Metam-sodium

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

NOAEL was considered to be 11.5mg/kg/day for male and 13.5 mg/kg/day female for P and F1 generation when Alpk: Apf SD male and female rats were treated with Metam-sodium orally by gavage for in drinking water for 65 days and more days.

Thus, based on the above studies on Metam-sodium, it can be concluded that Metam-sodium is toxic to reproduction till dose of 13.5 mg/kg bw. Thus, comparing this effect with the criteria of CLP regulation, Metam-sodium can be classified under “category II” for reproductive toxicity.

Thought, the test substance Metam-sodium is classified under category II, Metam-sodium is extensive and rapidly metabolize suggesting a decomposition of metam into MITC, CO2, and COS. MITC is further conjugated to glutathione and excreted in urine while CO2 and COS are excreted via expired air. The other significant pathway for metam is the release of CS2, which  could be related to the acidic conditions existent in the stomach of the rat (pH=3.8-5) following oral ingestion. Excretion is almost complete within 24-48 h after administration, with minor portions excreted up to 168 h after dosing. Hence, Metam-sodium is show Low bio-accumulation potential. The ADI proposed by the RMS in the DAR was 0.001 (EFSA Scientific Report (2008) 203, 1-97) and Metam-sodium is use as a pesticide, plant fumigant to control weeds, nematodes, fungi, bacteria and insects (United states environment protaction agecny, 1994). Hence, Metam-sodium is considered to be of no safety concern.

Link to relevant study records

Reference

Endpoint:

screening for reproductive / developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Justification for type of information:

Data is from secondary source

Qualifier:

according to guideline

Guideline:

other: as below

Principles of method if other than guideline:

Multigeneration reproduction study of Metam-sodium in Rats

GLP compliance:

not specified

Limit test:

no

Specific details on test material used for the study:

- Name of test material (as cited in study report): Metam-sodium
- Molecular formula (if other than submission substance): C2H4NNaS2
- Molecular weight (if other than submission substance): 129.1826 g/mole
- Substance type: Organic

Species:

rat

Strain:

other: Alpk: Apf SD

Sex:

male/female

Details on test animals or test system and environmental conditions:

- Source: Barriered animal breeding unit at Zeneca Pharmaceuticals, Alderley Park, Macclesfield, Cheshire, UK
- Age at study initiation: (P) x wks; (F1) x wks: 10 weeks

Route of administration:

oral: drinking water

Type of inhalation exposure (if applicable):

not specified

Vehicle:

water

Remarks:

drinking

Details on exposure:

VEHICLE
- Justification for use and choice of vehicle (if other than water): drinking water
- Concentration in vehicle: 0, 1.2, 3.2 and 11.5 mg/kg/day for males and 0, 1.8, 3.9 and 13.5 mg/kg/day for females.

Details on mating procedure:

Details on study schedule
- F1 parental animals not mated until [...] weeks after selected from the F1 litters.
- Selection of parents from F1 generation when pups were [...] days of age.
- Age at mating of the mated animals in the study: [...] weeks
(Explain how study was performed on perents and offspring separately whatever information we have) At 21 days of age, pups from the parental (F0) generation
were selected as parents for the F1 generation.
- M/F ratio per cage: 1:1

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

65 days and more

Frequency of treatment:

Daily

Details on study schedule:

not specified

Dose / conc.:

0 mg/kg bw/day

Dose / conc.:

1.2 mg/kg bw/day

Remarks:

for male

Dose / conc.:

3.2 mg/kg bw/day

Remarks:

for male

Dose / conc.:

11.5 mg/kg bw/day

Remarks:

for male

Dose / conc.:

1.8 mg/kg bw/day

Remarks:

for female

Dose / conc.:

3.9 mg/kg bw/day

Remarks:

for female

Dose / conc.:

13.5 mg/kg bw/day

Remarks:

for female

No. of animals per sex per dose:

Total: 240
0 (vehicle) mg/kg/day: 30 male, 30 female
1.2 mg/kg/day: 30 male
3.2 mg/kg/day: 30 male
11.5 mg/kg/day: 30 male
1.8 mg/kg/day: 30 female
3.9 mg/kg/day: 30 female
13.5 mg/kg/day: 30 female

Control animals:

yes, concurrent vehicle

Details on study design:

Not specified

Positive control:

Not specified

Parental animals: Observations and examinations:

Survival, Clinical sign, Body weight and weight gain, food consumption and water consumption were examined.

