Registration Dossier
Registration Dossier
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EC number: 231-836-6 | CAS number: 7758-19-2
Endpoint summary
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 was observed. 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. Nevertheless, the WHO have assigned this study a NOAEL of 35 ppm (2.9 mg chlorite/kg bw/day for males and 4 mg chlorite/kg bw/day for females, i.e. 4 mg sodium chlorite/kg bw/day for males and 5 mg sodium chlorite/kg bw/day for females) based on lower auditory startle amplitude, decreased absolute brain weight in the F1 and F2 generations and altered liver weights in two generations.
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
- 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
- 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 or test system 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: Equivalent to 4 (♂) and 5 (♀) mg/kg-bw/day (sodium chlorite). Decreases in water consumption 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.
- 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
- 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 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
- 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. Nevertheless, the WHO have assigned this study a NOAEL of 35 ppm (2.9 mg chlorite/kg bw/day for males and 4 mg chlorite/kg bw/day for females, i.e. 4 mg sodium chlorite/kg bw/day for males and 5 mg sodium chlorite/kg bw/day for females) based on lower auditory startle amplitude, decreased absolute brain weight in the F1 and F2 generations and altered liver weights in two generations.
- 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 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). 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. Nevertheless, the WHO have assigned this study a NOAEL of 35 ppm (2.9 mg chlorite/kg bw/day for males and 4 mg chlorite/kg bw/day for females, i.e. 4 mg sodium chlorite/kg bw/day for males and 5 mg sodium chlorite/kg bw/day for females) based on lower auditory startle amplitude, decreased absolute brain weight in the F1 and F2 generations and altered liver weights in two generations.
Reference
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 | - | - | - | - | - | - | - | - | |
Effect on fertility: via oral route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 4 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: 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 (36 and 58 mg sodium chlorite/kg bw/day) 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 (12 mg sodium chlorite/kg bw/day).
Key study: OECD 414 (GLP study). A prenatal developmental study by oral route was performed with sodium chlorite in rats. The NOAEL for maternal toxicity could not be established due to macroscopic lesions in all the treated groups (LOAEL = 5 mg/kg bw/day). The NOAEL for fetal toxicity could be established at 25 mg/kg bw/day (highest dose tested) since no test item-related and toxicologically relevant external, visceral, craniofacial and skeletal findings were observed in the foetuses of the treatment groups.
Link to relevant study records
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- From 11 May 2021 to 19 July 2021
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
- Species:
- rat
- Strain:
- Wistar
- Remarks:
- Crl:WI(Han)
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River, 97633 Sulzfeld, Germany
- Age at study initiation: 11-13 weeks old
- Weight at study initiation: before initiation of pairing: males: 322 - 383 g; females: 185 - 258 g
- Fasting period before study: No
- Housing: The animals were kept individually in IVC cages (type III H, polysulphone cages) on Altromin saw fibre bedding.
- Diet: ad libitum access to Altromin 1324 maintenance diet
- Water: ad libitum access to drinking tap water
- Acclimation period: at least five days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3 °C
- Humidity (%): 55 ± 10%
- Air changes (per hr): 10x / hour
- Photoperiod (hrs dark / hrs light): 12/12 - Route of administration:
- oral: gavage
- Vehicle:
- water
- Remarks:
- aqua ad injectionem
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
A correction factor of 3.15 was applied to consider the amount of active components in the test item. The test item was weighed into a tared vial on a suitable precision balance and the vehicle was added to give the appropriate final concentration of the test item. The formulation was vortexed and/or stirred until visual homogeneity was achieved. The prepared formulation was stored protected from light and at room temperature.
VEHICLE
- Concentration in vehicle: 0.5, 1.25 and 2.5 mg/mL
- Amount of vehicle: 10 mL/kg bw/day
- Lot/batch: 2005066 - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Before beginning of the treatment period, formulation samples of 0.5, 1, 12.5 and 25 mg/mL were prepared and analysed in order to obtain knowledge about stability and homogeneity of the test item in the selected vehicle. The formulations were stable for 6 h and for 10 days at room temperature and for 10 days at 2 to 8 and -15 to -35 °C. The test item formulation was shown to be homogenous. Samples (duplicates) were taken for substance concentration determination by a previously validadted analytical method. in the first and in the last week of the study for all doses (8 samples in total).
