Freitag, 26. Februar 2016

Toxicity to reproduction.001 to 005

Toxicity to reproduction.001

Administrative data

Study result type:
experimental result
Study period:
no data
Reliability:
4 (not assignable)

Data source

Reference
Reference Type:
publication
Title:
Effects of chlorine dioxide on thyroid function in neonatal rats.
Author:
Orme J, Taylor DH, Laurie RD and Bull RJ
Year:
1985
Bibliographic source:
Journal of Toxicology and Environmental Health, 15: 315 - 322

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Rat dams were exposed to chlorine dioxide in the drinking water for 2 weeks prior to mating and throughout gestation and lactation at concentrations of 2, 20 and 100 mg/L
GLP compliance:
no data
Test type:
other: neurotoxicity on pups
Limit test:
no

Test materials

Identity of test material same as for substance defined in section 1 (if not read-across):
yes
Test material identityopen allclose all
Details on test material:
no data

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Age at study initiation: siwty-d-old females
No other information

Administration / exposure

Route of administration:
oral: drinking water
Vehicle:
water
Details on exposure:
no data
Details on mating procedure:
no data
Analytical verification of doses or concentrations:
no data
Details on analytical verification of doses or concentrations:
no data
Duration of treatment / exposure:
from 14 days prior to breeding until pups were weaned at 21 days of age.
Frequency of treatment:
ad libitum
Details on study schedule:
End of study: postnatal day 60
Doses / concentrations
Doses / concentrations:
2, 20 and 100 mg/L
Basis:
actual ingested
No. of animals per sex per dose:
8 males per litter were examined
Control animals
Control animals:
yes, concurrent vehicle
Further details on study design:
no data
Positive control:
Propylthiouracil (PTU) at 5 mg/L, as a well-known antithyroid compound

Examinations

Parental animals: Observations and examinations:
Dam food and water consumption as well as dam and pup body weights were monitored weekly.
Estrous cyclicity (parental animals):
no data
Sperm parameters (parental animals):
no data
Litter observations:
Age of eye opening for pups was noted.
Litter activity is monitored continuously between 14 and 21 days postpartum by an Hp 9825 computer, which records the data at 10 min intervals.
Postmortem examinations (parental animals):
Thyroid function was determined in dam by triiodothyronine (T3) and thyroxine (T4) radioimmunoassays. Blood samples were collected from dams by cardiac puncture. Serum, separated from the samples, was frozen prior to analysis.
Postmortem examinations (offspring):
Upon weaning, pups were removed from the cages and serum samples were collected to assess thyroid function.
Thyroid function was determined in pup serum by triiodothyronine (T3) and thyroxine (T4) radioimmunoassays. Blood samples were collected from pups by decapitation. Serum, spearated from teh samples, was frozen prior to analysis.
Statistics:
SAS ANOVA procedure
Reproductive indices:
no data
Offspring viability indices:
no data

Results and discussion

Effect levelsopen allclose all

Results of examinations: parental animals

Clinical signs (parental animals):
no effects
Body weight and food consumption (parental animals):
no effects
Test substance intake (parental animals):
no data
Reproductive function: estrous cycle (parental animals):
not examined
Reproductive function: sperm measures (parental animals):
not examined
Reproductive performance (parental animals):
not examined
Organ weights (parental animals):
not examined
Gross pathology (parental animals):
not examined
Histopathology (parental animals):
not examined
Details on results (parental animals):
no effect

Results of examinations: offspring

Viability (offspring):
no data
Clinical signs (offspring):
no effects
Body weight (offspring):
no effects
Sexual maturation (offspring):
not examined
Organ weights (offspring):
not examined
Gross pathology (offspring):
no data
Histopathology (offspring):
no data
Details on results (offspring):
No significant treatment-related effects were seen in pup body weights or age at eye opening. Consistent, but not significantly lower activity levels were observed in 100 mg/L pups, relative to controls, on postpartum days 15–20. At 100 mg/L, pups also exhibited significantly depressed serum T4 and elevated T3 levels, relative to controls, when tested on postpartum day 21. A significant correlation was noted between T4 levels and locomotor activity.
Any other information on results incl. tables:
no other information