Oestrous cyclicity (parental animals):

Not specified

Sperm parameters (parental animals):

Not specified

Litter observations:

Clinical sign and Body weights sex were examined.

Postmortem examinations (parental animals):

Gross pathology and histopathology was examined

Postmortem examinations (offspring):

Gross pathology and histopathology was examined

Statistics:

Not specified

Reproductive indices:

Not specified

Offspring viability indices:

Not specified

Clinical signs:

not specified

Dermal irritation (if dermal study):

not specified

Mortality:

no mortality observed

Description (incidence):

No effect on survival of treated male and female rats were observed.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

When treated wtih 11.5 mg/kg/day for male and 13.5 mg/kg/day for female, Decreased in body weight was observed in treated male and female rats as compared to control.
When treated wtih 30 mg/kg bw, slight Decreased in body weight was observed.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

When treated wtih 11.5 mg/kg/day for male and 13.5 mg/kg/day for female, Decreased in food consumption was observed in treated male and female rats

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

effects observed, treatment-related

Description (incidence and severity):

When treated wtih 11.5 mg/kg/day for male and 13.5 mg/kg/day for female, Decreased in water consumption was observed in treated male and female rats

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Changes in the epithelium of
nasal passages in adult females were observed at 13.5 mg/kg/day.
Systemic toxicity consisted of (1) duct hypertrophy of Bowman's gland with loss of alveolar cells,
(2) degeneration, disorganization, and/or
atrophy of the olfactory epithelium, and
(3) dilation of the Bowman's gland ducts. Changes in Bowman's glands were accompanied in all affected animals by degeneration, disorganization, and/or atrophy of the olfactory epithelium.

No effect were observed in male rats.

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Reproductive function: oestrous cycle:

not specified

Reproductive function: sperm measures:

not specified

Reproductive performance:

no effects observed

Description (incidence and severity):

No effect on Reproductive performance was observed in treated rats as compared to control.

Dose descriptor:

NOAEL

Effect level:

30 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

mortality

gross pathology

reproductive performance

Remarks on result:

other: No effect observed

Critical effects observed:

not specified

System:

other: not specified

Organ:

not specified

Treatment related:

not specified

Dose response relationship:

not specified

Relevant for humans:

not specified

Clinical signs:

not specified

Dermal irritation (if dermal study):

not specified

Mortality / viability:

not specified

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Decrease in F1 mean pup weight on Day 22 were observed as compared to control.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

When treated wtih 11.5 mg/kg/day for male and 13.5 mg/kg/day female, marginal decreased in food consumption was observed in treated male and female rats

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Sexual maturation:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

not specified

Histopathological findings:

not specified

Other effects:

no effects observed

Description (incidence and severity):

No effect on Reproductive performance was observed in treated F1 pups as compared to control.

Behaviour (functional findings):

not specified

Developmental immunotoxicity:

not specified

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

11.5 mg/kg bw/day

Based on:

test mat.

Sex:

male

Basis for effect level:

other: No effect on reproduction

Remarks on result:

other: No effect observed

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

13.5 mg/kg bw/day

Based on:

test mat.

Sex:

female

Basis for effect level:

other: No effect on reproduction

Remarks on result:

other: No effect observed

Critical effects observed:

not specified

System:

other: not specified

Organ:

not specified

Treatment related:

not specified

Dose response relationship:

not specified

Relevant for humans:

not specified

Clinical signs:

not specified

Dermal irritation (if dermal study):

not specified

Mortality / viability:

not specified

Body weight and weight changes:

no effects observed

Description (incidence and severity):

Decrease in mean body weight gain for F2 litters was observed.