- Details on mating procedure:
- - Impregnation procedure: cohoused
- M/F ratio per cage: 1:2
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy. - Duration of treatment / exposure:
- 7 days per week from GD 5 to GD 19.
- Frequency of treatment:
- Once a day
- Duration of test:
- From 11 May 2021 to XXXX
- Dose / conc.:
- 5 mg/kg bw/day (nominal)
- Remarks:
- Low dose
- Dose / conc.:
- 12.5 mg/kg bw/day (nominal)
- Remarks:
- Mid dose
- Dose / conc.:
- 25 mg/kg bw/day (nominal)
- Remarks:
- High dose
- No. of animals per sex per dose:
- 23
- Control animals:
- yes, concurrent no treatment
- Details on study design:
- - Dose selection rationale: Based on a dose range finding study (see endpoint "Developmental toxicity / teratoginicity DRF"), the highest dose of 25 mg/kg bw/day was chosen with the aim of inducing toxic effects, but not death or severe suffering.
- Fasting period before blood sampling for (rat) dam thyroid hormones: No
- Time of day for (rat) dam blood sampling: Haematological parameters from all dams were examined at the end of the treatment period prior to or as part of the sacrifice of the animals - Maternal examinations:
- CLINICAL OBSERVATIONS: Yes
- Time schedule: General clinical observations were made at least once a day. Twice daily all animals were observed for morbidity and mortality except on weekends and public holidays when observations were made once daily.
- Cage side observations included: spontaneous activity, lethargy, recumbent position, convulsions, tremors, apnoea, asphyxia, vocalisation, diarrhoea, changes in the skin and fur, eyes and mucous membranes (salivation, discharge), piloerection and pupil size. Changes in gait, posture, response to handling as well as the presence of clonic or tonic movements, stereotypes, difficult or prolonged parturition or bizarre behaviour were recorded.
BODY WEIGHT: Yes
- Time schedule for examinations: All animals were weighed once before initiation of pairing. The sperm-positive females were weighed on gestation days 0, 5, 8, 11, 14, 17 and 20.
FOOD CONSUMPTION: Yes. Food consumption of the pregnant females was controlled on days of body weight determination.
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Observations: Each dam was examined macroscopically for any structural abnormalities or pathological changes. Any macroscopic findings were preserved in 4% neutral-buffered formaldehyde. Organs: all gross lesions, kidneys, liver, larynx, lungs, nasal cavities, oesophagus, spleen, stomach, trachea, ovaries, thymus.
- Histopathology: Thyroid/parathyroid glands from all dams were preserved in 4% neutral-buffered formaldehyde. The weight of thyroid/parathyroid glands was measured after 24 hour fixation. - Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes - Blood sampling:
- - Blood: Yes (for haematology parameters)
- Serum: Yes (for thyroid hormones)
- Volume: 500 µL
- Haematology parameters: haematocrit value (HCT); haemoglobin content (HGB); red blood cell count (RBC); mean corpuscular volume (MCV); mean corpuscular haemoglobin (MCH); mean corpuscular haemoglobin concentration (MCHC)
reticulocytes (RET); platelet count (PLT); white blood cells (WBC); neutrophils (Neut); lymphocytes (Lym); monocytes (Mono); eosinophils (Eos); basophils (Baso); large unstained cells (Luc).
- Thyroid hormones: T3, T4, TSH. - Fetal examinations:
- - External examinations: Yes: all per litter
- Reproductive tract: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: Yes: half per litter
- Anogenital distance of all live rodent pups: Yes: all per litter - Statistics:
- A statistical assessment of the results of the body weight and food consumption was performed by comparing values of dosed animals with control animals using a one-way ANOVA and a post-hoc Dunnett Test. Results of absolute and relative organ weights, thyroid hormones and foetal evaluation parameters like external, visceral, craniofacial and skeletal parameters were statistically analysed by comparing values of dosed with control animals using either a parametric one-way ANOVA and a post-hoc Dunnett Test or a non-parametric Kruskal-Wallis Test and a post-hoc Dunn’s Test, based on the results of homogeneity and normality tests. The statistics were performed with GraphPad Prism V.6.01 software or Ascentos 1.3.4 software (p<0.05 is considered as statistically significant).
