Registration Dossier

Administrative data

Endpoint:
fertility, other
Remarks:
based on test type (migrated information)
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
other information
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
other: secondary literature - cited from OECD SIDS and US EPA

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2006
Report date:
2006

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Principles of method if other than guideline:
In a combined, repeated-dose reproductive/developmental toxicity study, Sprague-Dawley rats (10/sex/dose) were administered CASRN 61617-00-3 orally in the diet at 1000, 2750 or 7500 ppm (~ 50, 138 or 375 mg/kg-bw/day). Treatment began two weeks prior to mating and continued throughout gestation, up to postnatal day 5 (~ 47 days). Doses were reduced to 900, 2500 or 6750 ppm on day 29 (~ 45, 125 or 338 mg/kg-bw/day) and on day 33, the high-dose group was further reduced to 5500 ppm (~ 275 mg/kg-bw/day) due to observed toxicity (type not specified in robust summary).
GLP compliance:
yes

Test material

Constituent 1
Chemical structure
Reference substance name:
1,3-dihydro-4(or 5)-methyl-2H-benzimidazole-2-thione, zinc salt
EC Number:
262-872-0
EC Name:
1,3-dihydro-4(or 5)-methyl-2H-benzimidazole-2-thione, zinc salt
Cas Number:
61617-00-3
Molecular formula:
C8H8N2S.1/2Zn
IUPAC Name:
Zinc bis[4(or 5)-methyl-2-thioxo-2,3-dihydrobenzimidazol-1-ide]
Details on test material:
methyl-2-mercaptobenzimidazole, zinc salt = Vanox ZMTI; purity 99.9%

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female

Administration / exposure

Route of administration:
oral: feed
Vehicle:
other: diet
Details on mating procedure:
Following 2 weeks of dosing, male and female rats were paired within their dose groups to produce litters
Duration of treatment / exposure:
Treatment began 2 weeks prior to mating and continued throughout gestation, up to postnatal day 5 (ca. 47 days)
Frequency of treatment:
daily
Details on study schedule:
At day 5 post partum, all surviving females, males and offpring were killed and examined macroscopically
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
1000, 2750 or 7500 ppm (ca. 50, 138 or 375 mg/kg bw/day) day 1-28
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
900, 2500 or 6750 ppm (ca. 45, 125 or 338 mg/kg bw/d) day 29-32
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
high dose group was further reduced to 5500 ppm (ca. 275 mg/kg bw/d) day 33-45
Basis:
nominal in diet
No. of animals per sex per dose:
10/sex/dose
Control animals:
yes, concurrent vehicle

Results and discussion

Results: P0 (first parental generation)

Effect levels (P0)

open allclose all
Dose descriptor:
LOAEL
Effect level:
45 - 50 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: based on increased gestation lenght
Dose descriptor:
NOAEL
Effect level:
275 - 338 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: based on no effects observed at the highest dose tested

Overall reproductive toxicity

Reproductive effects observed:
not specified

Any other information on results incl. tables

The combined repeated-dose reproductive/developmental toxicity study showed both systemic and reproductive toxicity in orally exposed rats. Significant decrements in body weight gain and organ weights were observed at all levels of treatment, including the lowest dose tested (45-50 mg/kg/day). Female reproductive toxicity, as evidenced by increased gestation length, occurred at all doses. The NOAEL for male reproductive toxicity was approximately 275-338 mg/kg/day, based on no effects at the highest dose tested. Developmental toxicity could not be evaluated due to a high incidence of mortality in the dams.

Applicant's summary and conclusion

Executive summary:

The administration of Vanox ZMTI to male and female rats at dose levels of up to 7500 ppm (~ 375 mg/kg bw/d) (adjusted to 6750 ppm (~ 338 mg/kg bw/d and then to 5500ppm (~ 275 mg/kg bw/d)) for a period of up to forty seven days; which included a mating period, gestation and early lactation phase, resulted in treatment-related upon mating performance, fertility and the parturition process. The "No Observed Adverse Effect Level" (NOAEL) for reproductive effects upon adults was not established.

The LOAEL for systemic toxicity = 45 -50 mg/kg bw/d.