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Sexual maturation:

not specified

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

When treated wtih 11.5 mg/kg/day for male, decreases 8-9% in testes and epididymis weight in male pups in the F1a and F2a litters.

Gross pathological findings:

not specified

Histopathological findings:

not specified

Other effects:

not specified

Behaviour (functional findings):

not specified

Developmental immunotoxicity:

not specified

Dose descriptor:

NOAEL

Generation:

F2

Effect level:

3.2 mg/kg bw/day

Based on:

test mat.

Sex:

male

Basis for effect level:

body weight and weight gain

organ weights and organ / body weight ratios

Remarks on result:

other: No effect observed

Dose descriptor:

NOAEL

Generation:

F2

Effect level:

3.9 mg/kg bw/day

Based on:

test mat.

Sex:

female

Basis for effect level:

body weight and weight gain

organ weights and organ / body weight ratios

Remarks on result:

other: No effect observed

Critical effects observed:

not specified

System:

other: not specified

Organ:

not specified

Treatment related:

not specified

Dose response relationship:

not specified

Relevant for humans:

not specified

Reproductive effects observed:

not specified

Treatment related:

not specified

Relation to other toxic effects:

not specified

Dose response relationship:

not specified

Relevant for humans:

not specified

Conclusions:

NOAEL was considered to be 11.5 mg/kg/day for male and 13.5 mg/kg/day female for P and F1 generation when Alpk: Apf SD male and female rats were treated with Metam-sodium orally by gavage for 65 days and more days.

Executive summary:

In a Reproduction Toxicity Test, Alpk: Apf SD male and female rats were treated with Metam-sodiumin the concentration of 0,11.5 mg/kg/day for male and13.5 mg/kg/day female orally in drinking water for 65 days and more days.No effect on survival of treated male and female rats were observed.Decreased in body weight was observed at11.5 mg/kg/day for male and13.5 mg/kg/day female rats as compared to control.Slight Decreased in body weight was observed at 3.2 mg/kg bw in male and 3.9 mg/kg bw mg/kg bw in female. Decreased in food consumption and water consumption was observed at11.5 mg/kg/day for male and13.5 mg/kg/day female rats.Red spot on pituitary gland, Twisted snout was observed at11.5 mg/kg/day for male and13.5 mg/kg/day female. However relation to treatment was doubtful.Changes in the epithelium of nasal passages in adult females were observed at13.5 mg/kg/day. Systemic toxicity consisted of (1) duct hypertrophy of Bowman's gland with loss of alveolar cells,(2) degeneration, disorganization, and/oratrophy of the olfactory epithelium, and (3) dilation of the Bowman's gland ducts. Changes in Bowman's glands were accompanied in all affected animals by degeneration, disorganization, and/or atrophy of the olfactory epithelium.No effect were observed in male rats. Similarly, Decrease in F1 mean pup weight on Day 22 and marginal decreased in food consumption were observed at 11.5 mg/kg/day for male and13.5 mg/kg/day female as compared to control.Decrease in mean body weight gain for F2 litters was observed.Decreases 8-9% in testes and epididymis weight in male pups in the F1a and F2a litters at11.5 mg/kg/day in male rats were observed. In addition,No effect onReproductive performancewas observed in treated P and F1 rats as compared to control.Therefore, NOAEL was considered to be 11.5mg/kg/day for male and 13.5 mg/kg/day female for P and F1 generation when Alpk: Apf SD male and female rats were treated with Metam-sodium orally by gavage for in drinking water for 65 days and more days.

