Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

Chlorine dioxide and chlorite are characterized together for toxicity to reproduction because studies conducted with chlorite, the predominant degradation product of chlorine dioxide, are likely relevant to characterizing the toxicity of chlorine dioxide. In addition, studies conducted with chlorine dioxide may be relevant to characterizing the toxicity of chlorite. Chlorine dioxide is fairly unstable and rapidly dissociates, predominantly into chlorite and chloride, and to a lesser extent, chlorate. There is a ready interconversion among these species in water (before administration to animals) and in the gut (after ingestion). Therefore, what exists in water or the stomach is a mixture of these chemical species (i.e., chlorine dioxide, chlorite, chlorate) and possibly their reaction products with the gastrointestinal contents.

Key study: Experimental results: 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.

Key study: Experimental results: One generation study with chlorine dioxide in the rat. No treatment-related effects were observed for parents in any dose groups. For F1 generation only the females showed any treatment-related changes: decreased vaginal weights in highest dose group.

 

Justification for selection of Effect on fertility via oral route:
Two-generation reproduction study with the test substance.

Link to relevant study records
Reference
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.
Qualifier:
according to
Guideline:
EPA OPPTS 870.3800 (Reproduction and Fertility Effects)
Deviations:
no
GLP compliance:
yes
Limit test:
no
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
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
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
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
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: 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.
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.
Key result
Critical effects observed:
no
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: 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.
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
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
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
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.
Behaviour (functional findings):
not specified
Developmental immunotoxicity:
not examined
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.
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
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
Key result
Reproductive effects observed:
no

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

-

-

-

-

-

-

-

-

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.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
2.9 mg/kg bw/day
Study duration:
chronic
Species:
rat
Quality of whole database:
Klimisch 2. EPA guideline and GLP.
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available

Effects on developmental toxicity

Description of key information

Key study experimental results: Study perfomed in rabbit according to EPA OPP 83-3 (Prenatal Developmental Toxicity Study). Oral administration of sodium chlorite during organogenesis at 600 and 1200 ppm elicited dose related reductions in maternal water with consequent reductions in maternal food consumption, production of faecal pellets and body weight gain. Despite the maternal effects there was no evidence of embryo-lethality or teratogenicity.

There are additional studies in a second specie, i.e. rat.

Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
EPA OPP 83-3 (Prenatal Developmental Toxicity Study)
Deviations:
no
GLP compliance:
yes
Limit test:
no
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
Source:Interfauna UK Ltd., Huntington, Cambs., UKAge/weight at study initiation:Age: 4 – 5 months oldWeight: 3.05 – 4.00 kg (at mating)
Route of administration:
oral: drinking water
Vehicle:
water
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
Mating period: Timed mated at start of study, mating period not stated.
Duration of treatment / exposure:
Duration of treatment: Days 7-19 (post mating)Post exposure period: 9 days
Dose / conc.:
200 mg/L drinking water
Remarks:
12.2 mg sodium chlorite/kg-bw/day or 9 mg chlorite/kg-bw/day
Dose / conc.:
600 mg/L drinking water
Remarks:
36.6 mg sodium chlorite/kg-bw/day or 27 mg chlorite/kg-bw/day
Dose / conc.:
1 200 mg/L drinking water
Remarks:
58.7 mg sodium chlorite/kg-bw/day or 44 mg chlorite/kg-bw/day
No. of animals per sex per dose:
16 or 17
Control animals:
yes, concurrent vehicle
Maternal examinations:
CLINICAL OBSERVATIONS: Yes
- Time schedule: Daily from day 3 of pregnancy. The appearance time, degree and continuance of clinical signs were noted.