Applicant's summary and conclusion

Conclusions:
LOAEL was determined to be 14 mg/kg bw/day based on altered serum thyroid hormone levels.
Executive summary:
Chlorine dioxide was administered to Sprague-dawley rats indirectly in drinking water at dose level of 2, 20 and 100 mg/L from 14 days prior to breeding until the pups reached 21 years of age.
No significant treatment-related effects were seen in pup body weights or age at eye opening. Consistent, but not significantly lower activity levels were observed in 100 mg/L pups, relative to controls, on postpartum days 15–20. At 100 mg/L, pups also exhibited significantly depressed serum T4 and elevated T3 levels, relative to controls, when tested on postpartum day 21. A significant correlation was noted between T4 levels and locomotor activity.
LOAEL was determined to be 100 mg/L (14 mg/kg bw/day) based on altered serum thyroid hormone levels.















Toxicity to reproduction.005

Administrative data

Purpose flag:
key study
Study result type:
read-across from supporting substance (structural analogue or surrogate)
Study period:
No data
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
Considering the metabolism pathway of chlorine dioxyde which is likely to undergo rapid redox reactions within biological tissues rather than to be absorbed as parent compound, this study can be used for the assessment of ClO2.

Data source

Reference
Reference Type:
publication
Title:
Two-generation reproduction and development neurotoxicity study with sodium chlorite in the rat
Author:
Gill MW, Swanson MS, Murphy SR and Bailey GP
Year:
2000
Bibliographic source:
Journal of Applied Toxicology, 20: 291-303

Materials and methods

Test guidelineopen allclose all
Principles of method if other than guideline:
Not applicable
GLP compliance:
no data
Test type:
two-generation study
Limit test:
no

Test materials

Identity of test material same as for substance defined in section 1 (if not read-across):
no
Test material identityopen allclose all
Identifier:
CAS number
Identity:
7758-19-2
Identifier:
EC number
Identity:
231-836-6
Identifier:
IUPAC name
Identity:
sodium chlorite
Details on test material:
- Name of test material (as cited in study report): Sodium chlorite
- Analytical purity: 81.4 %
- Impurities (identity and concentrations): Sodium chloride and small amount of Sodium hydroxide and Sodium chlorate

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Iffa Credo, Belgium.
- Age at study initiation: approximately 6 weeks old at the start of F0 prebreed exposure period.
- Weight at study initiation: (P) Males: 80-99 g; Females: 60-79 g
- Housing: - during mating: one male was housed with each female
- during pregnancy: each female was housed individually
- during period of lactation: each dam was housed with its litter, in solid-bottomed polypropylene cages with sawdust bedding.
- Diet: pelleted SQC Rat and Mouse No. 3 expanded diet, Special Diets Services Limited, Witham, Essex (UK) ad libitum.
- Water: purified water (with or without chemical) provided from polycarbonates bottles fitted with stainless-steel tops and sipper tubes ad libitum
- Acclimation period: no data

ENVIRONMENTAL CONDITIONS
- Temperature: appropriate
- Humidity: appropriate
- Air changes: no data
- Photoperiod: appropriate

Administration / exposure

Route of administration:
oral: drinking water
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: direct addition of the test material to purified water (UHP). Treated drinking wter were made fresh each week.
Details on mating procedure:
- M/F ratio per cage: 1:1
- Length of cohabitation: no data
- Proof of pregnancy: no data
- After successful mating each pregnant female was caged individually
- Any other deviations from standard protocol: due to a reduced number of litters observed in the F1-F2a generation, the F1 generation animals were re-paired following weaning of the F2a generation to produce and F2b generation.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The homogeneity, stability and concentration of sodium chlorite in the drinking water solutions were evalued analytically. The results of these analysis confirmed that the treated drinking water solutions were homogeneous and stable under the conditions of use. The concentration of sodium chlorite in the drinking water was adjusted to account fot the purity of the test substance.
Duration of treatment / exposure:
The F0 and F1 animals received treated drinking water through a 10-week prebreed period as well as during mating, gestation, parturition and lactation.
Frequency of treatment:
Continuously
Details on study schedule:
- Selection of parents from F1 generation: at weaning
Doses / concentrations
Doses / concentrations:
0, 35, 70 and 300 ppm
Basis:
nominal in water
Remarks:
Dose concentrations decreased by 50% to 0, 17.5, 35 and 150 ppm during lactation.
No. of animals per sex per dose:
25-30 animals/sex/group
Control animals
Control animals:
yes, concurrent vehicle
Further details on study design:
- Dose selection rationale: based on the results of a 90-day oral (gavage) toxicity study in rats, an oral (drinking water) developmental toxicity study in rabbits and an oral (drinking water) dose range-finding study in rats. The highest concentration selected (3000 ppm) was expected to be high enough to cause some systemic toxicity and to satisfy the regulatory requirement for a maximum tolerated dose, but not so high as to jeopardize the health of the animals as a result of decreases in palatability and water consupmtion. The 70 and 35 ppm concentrations were expected to produce graded effects or no effects.
Positive control:
No