Effect on fertility: via oral route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

13.5 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

Data is Klimish 4 and from European Commission

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

Reproductive toxicity:

In different studies, Metam-sodium has been investigated for reproductive toxicity to a greater or lesser extent. Study based on in vivo experiments, i.e. most commonly in rats for Metam-sodium and summarized below

In a experimental study given by European Commission (European Commission, European Chemicals Bureau, 2000), Carlocket al(Handbook of Pesticide Toxicology, Chapter 87, Volume 2.2001.) and US EPA (United states environment protection agency, 1994), Alpk: Apf SD male and female rats were treated with Metam-sodiumin the concentration of 0, 11.5 mg/kg/day for male and 13.5 mg/kg/day female orally in drinking water for 65 days and more days. No effect on survival of treated male and female rats was observed. Decreased in body weight was observed at11.5 mg/kg/day for male and13.5 mg/kg/day female rats as compared to control. Slight Decreased in body weight was observed at 3.2 mg/kg bw in male and 3.9 mg/kg bw mg/kg bw in female. Decreased in food consumption and water consumption was observed at11.5 mg/kg/day for male and13.5 mg/kg/day female rats.Red spot on pituitary gland, Twisted snout was observed at11.5 mg/kg/day for male and13.5 mg/kg/day female. However relation to treatment was doubtful. Changes in the epithelium of nasal passages in adult females were observed at13.5 mg/kg/day. Systemic toxicity consisted of (1) duct hypertrophy of Bowman's gland with loss of alveolar cells,(2) degeneration, disorganization, and/oratrophy of the olfactory epithelium, and (3) dilation of the Bowman's gland ducts. Changes in Bowman's glands were accompanied in all affected animals by degeneration, disorganization, and/or atrophy of the olfactory epithelium. No effect were observed in male rats. Similarly, Decrease in F1 mean pup weight on Day 22 and marginal decreased in food consumption were observed at 11.5 mg/kg/day for male and13.5 mg/kg/day female as compared to control. Decrease in mean body weight gain for F2 litters was observed. Decreases 8-9% in testes and epididymis weight in male pups in the F1a and F2a litters at11.5 mg/kg/day in male rats were observed. In addition, No effect on Reproductive performance was observed in treated P and F1 rats as compared to control. Therefore, NOAEL was considered to be 11.5mg/kg/day for male and 13.5 mg/kg/day female for P and F1 generation when Alpk: Apf SD male and female rats were treated with Metam-sodium orally by gavage for in drinking water for 65 days and more days.

In another experimental study given by Carlocket al(Handbook of Pesticide Toxicology, Chapter 87, Volume 2.2001.), Wistar male and female rats were treated with Metam-sodium in the concentration of 0, 10, 40, or 120 mg/kg/day orally by gavage on Days 6-15 of gestation. Significantly decreased in body weight gain was observed in treated female rats at 40 and 120 mg/kg as compared to control. Cesarean section observations revealed that there was a statistically significant increase in the percentage of postimplantation loss and a significant decrease in the percentage of live fetuses per dam at 10 and 120 mg/kg. But not at the 40 mg/kg dose level. It is possible that the effects observed at the 10 mg/kg dose level were statistical anomalies, but this remains unconfirmed in the absence of a review of the individual data, which were not available. Since there were no statistically significant changes in Cesarean section observations in the 40 mg/kg group, it is likely that the statistically significant changes in percentage of live fetuses per dam and the percentage of postimplantation loss in the 10 mg/kg group are not treatment-related. In addition, significant decrease in fetal weight was observed at 120 mg/kg as compared to control. Meningocele (hernial protrusion of the meniges through a bony defect) in two fetuses from one litter at 120 mg/kg. Since this is a rare finding that was not present in historical controls, this anomaly was considered to be treatment-related. Increased incidence of variations and a delay in the development of fetuses were observed at 40 and 120 mg/kg. Therefore, NOAEL was considered to be 10 mg/kg/day for P and F1 generation when Wistar male and female rats were treated with Metam-sodium orally by gavage on Days 6-15 of gestation.

