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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

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

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
1990
Reference Type:
publication
Title:
Developmental toxicity of sodium chlorite in the rabbit.
Author:
Harrington RM, Romano RR and Irvine L
Year:
1995
Bibliographic source:
Journal of the American College of Toxicology, 14(2): 108-118

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
EPA OPP 83-3 (Prenatal Developmental Toxicity Study)
Deviations:
no
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Sodium chlorite
EC Number:
231-836-6
EC Name:
Sodium chlorite
Cas Number:
7758-19-2
Molecular formula:
ClHO2.Na
IUPAC Name:
sodium chlorite
Details on test material:
Lot/Batch number: 9NF25810B
Description: White flaky powder
Purity: 80.58 %

Test animals

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)

Administration / exposure

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
Doses / concentrationsopen allclose all
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

Examinations

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.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

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

Maternal developmental toxicity

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.

Effect levels (maternal animals)

open allclose all
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

Maternal abnormalities

Key result
Abnormalities:
no effects observed

Results (fetuses)

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.

Effect levels (fetuses)

open allclose all
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

Fetal abnormalities

Key result
Abnormalities:
no effects observed

Overall developmental toxicity

Key result
Developmental effects observed:
not specified

Any other information on results incl. tables

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

Applicant's summary and conclusion

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.