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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
two-generation reproductive toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study without detailed documentation
Remarks:
EPA guideline and GLP. The report is a summary of a much more detailed study and hence some of the individual results and observations are not reported.

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
2000

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
EPA OPPTS 870.3800 (Reproduction and Fertility Effects)
Deviations:
no
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
liquid
Details on test material:
Specification: 81.4 %: Sodium chlorite; Balance: Sodium chloride and small amounts of sodium hydroxide and sodium chlorate
Purity: 81.4 %
Stability: Drinking water solutions were tested and the concentrations were found to be stable under the conditions of use.

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
Source:Iffa Credo, BelgiumAge at study initiation: 6 weeks old

Administration / exposure

Route of administration:
oral: drinking water
Vehicle:
water
Details on mating procedure:
Mating ratio= 1:1
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
Duration of exposure before mating:10 weeksDuration of exposure in general P, F1, F2 males, females:From beginning of the study until sacrifice of parent, F1, F2-generation
Doses / concentrationsopen allclose all
Dose / conc.:
35 ppm
Remarks:
Equivalent to 4 and 5 mg/kg-bw/day in males and females respectively (sodium chlorite).Equivalent to 2.9 and 4 mg/kg-bw/day in male and female respectively (chlorite).Dose decreased 50 % (to 17.5 ppm) during lactation
Dose / conc.:
70 ppm
Remarks:
Equivalent to 8 and 10 mg/kg-bw/day in males and females respectively (sodium chlorite).Equivalent to 6 and 7.5 mg/kg-bw/day in male and female respectively (chlorite).Dose decreased 50 % (to 35 ppm) during lactation
Dose / conc.:
300 ppm
Remarks:
Equivalent to 30 and 39 mg/kg-bw/day in males and females respectively (sodium chlorite).Equivalent to 22 and 29 mg/kg-bw/day in male and female respectively (chlorite).Dose decreased 50 % (to 150 ppm) during lactation
No. of animals per sex per dose:
30/sex/group for P generation25/sex/group for F1 generation
Control animals:
yes, concurrent vehicle

Examinations

Parental animals: Observations and examinations:
CLINICAL OBSERVATIONS: YesBODY WEIGHT: Yes FOOD CONSUMPTION AND COMPOUND INTAKE: YesWATER CONSUMPTION AND COMPOUND INTAKE: Yes
Oestrous cyclicity (parental animals):
Yes
Sperm parameters (parental animals):
Parameters: Sperm motility, sperm morphology
Litter observations:
Parameters: Number and sex of pups, stillbirths, live births, presence of gross, anomalies, weight gain, physical or behavioural abnormalities OTHER EXAMINATIONS:Hematological and thyroid hormone data analysed from 1 pup/sex/dose from each F1 generation, followed by additional evaluations at 13 weeks for all F1 animals selected to rear the F2 generation.Red blood cell count (RBC), Hemoglobin levels (Hb), Hematocrit (HCT), mean corpuscular volume (MCV), mean corpuscular haemoglobin (MCH), mean corpuscular haemoglobin concentrations (MCHC), total white blood cell count (WBC), methemoglobin concentration (MetHb) and total serum T3 and T4 concentrations were evaluated.
Postmortem examinations (parental animals):
HISTOPATHOLOGY:Reproductive organs from animals in the high-dose and control groups or any animal with suspected reduced fertility.Organ tissue details not stated
Postmortem examinations (offspring):
HISTOPATHOLOGY:Reproductive organs from animals in the high-dose and control groups or any animal with suspected reduced fertility.Organ tissue details not stated

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
no effects observed
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
There were no effects in food consumption.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Description (incidence and severity):
Dose-related decreases in water consumption were observed for males and females in the 70 and 300 ppm groups (ca. 25 % compared to control).Water consumption was ocassionally decreased in the 35 ppm group.
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
no effects observed

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
no effects observed
Description (incidence and severity):
There were no treatment-related changes in estrous cyclicity or sperm motility and morphology.
Reproductive function: sperm measures:
no effects observed
Description (incidence and severity):
There were no treatment-related changes in estrous cyclicity or sperm motility and morphology.
Reproductive performance:
not specified
Description (incidence and severity):
There were no treatment-related changes in mating, fertility, or gestational indices.

Effect levels (P0)

Key result
Dose descriptor:
NOAEL
Effect level:
35 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
water consumption and compound intake
Remarks on result:
other: Dose-related decreases in water consumption were observed for males and females in the 70 and 300 ppm groups (ca. 25 % compared to control). Water consumption was ocassionally decreased in the 35 ppm group.
Remarks:
The effect was not accompanied by changes in body weight.