Further supported by experimental study given by Carlocket al(Handbook of Pesticide Toxicology, Chapter 87, Volume 2.2001.) and US EPA (United states environment protection agency, 1994), Wistar male and female rats were treated with Metam-sodium in the concentration of 0, 5, 20 and 60 mg/kg/day by gavage on Days 6-17 of gestation. Piloerection, salivation, and urinary incontinence were observed in treated rats at 20 and 60 mg/kg/day. No clinical signs were observed in treated rats at 5 mg/kg/day. Decreased in body weight gain and food consumption was observed in treated female rats at 20 and 60 mg/kg/day as compared to control. Marginal decreased in body weight gain and food consumption was observed in treated female rats at 5 mg/kg/day as compared to control. In addition, decrease in fetal weight, reduced ossification of manus and pes and increased incidences of minor skeletal defects and/or variants were observed in fetus of treated rats. was observed at 20 and 60 mg/kg/day as compared to control. Therefore, NOAEL was considered to be 5 mg/kg/day for P and F1 generation when Wistar female rats were treated with Metam-sodium orally by gavage on Days 6-17 of gestation.

Thus, based on the above studies on Metam-sodium, it can be concluded that Metam-sodium is toxic to reproduction till dose of 13.5 mg/kg bw. Thus, comparing this effect with the criteria of CLP regulation, Metam-sodium can be classified under “category II” for reproductive toxicity.

Thought, the test substance Metam-sodium is classified under category II, Metam-sodium is extensive and rapidly metabolize suggesting a decomposition of metam into MITC, CO2, and COS. MITC is further conjugated to glutathione and excreted in urine while CO2 and COS are excreted via expired air. The other significant pathway for metam is the release of CS2, which  could be related to the acidic conditions existent in the stomach of the rat (pH=3.8-5) following oral ingestion. Excretion is almost complete within 24-48 h after administration, with minor portions excreted up to 168 h after dosing. Hence, Metam-sodium is show Low bio-accumulation potential. The ADI proposed by the RMS in the DAR was 0.001 (EFSA Scientific Report (2008) 203, 1-97) and Metam-sodium is use as a pesticide, plant fumigant to control weeds, nematodes, fungi, bacteria and insects (United states environment protaction agecny, 1994). Hence, Metam-sodium is considered to be of no safety concern.

Effects on developmental toxicity

Description of key information

NOAEL was considered to be 10 mg/kg/day for P and F1 generation when Wistar male and female rats were treated with Metam-sodium orally by gavage on Days 6-15 of gestation.

Thus, based on the above studies on Metam-sodium, it can be concluded that Metam-sodium is toxic to development till dose of 10 mg/kg bw. Thus, comparing this effect with the criteria of CLP regulation, Metam-sodium can be classified under “category II” for developmental toxicity.

Thought, the test substance Metam-sodium (CAS no 137-42-8) is classified under category II, Metam-sodium is extensive and rapidly metabolize suggesting a decomposition of metam into MITC, CO2, and COS. MITC is further conjugated to glutathione and excreted in urine while CO2 and COS are excreted via expired air. The other significant pathway for metam is the release of CS2, which  could be related to the acidic conditions existent in the stomach of the rat (pH=3.8-5) following oral ingestion. Excretion is almost complete within 24-48 h after administration, with minor portions excreted up to 168 h after dosing. Hence, Metam-sodium is show Low bio-accumulation potential. The ADI proposed by the RMS in the DAR was 0.001 (EFSA Scientific Report (2008) 203, 1-97) and Metam-sodium is use as a pesticide, plant fumigant to control weeds, nematodes, fungi, bacteria and insects (United states environment protaction agecny, 1994). Hence, Metam-sodium is considered to be of no safety concern.