Examinations

Parental animals: Observations and examinations:
CLINICAL OBSERVATIONS: Yes

BODY WEIGHT: Yes

FOOD CONSUMPTION: Yes

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
Estrous cyclicity (parental animals):
Yes.
Sperm parameters (parental animals):
Sperm number, sperm motility and sperm morphology.
Sperm number and motility were measured using an automated computer-assisted sperm motility analysis (CASA) system (Hobson Tracker, Uk)
Litter observations:
STANDARDISATION OF LITTERS: No data

PARAMETERS EXAMINED
The following parameters were examined in F1 and F2 offspring: bodyweights and bodyweights changes , landmarks of pup development and sexual maturation.

OTHER EXAMINATIONS:
- Hematological and thyroid hormone evaluation 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.
- Neurotoxicological assessments were made on F1 and F2 generation
Postmortem examinations (parental animals):
HISTOPATHOLOGY: microscopic evaluation of gross lesions and reproductive organs from animals of the high-dose and control groups or any animals with suspected reduced fertility.
Postmortem examinations (offspring):
SACRIFICE
- The F1 offspring not selected as parental animals and all F2 offspring were sacrificed at 25 days of age.

GROSS NECROPSY
- Gross external evaluation

HISTOPATHOLOGY / ORGAN WEIGTHS
- Tissues prepared for microscopic examination and weighed: brain, liver, adrenals, spleen, thymus, kidneys, testes/ovaries
Statistics:
Interval data were subjected to an analysis of variance (ANOVA) with the absolute residuals from this analysissubjected to Levene’s test to identify possible differences in variances between treatment groups. For data with equal variances (P > 0.01), pairwise tests of all treated groups versus control were performed using William’s test. For a comparison of the high dose versus the control group, a two-sided test was performed with statistical significance noted at the P< 0.05, 0.01 and 0.001 levels. If the comparison of the high dose with the control group was not significant, one-sided tests were perfomed comparing the lower groups to the control. For data with unequal variances the Kruskall-Wallis-non-parametric ANOVA and Shirley’s non-parametric equivalent of Williams’ test were performed.
For nominal data Fisher’s Exact test was used to compare each treated group with the control.
Reproductive indices:
Mating index (%), Fertility index (%), Gestation index (%)
Offspring viability indices:
Viability and survival indices

Results and discussion

Effect levelsopen allclose all
Endpoint:
LOAEL
Generation:
P
Sex:
male/female
Effect level:
70 ppm (nominal)
Based on:
test mat.
Basis for effect level / Remarks:
Hematological toxicity
Endpoint:
NOAEL
Generation:
P
Sex:
male/female
Effect level:
300 ppm (nominal)
Based on:
test mat.
Basis for effect level / Remarks:
overall effects
Endpoint:
NOAEL
Generation:
other: fertility
Sex:
male/female
Effect level:
300 ppm (nominal)
Based on:
test mat.
Basis for effect level / Remarks:
overall effects
Endpoint:
NOAEL
Generation:
other: reproduction
Sex:
male/female
Effect level:
300 ppm (nominal)
Based on:
test mat.
Basis for effect level / Remarks:
overall effects

Results of examinations: parental animals

Clinical signs (parental animals):
no effects
Body weight and food consumption (parental animals):
yes
Remarks:
Reduced body weights, food and water consumption
Test substance intake (parental animals):
no data
Reproductive function: estrous cycle (parental animals):
no effects
Reproductive function: sperm measures (parental animals):
no data
Reproductive performance (parental animals):
no effects
Organ weights (parental animals):
no data
Gross pathology (parental animals):
no effects
Histopathology (parental animals):
no effects
Details on results (parental animals):
CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
No treatment-related clinical signs of toxicity or mortality that were attributed to treatment for F0 and F1 parental animals.