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- None of the females showed signs of abortion or premature delivery prior to the scheduled sacrifice.
Clinical signs observed which includes skin and fur, hairless area in one animal of the low dose group on right forepaw and one animal of the high dose group had hairless at right forepaw and abdomen. These clinical signs are considered to be incidental findings. No clinical signs were observed in mid dose group.
On the high dose group an animal showed slight spontaneous reduced activity, moving the bedding, slight wasp waist, nasal discharge, red urine and slight piloerection at post dose observation on days 16-18. One animal showed slight, spontaneous reduced activity. Another animal showed slight piloerection. Clinical signs observed in these animal are considered to be test item related during the treatment period. No clinical signs of toxicity or test item related were observed in low and mid dose groups. - Mortality:
- mortality observed, treatment-related
- Description (incidence):
- In the high dose group two animals were euthanized (before the date of scheduled sacrifice) due to animal welfare reasons and clinical signs of toxicity. One of the animals showed vocalization, moderate spontaneous reduced activity, moving the bedding, moderate wasp waist, moderate piloerection, slight increased salivations and red urine at post dose observation day 10. The other animal showed moderate spontaneous reduced activity, moderate piloerection and abnormal breathing at post dose observation day 14. These findings are considered to be test item related findings. Both rats were found to be pregnant at necropsy observation. No mortality occurred in other treated group and control during the treatment period. All other females survived until the date of scheduled sacrifice.
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- There were no test item related changes in mean body weight and mean body weight gain observed when compared to control on GDs 5-20.
- Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- The mean food consumption observed during GDs 5-20 comparable to control. No statistical significance was observed in mean food consumptions. No test item-related effect on mean food consumption was observed in the treated groups.
- Haematological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- At haematological evaluation, slight but statistically significant lower mean RBC count was observed in high dose group (9.43% below control) when compared to control. Haemoglobin was slightly lowered in high dose groups (8.97% below control) but without statistical significance. Statistically significant higher percent reticulocytes were observed in high dose group (181.11% above control) when compared to control. Statistically significant higher mean reticulocytes count was observed in high dose group (98.36% above control) when compared to control. The statistical significant higher reticulocytes were observed due to two individual animal abnormal values of reticulocytes in two animals at the highest dose. However, there were slight trend in decrease in mean RBC count, mean haemoglobin values and increase in mean reticulocytes count/percentage were observed in high dose groups and It is considered to be test item related findings.
Increase or decrease mean WBC count and/or percent eosinophils, basophils and leucocytes were observed in treated groups without dose dependency or statistical significance, hence they are not considered to be test item related. - Endocrine findings:
- no effects observed
- Description (incidence and severity):
- In all terminally sacrificed females, no statistically significant or toxicologically relevant effects were observed on group mean T3, T4 and TSH hormone levels and values were comparable to the control.
Statistical analysis of post-fixed thyroid/parathyroid weights from all dams revealed, no statistically significant differences in the absolute and relative (to body weight) thyroid/parathyroid weights of the treated groups when compared to the control.
At the histopathology evaluation, there were no histology changes in the thyroid and parathyroid glands that could be related to the treatment with the test item - Gross pathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- On the control group, one animal showed dark red lungs and liver, and thymus with spotted was found at necropsy.
At the low dose group, in seven animals, findings in heart (adhesion), lungs (dark red), oesophagus (black coloured), liver (dark red), kidneys (dark colored), spleen (enlarged), thymus (small, spotted or red) and/or head (abnormal red color) were observed at necropsy.
At the mid dose group, in eight animals, findings in stomach (spotted and abnormal coloured), colon (gas filled), lungs (supernumerary lobe), kidneys (right pelvis dilatation), ovaries (cyst), adrenal glands (dark coloured and enlarged), spleen (enlarged), thymus (small size or spotted red) or parotid lymph node (swollen) were observed at necropsy.