Link to relevant study records

Reference

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

secondary literature

Justification for type of information:

Data is from Scondray source

Qualifier:

according to guideline

Guideline:

other: as below

Principles of method if other than guideline:

Teratology study of Metam-sodium in Rats

GLP compliance:

not specified

Limit test:

no

Specific details on test material used for the study:

- Name of test material (as cited in study report): Metam-sodium
- Molecular formula (if other than submission substance): C2H4NNaS2
- Molecular weight (if other than submission substance): 129.1826 g/mole
- Substance type: Organic

Species:

rat

Strain:

Wistar

Details on test animals or test system and environmental conditions:

- Source: Barriered animal breeding unit at Zeneca Pharmaceuticals, Alderley Park, Macclesfield, Cheshire, UK

Route of administration:

oral: gavage

Type of inhalation exposure (if applicable):

not specified

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: An aqueous solution of metam sodium (42.2%) was administered at 0, 10, 40, or 120 mg/kg by gavage to pregnant Wistar rats

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

10 days

Frequency of treatment:

Daily

Duration of test:

Days 6-15 of gestation

Dose / conc.:

0 mg/kg bw/day

Dose / conc.:

10 mg/kg bw/day

Dose / conc.:

40 mg/kg bw/day

Dose / conc.:

120 mg/kg bw/day

No. of animals per sex per dose:

not specified

Control animals:

not specified

Details on study design:

not specified

Maternal examinations:

Body weight, Gross pathology and histopathology was examined.

Ovaries and uterine content:

Not specified

Fetal examinations:

Live fetuses, Gross pathology and histopathology was examined.

Statistics:

Not specified

Indices:

Not specified

Historical control data:

Not specified

Clinical signs:

not specified

Dermal irritation (if dermal study):

not specified

Mortality:

not specified

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

When treated wtih 40 and 120 mg/kg, significantly decreased in body weight gain was observed in treated female rats as compared to control.

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

not specified

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Other effects:

no effects observed

Description (incidence and severity):

Reproductive performance:
When treated wtih 10 and 120 mg/kg, Cesarean section observations revealed that there was a statistically significant increase in the percentage of postimplantation loss and a significant decrease in the percentage of live fetuses per dam. But not at the 40 mg/kg dose level.

It is possible that the effects observed at the 10 mg/kg dose level were statistical anomalies, but this remains unconfirmed in the absence of a review of the individual data, which were not available.

Since there were no statistically significant changes in Cesarean section observations in the 40 mg/kg group, it is likely that the statistically significant changes in percentage of live fetuses per dam and the percentage of postimplantation loss in the 10 mg/kg group are not treatment-related.

Number of abortions:

not specified

Pre- and post-implantation loss:

effects observed, treatment-related

Description (incidence and severity):

When treated wtih 10 and 120 mg/kg, Cesarean section observations revealed that there was a statistically significant increase in the percentage of postimplantation loss and a significant decrease in the percentage of live fetuses per dam. But not at the 40 mg/kg dose level.

It is possible that the effects observed at the 10 mg/kg dose level were statistical anomalies, but this remains unconfirmed in the absence of a review of the individual data, which were not available.

Total litter losses by resorption:

not specified

Early or late resorptions:

not specified

Dead fetuses:

effects observed, treatment-related

Description (incidence and severity):

Since there were no statistically significant changes in Cesarean section observations in the 40 mg/kg group, it is likely that the statistically significant changes in percentage of live fetuses per dam and the percentage of postimplantation loss in
the 10 mg/kg group are not treatment-related.

Changes in pregnancy duration:

not specified

Description (incidence and severity):

Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): not specified

Changes in number of pregnant:

not specified

Other effects:

not specified

Dose descriptor:

NOAEL

Effect level:

10 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

body weight and weight gain

dead fetuses

pre and post implantation loss

Remarks on result:

other: No effect observed

Abnormalities:

not specified

Description (incidence and severity):

not specified

Fetal body weight changes:

effects observed, treatment-related

Description (incidence and severity):

When treated wtih 120 mg/kg, Significant decrease in fetal weight were observed as compared to control.
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): not specified

Reduction in number of live offspring:

not specified

Changes in sex ratio:

not specified

Changes in litter size and weights:

not specified

Changes in postnatal survival:

not specified

External malformations:

effects observed, treatment-related

Description (incidence and severity):

When treated with 120 mg/kg bw, meningocele (hernial protrusion of the meniges through a bony defect ) in two fetuses from one litter.
Since this is a rare finding that was not present in historical controls, this anomaly was considered to be treatment-related.