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS) (See Table 7.8.1/1)
- F0 generation: No treatment-related changes in body weigh or food consumption that were attributed to treatment
- F1 generation: body weight and food consumption were significantly decreased at all measurement intervals for F1 males in the 300 ppm group. Additionally, very small but statistically significant decreases in body weights were noted during the first 3-6 weeks 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 lenghts of time during lactation, body weights for F0 and F1 females in the 300 ppm group were decreased compared to 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 %.

WATER CONSUMPTION (PARENTAL ANIMALS)
- F0 generation: dose-related decreases in water consumption in the 70 and 300 ppm groups (ca. 10-25 % decrease compared to control). Statistically descreased occasionally for F0 males in the 35 ppm group.
- F1 generation: 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 moset measurements intervals.

TEST SUBSTANCE INTAKE (PARENTAL ANIMALS)
No data

REPRODUCTIVE FUNCTION: ESTROUS CYCLE (PARENTAL ANIMALS)
No treatment-related changes in estrous cyclicity

REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS)
No treatment-related changes in sperm motility or morphology

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
No treatment-related changes in mating, fertility or gestational indices for the F0 and F1 generations.

ORGAN WEIGHTS (PARENTAL ANIMALS)
No data

GROSS PATHOLOGY (PARENTAL ANIMALS)
No treatment-related effect observed.

HISTOPATHOLOGY (PARENTAL ANIMALS)
No treatment-related microscopic changes in reproductive tissues for male and female parental animals.

Results of examinations: offspring

Viability (offspring):
no effects
Clinical signs (offspring):
no effects
Body weight (offspring):
yes
Sexual maturation (offspring):
yes
Organ weights (offspring):
no data
Gross pathology (offspring):
no effects
Histopathology (offspring):
no effects
Details on results (offspring):
NUMBER AND SEXES OF PUPS BORN
No treatment-related changes in the number of pups born, the pup gender ratio, live birth index or pup survival indices.

BODY WEIGHT (OFFSPRING)
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 changes in pup body weight from control increased with age and ranged from -6 % at birth to -10 % 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. 

LITTER DEVELOPMENT OBSERVATIONS
There were no clear treatment-related changes in pup developmental indices, including ear and eye opening, righting reflex, auditory startle response and pupil response. There was an decrease in the percent of F2a pups with eye open on PND 15 in the 300 ppm treatment group when compared to the control (71 +/- 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 controls F2b pups and 71.9 +/- 38.0 % for 300 ppm F2b pups)

SEXUAL MATURATION (OFFSPRING)
No treatment-related changes in ano-genital distances. There was a small but statistically significant increases in the average time to preputial separation for F1 pups in the70 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.

ORGAN WEIGHTS (OFFSPRING)
No data

GROSS PATHOLOGY (OFFSPRING)
No treatment-related changes in gross external alterations.

