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EC number: 232-092-5
CAS number: 7786-17-6
ANALYSIS OF DOSE PREPARATIONS
Samples of Day 6
> Accuracy of preparation:
- No test material was detected in the
- The concentrations analysed in the
100, 300 and 1000 mg/kg bw/day formulations were not in agreement with
target concentrations since the mean accuracies were outside the
acceptability range of 85-115%; with mean accuracies of 84%, 117% and
The 100 and 1000 mg/kg bw/day
formulations were not homogeneous since the coefficients of variation
were 17% and 42%, respectively.
Analysis of Group 2 and Group 4
formulations after storage yielded a relative difference of 27% and
-24%. The relatively large differences are probably caused by an
inhomogeneity in the formulations rather than degradation of the test
Samples of Day 10
- The concentrations analysed in the
100, 300 and 1000 mg/kg bw/day formulations were in agreement with
target concentrations, mean accuracies were between 85% and 115%.
The homogeneity of the 100 and 1000
mg/kg bw/day formulations was still above the criterion of 10%. However,
the resulting coefficients of variation were 14% and 11% respectively,
were still considered acceptable.
Analysis of 100 and 1000 mg/kg be/day
formulations after storage yielded a relative difference of 12% and
-9.4%. The formulations are found to be stable when the relative
difference is ≤ 10%. Since the relative difference of the 100 mg/kg
bw/day formulations of 12% was an increase in concentration, no
degradation occurred. The relatively large differences are probably
caused by an inhomogeneity in the formulations. The analytical method
showed a higher variability at the low concentration level (i.e. a
coefficient of variation of 11 and 18% of the procedural recovery
samples) which possibly results in a higher variability of the
analytical formulation results as well. The formulations are thus
considered to be stable during storage at room temperature under normal
laboratory light conditions for at least 6 hours.
Table 1: Reproductive Data Summary
Dose Group mg/kg bw/day
Females with living pups on Day 1
Females dead during delivery
Mating Index (%)
Fertility Index (%)
Conception Index (%)
Gestation Index (%)
Toxicity to reproduction was determined in a reproduction/development
toxicity screening test, performed under GLP conditions and in line with
the standardised guidelines OECD 421 and EPA OPPTS 870.3550. Based on
the results of a 10-day dose range finding study, Crl:WI(Han) rats were
dosed at 100, 300 and 1000 mg/kg bw/day, formulated in propylene glycol,
and administered via oral gavage.
Ten males per dose were exposed for 29 days (2 weeks prior to mating,
during mating, and up to termination), and ten females per dose were
exposed for 39-54 days (during 2 weeks prior to mating, during mating,
during post-coitum, and during at least 4 days of lactation).
The accuracy, homogeneity and stability results were outside the
acceptable range during the first formulation analysis. Subsequent
analyses revealed the formulations were prepared accurately and were
considered stable for at least 6 hours at room temperature, though
formulations were not homogeneous. The results were attributable to an
interaction between limited sensitivity of the analytical method and the
nature of the test material itself and were ultimately accepted. The
inhomogeneity of the test material had no negative impact on the study
as formulations were stirred constantly during dosing.
No signs of parental toxicity were noted in males or females during
exposure or at necropsy up to the maximum dose level tested. Thus the
NOAEL for parental toxicity was considered to be 1000 mg/kg bw/day.
Examination of the offspring revealed no signs of treatment related
No toxicologically relevant effects on reproductive parameters were
noted. There were 10, 9, 9 and 10 pregnant females in the control, 100,
300 and 1000 mg/kg groups, respectively. The mating, fertility and
conception indices, precoital time, and number of corpora lutea and
implantation sites were unaffected by treatment. Based on these findings
the NOAEL for reproductive toxicity was determined to be the highest
dose level, 1000 mg/kg bw/day.
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