (IUCLID Dataset of Metam-sodium (CAS no: 137-42-8), 18–FEB–2000), and European Food Safety Authority (EFSA, Draft Assessment Report (Metam-sodium) - Volume 3, Annex B, part 2, B.6, October 2007), for the target chemical Metam-sodium (CAS no: 137-42-8). The acute inhalation toxicity study was conducted according to OECD Guide–line 403 "Acute Inhalation Toxicity" in 10 Wistar rats at the concentration of 6.8 mg/L (6800 mg/m3). The rats were exposed to metam sodium (batch n° ZH 130 585, 42.2% aqueous solution) by head-nose to an aerosol air mixture for 4 hours (MMAD 50% = 2.6 μm; 90.1% was respirable). Animals were observed for mortality, clinical signs and body weight change for 7 days. No mortality was observed at 6.8 mg/L air (6800 mg/m3). Clinical signs during exposure animals attempt to escape. Reddish discharge from the nose and discharge from eyes were noted. After inhalation, hair in the genital area was covered with reddish crusts as well as part of the nose covered with reddish crusts. Stepping gait was slightly high and respiration was slightly sound. The poisoning symptoms confirmed the pronounced irritation described above (fully reversible within 7 days). Body weight gain of male rats was retarded in the first week of observation period but recovered in the second week. Body weight gain of females remained slightly retarded over the total observation period. No organ abnormalities were detected. Therefore, LC50 value was considered to be > 6.8 mg/L (>6800 mg/m3), when 10 Wistar rats were treated with Metam-sodium (CAS no: 137-42-8) via inhalation route by aerosol for 4 hours exposure.

The above experimental study is supported by another experimental study conducted by Timothy et al.(Pesticide Toxicology and International Regulation Volume 1 of Current Toxicology, 2004), US EPA; Office of Pesticide Programs (US EPA-Pesticides; Metam-sodium, 1986) and Chemical Review Section, National Registration Authority (The National Registration Authority for Agricultural and Veterinary Chemicals (NRA), NRA Special Review Series 97. 2, 1997), for the target chemical Metam-sodium (CAS no: 137-42-8).Acute inhalation toxicity study was conducted in 10 male and 10 female Sprague-Dawley rats at the concentration range of 4.3 – 5.1 mg/L. Rats were exposed for 4 hours in a 447 stainless steel and glass inhalation chamber to an aerosol generated from test material. The animals were observed twice daily for mortality, clinical signs and body weight change. Necropsy was performed. 1 out of 10 males were died. Toxic symptoms were observed were depression, blood-like stains about the face, dyspnea and prostration. Gross necropsy in male revealed reddish brown and grayish brown foci on lung lobes and dilation of the renal pelvis of the right kidney. No compound related abnormalities were noted in the females. Therefore, LC50 value was considered to be >4.7 mg/L, when male and female Sprague-Dawley rats were treated with Metam-sodium (CAS no: 137-42-8) via inhalation route by aerosol for 4 hours of exposure.

The above experimental studies are contradicted by other experimental studies. The studies are as follows –

The experimental study conducted by Jay A. Brown (Haz-Map®: Information on Hazardous Chemicals and Occupational Diseases, U.S. National Library of Medicine, October 2017), Robert Krieger (Hayes' Handbook of Pesticide Toxicology (Third Edition), 2010, Pages 2293–2306) and US EPA ARCHIVE DOCUMENT (US EPA-Pesticides; Metam-sodium, 1994), for the target chemical Metam-sodium (CAS no: 137-42-8). Acute inhalation toxicity study was conducted in rats at the concentration of 2.27 mg/L (2270 mg/m3). 50% mortality was observed at 2.27 mg/L (2270 mg/m3). Therefore, LC50 was considered to be 2.27 mg/L (2270 mg/m3), when rats were treated with Metam-sodium (CAS no: 137-42-8) via inhalation route.