At the high dose group, in ten animals, findings in spinal cord(black coloured), thoracic cavity (clear fluid filled and pale, small or enlarged thymus), heart (adhesion), lungs (dark red or adhesion), stomach (gas filled), duodenum and ileum (dark red), peyer's patches (enlarged), cecum (yellow fluid), pancreas (pale), kidneys (black), urinary bladder (dark red fluid filled), adrenals (enlarged), spleen (black or enlarged), vagina (dark red fluid), lumbar node (enlarged) and head (atrophie) were observed at necropsy.
These findins cannot be excluded to be test substance related, since these findings were also evidenced in the dose range finding study as well. - Histopathological findings: non-neoplastic:
- effects observed, non-treatment-related
- Description (incidence and severity):
- No test item-related histopathological findings were observed in thyroid glands and parathyroid of all females.
- Number of abortions:
- no effects observed
- Description (incidence and severity):
- None of the females showed signs of abortion or premature delivery prior to the scheduled sacrifice.
- Pre- and post-implantation loss:
- no effects observed
- Description (incidence and severity):
- No test item-related effects of toxicological relevance were noted for any prenatal parameters including implantation sites.
- Total litter losses by resorption:
- no effects observed
- Description (incidence and severity):
- No test item-related effects of toxicological relevance were noted for any prenatal parameters including losses by resorption.
- Early or late resorptions:
- no effects observed
- Description (incidence and severity):
- No test item-related effects of toxicological relevance were noted for any prenatal parameters including late resorptions.
- Dead fetuses:
- no effects observed
- Description (incidence and severity):
- No test item-related effects of toxicological relevance were noted for any prenatal parameters including number of live foetuses. No dead foetuses were noted in any of the groups.
- Changes in pregnancy duration:
- no effects observed
- Changes in number of pregnant:
- no effects observed
- Other effects:
- no effects observed
- Description (incidence and severity):
- No test item-related effects of toxicological relevance were noted for any prenatal parameters including terminal body weight, adjusted maternal weight (carcass weight), uterine weight, number of corpora lutea.
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- < 5 mg/kg bw/day (nominal)
- Based on:
- act. ingr.
- Basis for effect level:
- gross pathology
- Key result
- Abnormalities:
- no effects observed
- Fetal body weight changes:
- no effects observed
- Description (incidence and severity):
- No test item-related and statistically significant effects in mean foetal weight, male and female foetal weight on a per litter basis (group mean of individual litter mean) were observed in any of the treated groups when compared to the control group.
- Reduction in number of live offspring:
- no effects observed
- Changes in sex ratio:
- no effects observed
- Description (incidence and severity):
- No test item-related effects of toxicological relevance were noted for any prenatal parameters including number of male foetuses and sex ratios in treatment groups when compared to the control group.
- Changes in litter size and weights:
- no effects observed
- Anogenital distance of all rodent fetuses:
- no effects observed
- Description (incidence and severity):
- In males and female foetuses, the absolute and relative anogenital distance (AGD) in treatment groups remained unaffected when compared to the control group.
All male foetuses were checked for indications of incomplete testicular descent/ cryptorchidism and evaluation revealed the completion of testicular descent (abdominal) in all male foetuses from all groups. - External malformations:
- no effects observed
- Description (incidence and severity):
- No test item-related external abnormalities were observed in any of the treated groups.
- Skeletal malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Wavy ribs are typically classified as transient and reversible post-natally and may thus be considered as variations but not malformations. Observed ossification-related findings were observed at lower or higher incidences and without dose-dependency and thus were not considered as toxicologically relevant. There were also slightly higher or lower litter incidences of skeletal findings in the LD and MD groups, but they did not show any statistical significance or dose dependency.
- Visceral malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Visceral findings observed in the treated groups were at frequencies generally comparable to or, in some cases, slightly higher or lower in frequency compared to the control. As the observed findings were either minor variations and/or due to a lack of dose dependency and consistency, no toxicological significance can be attributed to these findings and they were considered to be spontaneous in nature. In addition, all these values were within the historical control range for this strain.
- Other effects:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Craniofacial examination findings were considered to be spontaneous in nature and not related to the treatment with the test item. Statistical analysis of the data revealed no statistical significance for any of these findings. In addition, all values were within the historical control range for this strain.
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- > 25 mg/kg bw/day
- Based on:
- act. ingr.
