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Toxicological information

Toxicity to reproduction

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Administrative data

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

Data source

Referenceopen allclose all

Reference Type:
secondary source
Title:
Reprroductive Toxicity study of Metam-sodium in Rats
Author:
European Commission
Year:
2000
Bibliographic source:
European Commission, European Chemicals Bureau, 2000
Reference Type:
review article or handbook
Title:
Multigeneration reproduction study of Metam-sodium in Rats
Author:
Linda L. Carlock
Year:
2001
Bibliographic source:
Handbook of Pesticide Toxicology, Chapter 87, Volume 2.2001. Toxicology and Regulatory Consulting, , UCB Chemicals Corporation
Reference Type:
secondary source
Title:
Metam-sodium: 2-Generation reproductive toxicity study in rats
Author:
US EPA
Year:
1994
Bibliographic source:
United states environment protection agency, 1994

Materials and methods

Test guideline
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

Test material

Constituent 1
Chemical structure
Reference substance name:
Metam-sodium
EC Number:
205-293-0
EC Name:
Metam-sodium
Cas Number:
137-42-8
Molecular formula:
C2H5NS2.Na
IUPAC Name:
sodium (methylcarbamothioyl)sulfanide
Details on test material:
SMILES:CNC(=S)S{-}.[Na]{+}
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

Test animals

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

Administration / exposure

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
Doses / concentrationsopen allclose all
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

Examinations

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

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

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 / performance (P0)

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.

Effect levels (P0)

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

Target system / organ toxicity (P0)

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

Results: F1 generation

General toxicity (F1)

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.

Developmental neurotoxicity (F1)

Behaviour (functional findings):
not specified

Developmental immunotoxicity (F1)

Developmental immunotoxicity:
not specified

Effect levels (F1)

open allclose all
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

Target system / organ toxicity (F1)

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

Results: F2 generation

General toxicity (F2)

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

Developmental neurotoxicity (F2)

Behaviour (functional findings):
not specified

Developmental immunotoxicity (F2)

Developmental immunotoxicity:
not specified

Effect levels (F2)

open allclose all
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

Target system / organ toxicity (F2)

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

Overall reproductive toxicity

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

Applicant's summary and conclusion

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.