The above study is supported by European Food Safety Authority (EFSA, Scientific Report (2008) 203, 1-97), National Institute for Agricultural Research (AGRITOX - Plant Protection Phentopharmaceuticals Database, 2012), US EPA; Office of Pesticide Programs (US EPA-Pesticides; Metam-sodium, 1993) and European Food Safety Authority (EFSA, Draft Assessment Report (Metam-sodium) - Volume 3, Annex B, part 2, B.6, October 2007), for the target chemical Metam-sodium (CAS no: 137-42-8). Acute inhalation toxicity study was conducted according to OCDE guideline 403 in male and female Sprague-Dawley rats. Rats were exposed to whole body by inhalation to a test atmosphere containing a liquid droplet aerosol generated from metam sodium (510 g/L) at 1.23, 2.43, 3.03 or 3.15 mg/L for a 4-hour period. A control group was exposed to air only. The animals were observed for mortality, clinical signs and body weight change. Necropsy was performed. Mortality was observed as - affected 2/5 males at 2.43 mg/L and 4/5 males and 4/5 females at 3.15 mg/L. During exposure, signs consistent with exposure to an irritant and toxic aerosol including, partial closing of the eyes, wetness around the eyes, mouth and snout, reddening of the ears, feet and tail, exaggerated respiratory movements and the adoption of a hunched or prone posture. During the observation period, the main signs seen were persistent signs indicative of a long-term effect on the respiratory tract. The signs had disappeared by day 6 at 1.23 mg/L but at higher levels were present throughout the observation period. Also seen was formation of scabs on the scrotal sac and ears, indicative of irritation of the skin. Body weight was reduced for up to 3 days following exposure. Organ weight: lung weight/body weight for rats dying was higher than control values. Lungs were congested and stomach was gas filled. Except for the low dose level, rats showed histopathological lung changes progressing to bronchiolar epithelial necrosis with inflammatory exudates. Some rats treated with 3.15, 3.03 and 2.43 mg/L and all rats treated with 1.23 mg/L surviving to termination showed increased incidence of prominent alveolar macrophages as compared to control. Food consumption was reduced for up to 9 days following exposure. Water consumption was reduced immediately following exposure, but in females, there was evidence of increased water consumption later. Hence, LC50valuewasconsidered as follows – combined (Male and female) = 2.54 mg/L; Males: 2.20 mg/L; and Females: 2.95 mg/L, when male and female Sprague-Dawley rats were treated with Metam-sodium (CAS no: 137-42-8) via inhalation route by aerosol to whole body exposure for 4 hours.

Though the classified study available for the acute inhalation toxicity, the reliability of the data is very less to justify the LC50 value. Thus, based on the above experimental studies on Metam-sodium (CAS no: 137-42-8), it can be concluded that LC50 value is >5 mg/L air. Thus, comparing this value with the criteria of CLP regulation, Metam-sodium cannot be classified for acute Inhalation toxicity.

Acute Dermal toxicity:

In different experimental studies, Metam-sodium (CAS no: 137-42-8) has been investigated for acute dermal toxicity to a greater or lesser extent. Often are the studies based on in vivo experiments in rodents, i.e. most commonly in rabbits and rats for Metam-sodium. The studies are summarized as below –

The experimental study conducted by U.S. National Library of Medicine (HSDB - Hazardous Substances Data Bank, 2008), for the target chemicalMetam-sodium (CAS no: 137-42-8) in rabbits at the concentration of 3074mg/kg bw. 50% mortality was observed at 3074mg/kg bw. Therefore, LD50 value was considered to be 3074 mg/kg bw, when rabbits were treated with Metam-sodium (CAS no: 137-42-8) by dermal application. 

The above experimental study is supported by another experimental study conducted by IFA GESTIS (GESTIS SUBSTANCE Database, 2017), for the target chemical Metam-sodium (CAS no: 137-42-8) inratsat the dose concentration of 3049 mg/kg bw of the application of a 42.2% solution to rats. No mortality was observed at 3049 mg/kg bw. Therefore, LD50 value was considered to be >3049 mg/kg bw, when rats were treated with Metam-sodium (CAS no: 137-42-8) by dermal application.

These experimental studies are further supported by European Food Safety Authority (EFSA, Scientific Report (2008) 203, 1-97), European Food Safety Authority (EFSA, Draft Assessment Report (Metam-sodium) - Volume 3, Annex B, part 2, B.6, October 2007) and US EPA; Office of Pesticide Programs (US EPA-Pesticides; Metam-sodium, 1993), for the target chemical Metam-sodium (CAS no: 137-42-8). The acute dermal toxicity study was conducted in 10 male and female CD rats at the concentration of 2000 mg/kg bw. The test substance (510 g/L) was applied onto the clipped skin and covered with gauze and impermeable dressing for 24 h after which the skin was washed in warm water. The animals were observed for mortality, clinical signs, and body weight change for 14 days. Necropsy was performed. 1 female rat died on day 2 out of 5 females. Localized ulceration was observed to the subcutaneous region in a single male and female. Sites of application of metam sodium showed well defined to moderate erythema in all males and a majority of surviving females on day 2 only. Slight to moderate edema was present in all surviving rats between days 2 and7. These dermal reactions were accompanied by staining of the dose site (green yellow) and /or localized hard white areas of skin in all surviving rats from day 2 of the study. Reactions progressed to scab formation in 2 males and 4 males, which persisted until day 15 in a single male and female. All rats were hypothermic on day 2.A body weight loss was recorded for the animals, except for 1 male rat, in which a slightly low body weight gain was recorded.Autopsy revealed slight congestion in the subcutaneous region which was green in color. Terminal autopsy revealed scabs of the subcutaneous region for 1 male and 3 female. Therefore, LD50 was considered to be >2000 mg/kg bw, when 10 male and female CD rats were treated with Metam-sodium (CAS no: 137-42-8) by dermal application occlusively for 24 hours.