- Remarks on result:
- not determinable due to absence of adverse toxic effects
- Key result
- Abnormalities:
- effects observed, non-treatment-related
- Key result
- Developmental effects observed:
- no
- Conclusions:
- The NOAEL for maternal toxicity could not be established due to macroscopic lesions in all the treated groups. The NOAEL for fetal toxicity could be established at 25 mg/kg bw/day (highest dose tested) since no test item-related and toxicologically relevant external, visceral, craniofacial and skeletal findings were observed in the foetuses of the treatment groups.
- Executive summary:
A prenatal developmental test in rats was performed according to OECD Guideline 414 (GLP test). Sodicum chlorite was administered daily by gavage from gestation day (GD) 5 to 19 to 23 pregnant rats per group at 5 (LD), 12.5 (MD) and 25 (HD) mg/kg bw/day. During the period of administration, the animals were observed precisely each day for signs of toxicity and mortality. Body weight and food consumption were measured on GD 0, 5, 8, 11, 14, 17 and 20. Animals that died during the study were examined macroscopically. All surviving female animals were sacrificed on the respective GD 20. Following the gross necropsy, the uteri and ovaries were removed, weighed and examined for number of implantations, resorptions (early and late), live and dead foetuses. Foetuses were identified using numbered plates, sexed and weighed. All foetuses were observed for external abnormalities, half of the foetuses for visceral and craniofacial abnormalities and the remaining half of the litter was observed for skeletal abnormalities. The uteri of the non-pregnant females were processed with 10% ammonium sulphide solution and checked for the early embryonic deaths. Thyroid/parathyroid glands from all dams were preserved. The weight of thyroid/parathyroid glands was measured after fixation. Blood samples were assessed for serum levels for thyroid hormones. A histopathological evaluation of the preserved thyroid/parathyroid glands was performed. Two HD group animals were euthanized due to animal welfare reason and clinical signs of toxicity. Based on clinical signs and gross lesion at necropsy observations, this mortality is considered to be test item related. No mortality occurred in other treated group and control during the treatment period. All other females survived until the date of scheduled sacrifice. Test item-related clinical signs were observed in three animals of HD groups; includes spontaneous reduced activity, moving the bedding, slight wasp waist, nasal discharge, red urine, piloerection, vocalization, increased salivations and abnormal breathing. No clinical signs of test item related were observed in LD and MD groups. No test item-related effects on mean body weight gain and food consumption were observed in any of the treated animals during the study. No test item-related effects were observed on prenatal parameters including terminal body weight, adjusted maternal weight (carcass weight), uterine weight, number of corpora lutea, implantation sites, early and late resorptions, percent pre- and post-implantation loss, number of live foetuses, anogenital distance (AGD), foetal weight, number of male and female foetuses, sex ratio and testicular descent in treatment groups when compared to the control. No test item or statistically significant or toxicologically relevant effect was observed on group mean T3, T4 and TSH hormone levels and no test item related changes were observed in thyroid/parathyroid weights from all dams. No gross or histopathological lesions were observed in thyroid/parathyroid glands. The macroscopic findings observed in dams in heart (adhesion), lungs (abnormal color, fluid filled, adhesion), stomach/intestine (abnormal color, enlarged), liver (abnormal color, enlarged), kidneys (abnormal color), thymus (abnormal color, adhesion and small), spleen (enlarged) and adrenals (enlarged) in the treated groups cannot be excluded to be test item related effects. Furthermore, no test item-related and toxicologically relevant external, visceral, craniofacial and skeletal findings were observed in the foetuses of treatment groups. Therefore, the NOAEL for maternal toxicity could not be established due to macroscopic lesions in all the treated groups. The NOAEL for fetal toxicity could be established at 25 mg/kg bw/day (highest dose tested).
- 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
- 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 or test system 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
- 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.
Referenceopen allclose all
Dose formulation analysis:
Nominal concentrations were confirmed for all dose groups, as measured concentrations were within acceptance criterion of 10%.