BODY WEIGHT: Yes
- Time schedule for examinations: Weighed on day 0 of pregnancy at the supplier’s premises. Bodyweights were recorded daily from day3 to day 22 and on days 25 and 28 of pregnancy.
FOOD CONSUMPTION AND COMPOUND INTAKE: Yes
- The amount of food was recorded every 2 days from day 3 to day 27 and over 1 day from day 27 to day 28 of pregnancy.
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes Water consumption was measured daily from day 3 to day 22 of pregnancy by weighing each water bottle after filling and weighing again 24 h later. During the dosing period (days 7 to 19 of pregnancy) residue drinking water formulations were discarded and replaced with fresh formulations daily.
Ovaries and uterine content:
Gravid uterine weightNumber of corpora luteaNumber and distribution of implantation sites. The implantations were classified as early or late resorptions.
Fetal examinations:
GENERALNr. of live foetuses, nr. of dead foetuses, foetal weight, external abnormalities
.SKELETALThe bones were identified and examined for normality with respect to shape, size and the extent of ossification.
SOFT TISSUEFoetuses were briefly fixed in alcohol prior to being skinned and dissected. The brain, eyes, palate and major organs and blood vessels in the thorax and abdomen were examined. The sex of the foetuses, as assessed from the appearance of the internal genitalia were recorded.
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
The only treatment – related observation was a dose – related reduction in the production of faecal pellets, which was associated with reductions in food consumption.
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Description (incidence):
There were no treatment related mortalities There were no treatment related mortalities.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Transient reductions in body weight gain were observed at 600 and 1200 ppm at the onset of dosing. The differences from the controls were statistically significant at 1200 ppm. At 200 ppm there were no difference from controls in bodyweight gain.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Statistically significant dose-related reduction in food consumption were observed at the onset at 600 and 1200 ppm. There were no treatment-related reductions in food consumption at 200 ppm.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Description (incidence and severity):
There was a dose-related effect of treatment on water consumption at 600 and 1200 ppm. At the onset of dosing, water consumption was reduced by over 50% at 1200 ppm and by 20 – 30% at 600 ppm. The differences were statistically significant. There was considered to be no effect of treatment on water consumption at 200 ppm.
Ophthalmological findings:
not examined
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
no effects observed
Description (incidence and severity):
There were no treatment-related abnormalities observed macroscopically at necropsy.
Neuropathological findings:
not examined
Other effects:
no effects observed
Other effects:
no effects observed
Description (incidence and severity):
Mean numbers of corpora lutea, implantations and live foetuses were similar in all groups and there was no adverse effect of treatment on post-implantation losses.
Dose descriptor:
LOAEL
Effect level:
600 mg/L drinking water
Basis for effect level:
other: maternal toxicity
Key result
Dose descriptor:
LOAEL
Effect level:
36 other: mg sodium chlorite/kg bw/day
Basis for effect level:
other: maternal toxicity
Dose descriptor:
LOAEL
Effect level:
27 other: mg chlorite/kg bw/day
Based on:
act. ingr.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
200 mg/L drinking water
Basis for effect level:
other: maternal toxicity
Key result
Dose descriptor:
NOAEL
Effect level:
12 other: mg sodium chlorite/kg bw/day
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
9 other: mg chlorite/kg bw/day
Based on:
act. ingr.
Basis for effect level:
other: maternal toxicity
Key result
Abnormalities:
no effects observed
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): not specified
Field "Description (incidence and severity)" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.DescriptionIncidenceAndSeverityFetalPupBodyWeightChanges): Mean foetal weight was slightly lower at 600 and 1200 ppm than in the control group, although this could not be definitely attributed to treatment. Mean foetal weight was similar to the control group at 200 ppm.
Changes in sex ratio:
no effects observed
Description (incidence and severity):
The sex ratio of the live foetuses was similar in all groups.
External malformations:
no effects observed
Description (incidence and severity):
There was no evidence of teratogenicity at any dose level.
Skeletal malformations:
not specified
Description (incidence and severity):
There was no evidence of teratogenicity at any dose level. At 600 and 1200 ppm there were slightly higher incidences of foetuses with retardation of ossification of some bones, than in the control group. This was not unexpected as there were lower mean foetal weights in these groups.
Other effects:
no effects observed
Description (incidence and severity):
There was no evidence of teratogenicity at any dose level.
Dose descriptor:
LOAEL
Effect level:
600 mg/L drinking water
Basis for effect level:
other: embryotoxicity
Key result
Dose descriptor:
LOAEL
Effect level:
36 other: mg sodium chlorite/kg bw/day
Basis for effect level:
other: embryotoxicity
Dose descriptor:
LOAEL
Effect level:
27 other: mg chlorite/kg bw/day
Based on:
act. ingr.
Basis for effect level:
other: embryotoxicity
Dose descriptor:
NOAEL
Effect level:
200 mg/L drinking water
Basis for effect level:
other: embryotoxicity
Key result
Dose descriptor:
NOAEL
Effect level:
12 other: mg sodium chlorite/kg bw/day
Basis for effect level:
other: embryotoxicity
Dose descriptor:
NOAEL
Effect level:
9 other: mg chlorite/kg bw/day
Based on:
act. ingr.
Basis for effect level:
other: embryotoxicity
Key result
Abnormalities:
no effects observed
Key result
Developmental effects observed:
not specified

Table A6_8_1(2)-1.   Table for Teratogenic effects: Maternal effects

Parameter

Control data

200 ppm

600 ppm

1200 ppm

dose-response
+ / -

historical

study

Number of dams examined

N/Aa

16

17

17

16

Clinical findings during application of test substance

N/A

N/Sb

N/S

N/S

N/S

Mortality of dams

(%)

N/A

1

(0.16)*

0

1

(0.16)*

0

Abortions

N/A

N/S

N/S

N/S

N/S

Body weight gain

N/A

Days 7 – 11 of pregnancy: transient loss

Food consumption

N/A

Days 7 – 11 of pregnancy: transient decrease

Water consumption

N/A

Significantly lower

Significantly lower

Pregnancies

N/A

13

13

12

14

Necropsy findings in dams dead before end of test

N/A

N/A

N/A

N/A

N/A

N/A

* Sacrificed in extremis – their condition was considered to be incidental and unrelated to sodium chlorite treatment

a N/A = not applicable

b N/S = not specified

Table A6_8_1(2)-2. Table for Teratogenic effects: Litter response (caesarean section data)