Skeletal malformations:

effects observed, treatment-related

Description (incidence and severity):

Increased incidence of variations and a delay in the development of fetuses at 40 and 120 mg/kg

Visceral malformations:

not specified

Other effects:

not specified

Dose descriptor:

NOAEL

Effect level:

10 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

fetal/pup body weight changes

external malformations

skeletal malformations

Remarks on result:

other: No effect observed

Abnormalities:

not specified

Description (incidence and severity):

not specified

Developmental effects observed:

not specified

Treatment related:

not specified

Relation to maternal toxicity:

not specified

Dose response relationship:

not specified

Relevant for humans:

not specified

Conclusions:

NOAEL was considered to be 10 mg/kg/day for P and F1 generation when Wistar male and female rats were treated with Metam-sodium orally by gavage on Days 6-15 of gestation.

Executive summary:

In aTeratology study, Wistar male andfemale rats were treated withMetam-sodiumin the concentration of0, 10, 40, or 120mg/kg/day orally by gavage on Days 6-15 of gestation.Significantly decreased in body weight gain was observed in treated female rats at 40 and 120 mg/kg as compared to control.Cesarean section observations revealed that there was a statistically significant increase in the percentage of postimplantation loss and a significant decrease in the percentage of live fetuses per dam at10 and 120 mg/kg. But not at the 40 mg/kg dose level.It is possible that the effects observed at the 10 mg/kg dose level were statisticalanomalies, but this remains unconfirmed in the absence of a review of the individual data, which were not available.Since there were no statistically significant changes in Cesarean section observations in the 40 mg/kg group, it is likely that the statistically significant changes in percentage of live fetuses per dam and the percentage of postimplantation loss inthe 10 mg/kg group are not treatment-related. In addition, developmental effect such as Significant decrease in fetal weight were observed at120 mg/kgas compared to control.Meningocele (hernial protrusion of the meniges through a bony defect ) in two fetuses from one litter at 120 mg/kg.Since this is a rare finding that was not present in historical controls, this anomaly was considered to be treatment-related. Increased incidence of variations and a delay in the development of fetuses were observed at 40 and 120 mg/kg.Therefore, NOAEL was considered to be 10mg/kg/day for P and F1 generation whenWistar maleand female rats were treated withMetam-sodiumorally by gavage on Days 6-15 of gestation.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

10 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

Data is Klimish 4 and from Handbook of Pesticide Toxicology

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

Developmental toxicity:

In different studies, Metam-sodium has been investigated for developmental toxicity to a greater or lesser extent. Study based on in vivo experiments, i.e. most commonly in rats for Metam-sodium and summarized below 

In a experimental study given by Carlocket al(Handbook of Pesticide Toxicology, Chapter 87, Volume 2.2001.) and US EPA (United states environment protection agency, 1994), Wistar male and female rats were treated with Metam-sodium in the concentration of 0, 10, 40, or 120 mg/kg/day orally by gavage on Days 6-15 of gestation. Significantly decreased in body weight gain was observed in treated female rats at 40 and 120 mg/kg as compared to control. Cesarean section observations revealed that there was a statistically significant increase in the percentage of postimplantation loss and a significant decrease in the percentage of live fetuses per dam at 10 and 120 mg/kg. But not at the 40 mg/kg dose level. It is possible that the effects observed at the 10 mg/kg dose level were statistical anomalies, but this remains unconfirmed in the absence of a review of the individual data, which were not available. Since there were no statistically significant changes in Cesarean section observations in the 40 mg/kg group, it is likely that the statistically significant changes in percentage of live fetuses per dam and the percentage of postimplantation loss in the 10 mg/kg group are not treatment-related. In addition, significant decrease in fetal weight was observed at 120 mg/kg as compared to control. Meningocele (hernial protrusion of the meniges through a bony defect) in two fetuses from one litter at 120 mg/kg. Since this is a rare finding that was not present in historical controls, this anomaly was considered to be treatment-related. Increased incidence of variations and a delay in the development of fetuses were observed at 40 and 120 mg/kg. Therefore, 