HAEMATHOLOGY AND THYROID HORMONES (F1 GENERATION): (See Tables 7.8.1/2-3)
For F1 PND 25 pups, statistically significant decreases in red blood cell parameters, including decreased red blood cell (RBC) count, Hb, HCT, hematocrit mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH) and mean corpuscular hemoglobin concentrations (MCHC) were observed for males and females in the 300 ppm group. In addition decreased WBC count was observed for animals in the 70 and 300 ppm groups. 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. The MetHb concentrations for PND 25 pups were increased compared to the control for males in the 300 ppm group and females in all treatment groups, although the increase for females occurred in a non-dose-related manner. The maximum MetHb concentration attained in any of the treatment groups was 1.5 % of Hb. 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.
Any other information on results incl. tables:
Table 7.8.1/1: Gestational and lactational mean body weights for female rats
Study period
Concentration (ppm)
0
35
70
300
F0 Generation
Gestation day
0
316 ± 22
306 ± 24
314 ± 23
304 ± 24
7
339 ± 25
329 ± 25
339 ± 23
327 ± 24
14
368 ± 27
360 ± 27
369 ± 27
355 ± 24
20
452 ± 35
441 ± 35
449 ± 36
426 ± 230**
Lactation day
0
342 ± 26
328 ± 27
333 ± 36
309 ± 24***
7
361 ± 25
349 ± 25
359 ± 30
341 ± 20**
14
374 ± 26
367 ± 22
375 ± 30
359 ± 22*
21
362 ± 24
352 ± 21
361 ± 26
348 ± 21*
F1 → F2a Generation
Gestation day
0
316 ± 25
309 ± 28
302 ± 44
314 ± 36
7
347 ± 24
339 ± 31
335 ± 44
341 ± 36
14
378 ± 24
371 ± 33
369 ± 47
372 ± 38
20
464 ± 32
455 ± 40
453 ± 53
438 ± 49
Lactation day
0
357 ± 30
344 ± 39
345 ± 53
330 ± 36*
7
377 ± 26
371 ± 37
374 ± 49
366 ± 37
14
386 ± 25
378 ± 36
389 ± 44
377 ± 32
21
368 ± 24
369 ± 27
368 ± 40
370 ± 38
F1 → F2b Generation
Gestation day
0
367 ± 28
363 ± 36
351 ± 35
354 ± 30
7
395 ± 29
390 ± 38
382 ± 36
380 ± 35
14
425 ± 32
420 ± 40
413 ± 39
412 ± 38
20
517 ± 36
503 ± 48
494 ± 37
485 ± 46*
Lactation day
0
401 ± 37
397 ± 40
396 ± 47
371 ± 49*
7
425 ± 32
417 ± 40
412 ± 35
400 ± 39*
14
428 ± 33
421 ± 34
416 ± 34
408 ± 35
21
398 ± 24
400 ± 31
394 ± 34
390 ± 90
* P < 0.05
** P < 0.01
*** P < 0.001
Table 7.8.1/2 : Haematology – group mean values on day 25 post-partum

RBC (106/µL)
Hb (%)
PCV (%)
MCV (fL)
MCH (pg
MCHC (g %)
WBC (103/µL)
Met. Hb (%)
MALES
0
4.8
9.3
29.7
61.5
19.3
31.4
5.8
0.7
35
4.8
9.1
28.8
59.9
18.8
31.5
5.4
0.9
70
4.9
9.1
28.5
58.5b
18.7
32.0
5.8
0.8
300
4.7
7.4c
24.2c
51.9c
16.0c
30.0a
4.1c
1.0a
FEMALES
0
5.1
10.2
31.6
62.2
20.1
32.3
5.6
0.9
35
5.0
9.6a
30.0a
59.8a
19.1b
31.9
5.1
1.2b
70
5.2
9.6a
30.0a
58.1c
18.6c
32.0
4.6a
1.0a
300
4.7c
7.7c
24.6c
52.5c
16.4c
31.3c
4.0b
1.4b
a = significantly different from control, p < 0.05
b = significantly different from control, p < 0.01
c = significantly different from control, p < 0.001

Table 7.8.1/3 : Haematology – group mean values at 13 weeks of age

RBC (106/µL)
Hb (%)
PCV (%)
MCV (fL)
MCH (pg
MCHC (g %)
WBC (103/µL)
Met. Hb (%)
MALES
0
8.8
16.4
44.7
50.6
18.5
36.6
12.9
1.1
35
8.7
16.1
43.4b
50.1
18.6
37.1a
13.7
1.2
70
8.7
16.1
42.9c
49.1b
18.4
37.5a
12.5
1.1
300
9.0
15.2c
41.5c
46.1c
16.9c
36.6a
12.5
1.3
FEMALES
0
8.0
15.6
42.9
53.4
19.5
36.4
9.7
1.4
35
7.9
15.5
42.0a
53.4
19.7
36.9b
9.0
1.5
70
7.9
15.4
41.7b
53.1
19.6
36.8b
9.1
1.4
300
7.7b
14.9c
40.2c
52.7
19.5
37.1c
8.5a
1.3
a = significantly different from control, p < 0.05
b = significantly different from control, p < 0.01
c = significantly different from control, p < 0.001