Parameter

Control data

200 ppm

600 ppm

1200 ppm

dose-response
+ / -

historical

study

Corpora lutea (Mean no. ± S.D)

N/A

11.9 ± 2.3

11.9 ± 1.9

12.8 ± 2.3

12.1 ± 2.7

Implantations (Mean no. ± S.D)

N/A

10.7 ± 2.2

10.8 ± 1.8

10.7 ± 2.4

10.1 ± 2.2

Total number of foetuses

N/A

111

125

108

124

Mean number of live foetuses

N/A

8.5 ± 2.9

9.6 ± 1.9

9.0 ± 2.6

8.9 ± 2.4

Pre-implantation loss (%)

N/A

10.4

8.4

16.1

14.9

Post-implantation loss (%)

N/A

21.3

11.1

15.4

12.6

Foetus weight (group mean) [g]

N/A

35 ± 4.2

35.8 ± 3.7

33.1 ± 2.6

33.2 ± 3.1

Foetal sex ratio [ratio m/f]

N/A

55:45

41:59

48:52

52:48

 

Table A6_8_1(2)-3. Table for Teratogenic effects examination of the foetuses

Parameter

Control data

200 ppm

600 ppm

1200 ppm

dose-response
+ / -

historical

Study

External and visceral malformations*

[%]

N/A

28.6

22.8

32.3

26.8

External and visceral anomalies*

[%]

N/A

1.5

0.5

6.6

2.6

Skeletal malformations*

[%]

N/A

0.0

0.8

5.4

0.0

Skeletal anomalies*

[%]

N/A

7.7

6.3

14.2

13.9

Conclusions:
Oral administration of sodium chlorite during organogenesis in the rabbit at 600 and 1200 ppm elicited dose related reductions in maternal water with consequent reductions in maternal food consumption, production of faecal pellets and body weight gain. Despite the maternal effects there was no evidence of embryo-lethality or teratogenicity. There was an indication of embryonic growth retardation but this was only slight, was not dose-related and could not conclusively be related to treatment. There was considered to be no effect of treatment on the mothers or on embryonic development at 200 ppm.
Executive summary:

The aim of the study was to determine the toxicity of the test material on the development of the rats.

The test procedure was: EPA OPP 83-3 (Prenatal Developmental Toxicity Study).

The test concentrations were: 0, 200, 600 and 1200 mg/L (0, 12.2, 36.6 and 58.7 mg sodium chlorite/kg/day or 0, 9, 27 and 44 mg chlorite/kg/day). Oral administration of sodium chlorite during organogenesis in the rabbit at 600 and 1200 ppm elicited dose related reductions in maternal water with consequent reductions in maternal food consumption, production of faecal pellets and body weight gain. Despite the maternal effects there was no evidence of embryo-lethality or teratogenicity. There was an indication of embryonic growth retardation but this was only slight, was not dose-related and could not conclusively be related to treatment. There was considered to be no effect of treatment on the mothers or on embryonic development at 200 ppm.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
9 mg/kg bw/day
Study duration:
subacute
Species:
rabbit
Quality of whole database:
Klimisch 1. This study was carried out in accordance with internationally valid GLP principles.
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

Chlorine dioxide and chlorite are characterized together for toxicity to reproduction because studies conducted with chlorite, the predominant degradation product of chlorine dioxide, are likely relevant to characterizing the toxicity of chlorine dioxide. In addition, studies conducted with chlorine dioxide may be relevant to characterizing the toxicity of chlorite. Chlorine dioxide is fairly unstable and rapidly dissociates, predominantly into chlorite and chloride, and to a lesser extent, chlorate. There is a ready interconversion among these species in water (before administration to animals) and in the gut (after ingestion). Therefore, what exists in water or the stomach is a mixture of these chemical species (i.e., chlorine dioxide, chlorite, chlorate) and possibly their reaction products with the gastrointestinal contents.

Key study: Experimental results: The test procedure was: EPA OPP 83-3 (Prenatal Developmental Toxicity Study). Oral administration of sodium chlorite during organogenesis in the rabbit at 600 and 1200 ppm elicited dose related reductions in maternal water with consequent reductions in maternal food consumption, production of faecal pellets and body weight gain. Despite the maternal effects there was no evidence of embryo-lethality or teratogenicity. There was an indication of embryonic growth retardation but this was only slight, was not dose-related and could not conclusively be related to treatment.


Justification for selection of Effect on developmental toxicity: via oral route:
Highest quality study (Klimish score =1) on developmental toxicity.

Justification for classification or non-classification

Based on the available data on effects on fertility and developmental toxicity, the substance is not classified according to the CLP Regulation (EC) no. 1272/2008.