Target system / organ toxicity (P0)

Key result
Critical effects observed:
no

Results: P1 (second parental generation)

General toxicity (P1)

Clinical signs:
no effects observed
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Body weight and food consumption were significantly decreased at all measurement intervals for F1 males in the 300 ppm group ( ca 20% decreased) at most measurement intervals.Additionally, very small but statistically significant decreases in body weight were noted during the first 3-6weeks of the prebreed treatment period for F1 males in the 70 ppm group and F1 females in the 300 ppm group.During the last 7 days of gestation, at parturition and for varying lengths of time during lactation, body weights for F0 and F1 females in the 300 ppm group were decreased compared to females in the control group. The magnitude of the change in body weight from the control for dams in the 300 ppm treatment group generally was -4% to -6%.
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Description (incidence and severity):
For F1 generation parental animals, dose-related decreases in water consumption were observed for males at all sodium chlorite treatment levels (ca. 10– 25% decreased) and for females in the 300 ppm group (ca. 20% decreased) at most measurement intervals.
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
For F1 adult animals (at week 13), small decreases in RBC count, Hb, HCT, MCV, MCH and WBC count and a small increase in MCHC was observed for male and/or female rats in the 300 ppm group. Very small but statistically significant changes in some of these endpoints also were observed for male and female animals in the 35 and 70 ppm groups.Finally, there were no treatment-related changes in the total serum concentrations of the thyroid hormones T3 or T4 for F1 PND 25 or F1 13-week-old animals.
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not specified
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
A minor, albeit statistically significant, decrease in absolute brain weight (28%) was observed for male pups in the 300 ppm group sacrificed on PND 11 compared to the control. Decreased brain weight for these pups was associated with decreased pup weight at birth and a 14% decrease in pup weight on PND 11 compared to the control. Accordingly, brain weight to body weight ratios on PND 11 were increased for male pups in the 300 ppm group, although this increase (16%) was not statistically significantly different from the control. Decreases in absolute brain weight were not observed for female PND 11 pups, for male pups in the 35 and 70 ppm groups or for male or female PND 25 pups.
Gross pathological findings:
not examined
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
There were no treatment-related microscopic changes in reproductive tissues for male and female parental animals.Microscopic examination of the central and peripheral nervous system tissues for male and female PND 60 animals did not reveal any treatment-related alterations or pathology.
Histopathological findings: neoplastic:
not examined
Other effects:
no effects observed
Description (incidence and severity):
There were no gross or microscopic lesions noted in the brains or spinal cords of F1 PND 11 pups. In addition, there was no evidence of developmental changes, or anomalies in cell migration for PND 11 pups.

Reproductive function / performance (P1)

Reproductive function: oestrous cycle:
no effects observed
Description (incidence and severity):
There were no treatment-related changes in estrous cyclicity.
Reproductive function: sperm measures:
no effects observed
Description (incidence and severity):
There were no treatment-related changes in sperm motility and morphology.
Reproductive performance:
no effects observed
Description (incidence and severity):
There were no treatment-related changes in mating, fertility or gestational indices for F1 generation.

Details on results (P1)

There were no abnormalities or treatment-related changes observed in the Functional Observation Battery for F1 animals examined on PNDs 21 or 60 and there were no treatment-related differences in motor activity observed for F1 animals evaluated on PNDs 17, 21 or 60

Effect levels (P1)

open allclose all
Key result
Dose descriptor:
LOAEL
Effect level:
300 mg/L drinking water
Based on:
test mat.
Sex:
male/female
Basis for effect level:
haematology
Remarks on result:
other: Equivalent to 30 and 39 mg sodium chlorite/kg-bw/day in male and female rats respectively
Key result
Dose descriptor:
LOAEL
Effect level:
> 300 mg/L drinking water
Based on:
test mat.
Sex:
male/female
Basis for effect level:
neuropathology
Remarks on result:
other: Equivalent to > 30 and > 39 mg sodium chlorite/kg-bw/day in male and female rats respectively
Key result
Dose descriptor:
NOAEL
Effect level:
70 mg/L drinking water
Based on:
test mat.
Sex:
male/female
Basis for effect level:
haematology
Remarks on result:
other: Equivalent to 8 and 10 mg sodium chlorite/kg-bw/day in male and female rats respectively
Key result
Dose descriptor:
NOAEL
Effect level:
300 mg/L drinking water
Based on:
test mat.
Sex:
male/female
Basis for effect level:
neuropathology
Remarks on result:
other: Equivalent to 30 and 39 mg sodium chlorite/kg-bw/day

Target system / organ toxicity (P1)

Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
300 mg/L drinking water
System:
haematopoietic
Treatment related:
yes
Dose response relationship:
yes
Relevant for humans:
not specified

Results: F2 generation

General toxicity (F2)

Clinical signs:
not specified
Dermal irritation (if dermal study):
not examined
Mortality / viability:
not specified
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Treatment related decreases in body weight were observed for male and female pups in the 300 ppm treatment group from the F1,F2a and F2b generations. The magnitude of the change in pup body weight from control increased with age and ranged from 26% at birth to 210% on PND 24.The decreases were statistically significant from birth to weaning for F1 pups and during the final 2–3 weeks of lactation for F2a and F2b pups
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Sexual maturation:
no effects observed
Description (incidence and severity):
There were no treatment-related changes in the number of pups born, the pup gender ratio, live birth index or pup survival indices, nor were there differences in ano–genital distance or gross external alterations for pups . There were no clear treatment-related changes in pup developmental indices, including ear and eye opening, righting reflex, auditory startle response and pupil response.
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not specified
Histopathological findings:
not specified
Other effects:
no effects observed
Description (incidence and severity):
There were no treatment-related changes in the number of pups born, the pup gender ratio, live birth index or pup survival indices, nor were there differences in ano–genital distance or gross external alterations for pups (data not shown). There were no clear treatment-related changes in pup developmental indices, including ear and eye opening, righting reflex, auditory startle response and pupil response.