All these experimental studies are contradicted by other experimental studies conducted on rabbits as well as rats. The studies are as follows –

The experimental study conducted by U.S. National Library of Medicine (HSDB - Hazardous Substances Data Bank, 2008), Timothy et al.(Pesticide Toxicology and International Regulation Volume 1 of Current Toxicology, 2004), and G. W. A. Milne (Gardner's Commercially Important Chemicals: Synonyms, Trade Names, and Properties, 2005), for the target chemical Metam-sodium (CAS no: 137-42-8). The acute dermal toxicity study was conducted in rabbits at the concentration of 1300 mg/kg bw. 50% mortality was observed at 1300 mg/kg bw. Therefore, LD50 value was considered to be 1300 mg/kg bw, when rabbits were treated with Metam-sodium by dermal application.

This study is supported by Richard J. Lewis (Sax's Dangerous Properties of Industrial Materials, 12th Edition, 5 Volume Set, 2012), U.S. National Library of Medicine (ChemIDplus, 2017), IFA GESTIS (GESTIS SUBSTANCE Database, 2017), Shmuel Yannai (Dictionary of Food Compounds with CD-ROM, Second Edition, 2012), RTECS (registry of toxic effect of chemical substance data base, 2017) and Chemical Review Section, National Registration Authority (The National Registration Authority for Agricultural and Veterinary Chemicals (NRA), NRA Special Review Series 97. 2, 1997), for the target chemical Metam-sodium (CAS no: 137-42-8).Acute Dermal toxicity study was conducted in male and female rabbits at the concentration of 800 mg/kg bw. 50% mortality was observed at 800 mg/kg bw. Therefore, LD50 value was considered to be 800 mg/kg bw, when male and female rabbits were treated with Metam-sodium (CAS no: 137-42-8) by dermal application.

These studies are supported by Richard J. Lewis (Sax's Dangerous Properties of Industrial Materials, 12th Edition, 5 Volume Set, 2012) and U.S. National Library of Medicine (ChemIDplus, 2017) for the target chemical Metam-sodium (CAS no: 137-42-8) in rats at the concentration of 636 mg/kg bw . 50% mortality was observed at 636 mg/kg bw. Therefore, LD50 value was considered to be 636 mg/kg bw, when rats were treated with Metam-sodium (CAS no: 137-42-8) by dermal application.

The above experimental studies are supported by Robert Krieger (Hayes' Handbook of Pesticide Toxicology (Third Edition), 2010, Pages 2293–2306), and US EPA ARCHIVE DOCUMENT (US EPA, US EPA-Pesticides; Metam-sodium, 1994),for the target chemical Metam-sodium (CAS no: 137-42-8) in male and female rabbits at the concentration of 368 mg/kg bw. 50% mortality was observed at 368 mg/kg bw. Therefore, LD50 was considered to be 368 mg/kg bw, when male and female rabbits were treated with Metam-sodium (CAS no: 137-42-8) by dermal application.

All the above studies are further supported by US EPA; Office of Pesticide Programs (US EPA-Pesticides; Metam-sodium, 1986) for the taget chemical Metam-sodium (CAS no: 137-42-8). Acute dermal toxicity study was conducted in Albino rabbits at the dose concentration as - Group I – 2000 mg/kg; Group II – 1584 mg/kg; Group III – 1259 mg/kg; Group IV – 794 mg/kg. Animals were clipped closely on the abdomen and received dermal application of the test material under occlusive wrap for 24 hours of exposure. After exposure, the wrap and residual material were removed. Irritation was observed and test site was rewrapped in gauze for 3 days. The animals were observed twice daily for mortality, clinical signs and body weight change for 14 days. Necropsy was performed. Mortalities were observed as - At 2000 mg/kg – 9/10 animals were died; at 1584 and 1259 mg/kg – 6/8 animals were died; at 794 mg/kg –No death s occurred. Toxic symptoms included severe depression, ataxia, prostration, and shallow respiration. Gross necropsy revealed reddened and pale lungs, mottled livers, darkened or dark-edged spleens, pale spleens, distended gallbladders, yellowish fluid in the intestines, reddened stomach mucosa, small gallbladder, darkened spots on the stomach mucosa, pale uterine horns, and darkened thymus. Therefore, LD50 was considered to be1012 mg/kg bw, with 95% confidence limit of 720-1421 mg/kg bw, when male and female Albino rabbits were treated with Metam-sodium (CAS no: 137-42-8) by dermal application occlusively.

Though the complete study is not available for target chemical Metam-sodium (CAS no: 137-42-8) and less reliability of data references for acute dermal toxicity, the LD50 value is considered to be >2000 mg/kg bw. Thus, comparing this value with the criteria of CLP regulation, Metam-sodium cannot be classified for acute dermal toxicity.

Justification for classification or non-classification

Based on the above experimental studies on Metam-sodium (CAS no: 137-42-8), it can be concluded that LD50 value is between 300-2000 mg/kg bw for acute oral toxicity; LD50 value is >2000 mg/kg bw for acute dermal toxicity; and LC50 value is >5 mg/L air for acute inhalation toxicity. Thus, comparing these values with the criteria of CLP regulation, Metam-sodium can be classified as “Category 4” for acute oral toxicity; cannot be classified for acute dermal and inhalation toxicity.