In another experimental study given by Carlocket al(Handbook of Pesticide Toxicology, Chapter 87, Volume 2.2001.) and US EPA (United states environment protection agency, 1994), Wistar male and female rats were treated with Metam-sodium in the concentration of 0, 5, 20 and 60 mg/kg/day by gavage on Days 6-17 of gestation. Piloerection, salivation, and urinary incontinence were observed in treated rats at 20 and 60 mg/kg/day. No clinical signs were observed in treated rats at 5 mg/kg/day. Decreased in body weight gain and food consumption was observed in treated female rats at 20 and 60 mg/kg/day as compared to control. Similarly, Marginal decreased in body weight gain and food consumption was observed in treated female rats at 5 mg/kg/day as compared to control. In addition, decrease in fetal weight, reduced ossification of manus and pes and increased incidences of minor skeletal defects and/or variants were observed in fetus of treated rats was observed at 20 and 60 mg/kg/day as compared to control. Therefore, NOAEL was considered to be 5 mg/kg/day for P and F1 generation when Wistar female rats were treated with Metam-sodium orally by gavage on Days 6-17 of gestation.

Thus, based on the above studies on Metam-sodium, it can be concluded that Metam-sodium is toxic to development till dose of 10 mg/kg bw. Thus, comparing this effect with the criteria of CLP regulation, Metam-sodium can be classified under “category II” for developmental toxicity.

Thought, the test substance Metam-sodium (CAS no 137-42-8) is classified under category II, Metam-sodium is extensive and rapidly metabolize suggesting a decomposition of metam into MITC, CO2, and COS. MITC is further conjugated to glutathione and excreted in urine while CO2 and COS are excreted via expired air. The other significant pathway for metam is the release of CS2, which  could be related to the acidic conditions existent in the stomach of the rat (pH=3.8-5) following oral ingestion. Excretion is almost complete within 24-48 h after administration, with minor portions excreted up to 168 h after dosing. Hence, Metam-sodium is show Low bio-accumulation potential. The ADI proposed by the RMS in the DAR was 0.001 (EFSA Scientific Report (2008) 203, 1-97) and Metam-sodium is use as a pesticide, plant fumigant to control weeds, nematodes, fungi, bacteria and insects (United states environment protaction agecny, 1994). Hence, Metam-sodium is considered to be of no safety concern.

Justification for classification or non-classification

Based on the above studies on Metam-sodium, it can be concluded that Metam-sodium is toxic to reproduction and development . Thus, comparing this effect with the criteria of CLP regulation, Metam-sodium can be classified under “category II” for developmental toxicity.

Thought, the test substance Metam-sodium (CAS no 137-42-8) is classified under category II, Metam-sodium is extensive and rapidly metabolize suggesting a decomposition of metam into MITC, CO2, and COS. MITC is further conjugated to glutathione and excreted in urine while CO2 and COS are excreted via expired air. The other significant pathway for metam is the release of CS2, which  could be related to the acidic conditions existent in the stomach of the rat (pH=3.8-5) following oral ingestion. Excretion is almost complete within 24-48 h after administration, with minor portions excreted up to 168 h after dosing. Hence, Metam-sodium is show Low bio-accumulation potential. The ADI proposed by the RMS in the DAR was 0.001 (EFSA Scientific Report (2008) 203, 1-97) and Metam-sodium is use as a pesticide, plant fumigant to control weeds, nematodes, fungi, bacteria and insects (United states environment protaction agecny, 1994). Hence, Metam-sodium is considered to be of no safety concern.