Summary of macroscopic findings (dams):
| Tissue/Organs | Macroscopic Observations | Groups | |||
| Control(0 mg/kg bw/day) | LD(5 mg/kg bw/day) | MD(12.5 mg/kg bw/day) | HD(25 mg/kg bw/day) | ||
| No. of animals | 23 | 23 | 23 | 23 | |
| Spinal cord | Abnormal colour, black | 0 | 0 | 0 | 1 (78+) |
| Thoracic cavity | Fluid filled clear | 0 | 0 | 0 | 1 (84+) |
| Heart | Adhesion | 0 | 1 (24) | 0 | 2 (71, 84+) |
| Lung | Dark, dark read | 1 (8) | 0 | 0 | 2 (78+, 84+) |
| Adhesion | 1 (22) | 0 | 0 | 1 (71) | |
| Stomach | Abnormal colour, spotted | 0 | 0 | 1 (57) | 0 |
| Gas filled | 0 | 0 | 0 | 1 (78+) | |
| Fluid filled, yellow | 0 | 0 | 0 | 1 (77) | |
| Duodenum | Abnormal colour, dark red | 0 | 0 | 0 | 1 (78+) |
| Jejunum | Abnormal colour, dark red | 0 | 0 | 0 | 1 (78+) |
| Ileum | Abnormal colour, dark red | 0 | 0 | 0 | 1 (78+) |
| Peyer’s patches | Enlarged | 0 | 0 | 0 | 1 (78+) |
| Cecum | Fluid filled, yellow | 0 | 0 | 0 | 1 (78+) |
| Colon | Gas filled | 0 | 0 | 1 (56) | 0 |
| Liver | Abnormal colour dark red | 1 (8) | 1 (29) | 0 | 0 |
| Supernumerary lobe | 0 | 0 | 1 (65) | 0 | |
| Pancreas | Abnormal colour, pale | 0 | 0 | 0 | 1 (78+) |
| Kidney | Abnormal colour, black, dark | 0 | 1 (30) | 0 | 3 (78+, 84+, 77) |
| Dilatation | 0 | 0 | 1 (67) | 0 | |
| Urinary bladder | Fluid filled, dark red | 0 | 0 | 0 | 1 (78+) |
| Ovaries | Cyst | 0 | 0 | 2 (56, 63) | 0 |
| Vagina | Fluid filled, dark red | 0 | 0 | 0 | 1 (84+) |
| Thyroid gland | Abnormal colour, pale | 0 | 0 | 0 | 1 (77) |
| Parathyroid glands | Abnormal colour, pale | 0 | 0 | 0 | 1 (77) |
| Adrenal glands | Abnormal colour, dark, reddish | 0 | 0 | 1 (58) | 1 (84+) |
| Enlarged | 0 | 0 | 2 (58, 54) | 2 (84+, 78+) | |
| Spleen | Abnormal colour, black | 0 | 0 | 0 | 1 (78+) |
| Enlarged | 0 | 1 (33) | 4 (49, 51, 56, 61) | 8 (71, 77, 80, 81, 83, 84+, 85, 90) | |
| Thymus | Abnormal color, pale, red, spotted | 2 (7, 8) | 2 (40, 31) | 0 | 1 (84+) |
| Adhesion | 0 | 0 | 0 | 1 (71) | |
| Enlarged | 0 | 0 | 0 | 1 (78+) | |
| Small | 0 | 1 (32) | 1 (58) | 1 (77) | |
| Attached to heart | 0 | 1 (24) | 0 | 0 | |
| Mesentric Lymphnode | Enlarged | 0 | 0 | 0 | 1 (78+) |
| Parotid lymph node | Swelling | 0 | 0 | 1 (51) | 0 |
| Lumbar lymph node | Enlarged | 0 | 0 | 0 | 2 (83, 90) |
| Abdominal cavity | Adhesion | 0 | 0 | 0 | 1 (78+) |
| Head | Abnormal colour, red | 0 | 1 (30) | 0 | 0 |
| Atrophie | 0 | 0 | 0 | 1 (76) | |
(animal) (+ = intercurrent death)
All the above macroscopic findings observed in the LD, MD and HD groups cannot be excluded to be test item related, since these findings were also evidenced in the dose range finding study.
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 |
||||||||||||
Effect on developmental toxicity: via oral route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 12 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.
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.
Additional information
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