Developmental neurotoxicity (F2)

Behaviour (functional findings):
not specified

Developmental immunotoxicity (F2)

Developmental immunotoxicity:
not examined

Details on results (F2)

There was a decrease in the percent of F2a pups with eyes open on PND 15 in the 300 ppm treatment group when compared to the control (76.1 ± 30.6% for control (mean ± SD) and 47.4 ± 38.1% for 300 ppm) but similar effects were not observed for F1 or F2b pups (80.3 ± 34.4% for control F1 pups and 67.9 ± 35.6% for 300 ppm F1 pups; 73.0 ± 32.6% for control F2b pups and 71.9 ± 38.0% for 300 ppm F2b pups). There were small but statistically significant increases in the average time to preputial separation for F1 pups in the 70 and 300 ppm groups and in the vaginal opening for F1 pups in the 300 ppm group. Similar changes were not observed for F2 generation pups.

Effect levels (F2)

open allclose all
Key result
Dose descriptor:
NOAEL
Generation:
other: F1 and F2 generations
Effect level:
35 mg/L drinking water
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: See remarks:
Key result
Dose descriptor:
NOAEL
Generation:
other: F1 and F2 generations
Effect level:
2.9 other: mg sodium chlorite/kg-bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: See remarks

Target system / organ toxicity (F2)

Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
70 mg/kg bw (total dose)
Organ:
brain
liver
Treatment related:
yes
Dose response relationship:
not specified
Relevant for humans:
not specified

Overall reproductive toxicity

Key result
Reproductive effects observed:
no

Any other information on results incl. tables

The F1 generation is the second parent generation. Details on the results can be found in Results P1 (Second parent generation).

Table A6_8_2(2)-2         Table for reproductive toxicity study

 

Parameter

control

low dose

medium dose

High dose

Genera­tion

m

f

m

f

m

f

m

f

Mortality

Incidences of significance

P

-

-

-

-

-

-

-

-

F1

-

-

-

-

-

-

-

-

Food consumption

Change relative to control

P

-

-

-

-

-

-

-

-

F1

Water consumption

% decrease relative to control

P

-

-

-

-

10 - 25 % decrease

F1

-

-

10-25

-

10-25

-

10-25

20

Body weight gain

Change relative to control

P

-

-

-

-

-

-

-

-

F1

F2a/b

Clinical Observations

Incidences of significance

P/F1

-

-

-

-

-

-

-

-

Organ weights

% of control

Histopathologic examination

Incidence

All

-

-

-

-

-

-

-

-

Hematological examination:

Significant changes vs control

RBC, Hb, HCT, MCV, MCH, MCHC

F1

WBC

F1

MetHb

F1

T3 and T4

F1

-

-

-

-

-

-

-

-

Reproductive Performance

Significant changes vs control

Mating index

All

-

-

-

-

-

-

-

-

Fertility index

All

-

-

-

-

-

-

-

-

Birth index

All

-

-

-

-

-

-

-

-

Live birth index

All

-

-

-

-

-

-

-

-

Gestation index

All

-

-

-

-

-

-

-

-

Sex ratio

All

-

-

-

-

-

-

-

-

Survival index

All

-

-

-

-

-

-

-

-

Sperm characterization

P/F1

-

-

-

-

-

-

-

-

Deformations

Significant changes vs control

All

-

-

-

-

-

-

-

-

Applicant's summary and conclusion

Conclusions:
No evidence of reproductive toxicity. Based on the results of this study the NOEL for effects on reproduction and thyroid hormones is 300 ppm. The NOAELs for hematological toxicity and neurotoxicity are considered to be 70 and 300 ppm, respectively. These NOAELs are equivalent to approximately 8 and 30 mg sodium clorite/kg-bw/day, respectively, for males and approximately 10 and 39 mg sodium clorite/kg-bw/day , respectively, for females.
Executive summary:

A two-generation reproduction and development neurotoxicity study with sodium chlorite in the rat was conducted according to EPA OPPTS 870.3800 (Reproduction and Fertility Effects). No evidence of reproductive toxicity was observed. Sodium chlorite resulted in a decrease in the water consumption in all groups and food consumption and body weights in 70 and 300 ppm groups. Pup body weights were decreased in the 300 ppm group and small delays were observed in times to preputial separation and vaginal opening. Mild anaemia and mild methemoglobinemia were observed for animals in the 300 ppm group. Thyroid hormone levels were not affected by the treatment. Changes to the nervous system were limited to small decreases in amplitude of auditory startle responses for post natal day 25 pups in the 70 and 300 ppm groups of questionable neurotoxicological significance.