Applicant's summary and conclusion

Conclusions:
Under the test conditions, there were no adverse effects on reproduction and fertility, therefore:
The NOAEL (Parental) = 88 mg ClO2/kg bw/d, based on the hematotoxicity observed at 330 mg ClO2/kg bw/d
The NOAEL (Developmental) = 330 mg ClO2/kg bw/d, the highest dose tested.
The NOAEL (Fertility) = 330 mg ClO2/kg bw/d, the highest dose tested.
Executive summary:
In a two-generation study (Gill et al., 2000), Sodium chlorite was administered to 25-30 Sprague-Dawley rat/sex/dose in water at dose levels of 0, 35, 70 or 300 ppm for 10 weeks prior to mating, then throughout the study according to EPA Guideline OPPTS 870.3800 (similar to OECD 416) and in compliance with GLP. Due to the increase in water consumption normally observed in lactating rats, females received drinking water at concentrations of 17.5, 35 or 150 ppm during the lactation period.
25 male and 25 female F1 generation pups were selected from each group for rearing to sexual maturity. In addition animals from each group were allocated for neurotoxicity assessment.
F1 animals were paired for mating within dose group. Due to a reduced number of litters observed in the group receiving 70 ppm, the F1 generation animals were re-paired following weaning of the F2a generation to produce a F2b generation.
Blood samples were collected for haematological examination from the F1 pups killed on day 25 and at approximately 13 weeks of age for the F1 generation retained for the rearing.
Clinical signs, bodyweights, food and water consumption, fertility and mating performance, organ weights, macroscopic abnormalities at necropsy and histopathological findings were recorded for all parental animals. Litter size, clinical condition, growth and development to weaning, developmental neurotoxicological parameters and macroscopic abnormalities at necropsy were recorded for the offspring.
There were no effects of treatment at any dose level on parental mortality, mating performance, fertility, macroscopic findings at necropsy, or on the duration of gestation, numbers of pups born, pup survival, ano-genital distance at birth sexual development or macroscopic findings of the F1 and F2 pups at necropsy.
Reductions in bodyweight gain and food consumption observed in all generations are possibly related to the decrease in water consumption due to the palatability of the formulated drinking water.
Delays in preputial separation and vaginal opening observed in F1 animals were considered to be a result of lower body weight observed for these animals rather than a direct effect of Sodium chlorite on sexual developments.
At 300 ppm, significant lower red blood cell parameter values observed on day 25 and week 13. These effects were also observed in the 70 ppm dose group but they are not considered to be of toxicological concern since the hematological values are within the historical range or are sporadic.
Based on the results of these study, the following NOAEL were determined:
- NOAEL (parental) = 70 ppm (ca. 8 mg/kg bw/d for males and 10 mg/kg bw/d for females)
- NOAEL (developmental) = 300 ppm (ca. 30 mg/kg bw/d for males and 39 mg/kg bw/d for females), the highest dose tested
- NOAEL (fertility) = 300 ppm (ca. 30 mg/kg bw/d for males and 39 mg/kg bw/d for males), the highest dose tested.
Considering the metabolism pathway of chlorine dioxyde which is likely to undergo rapid redox reactions within biological tissues rather than to be absorbed as parent compound, this study can be used for the assessment of ClO2.
However correction of doses should be done using the metabolism percentage of ClO2 into ClO2- which is 11 % (Abdel Rhaman, 1980a).
In conclusion:
Under the test conditions, there were no adverse effects on reproduction and fertility, therefore:
The NOAEL (Parental) = 88 mg ClO2/kg bw/d, based on the hemato toxicity observed at 330 mg ClO2/kg bw/d.
The NOAEL (Developmental) = 330 mg ClO2/kg bw/d, the highest dose tested.
The NOAEL (Fertility) = 330 mg ClO2/kg bw/d, the highest dose tested.
Even if the results of the study showed that parental toxicity is observed at 300 ppm, ClO2has corrosive properties at doses as low as 40 mg/kg bw (Tos, 1996) and so effects that will be observed will be linked to corrosive properties rather than to repeated dose toxicity.
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