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Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

Based on available data from multiple available literature sources, there is no evidence of adverse effects on reproductive organs (see repeated dose toxicity). In addition, according to REACH Annex VIII column 2 a screening test for reproductive toxicity is not necessary for this tonnage band, if data is available from prenatal developmental toxicity or multi-generation studies.

Effect on fertility: via oral route
Endpoint conclusion:
no study available
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

A number of studies were located that examined the effect Sodium azide has on the reproduction and embryo-fetal development in experimental animals.

Reproductive toxicity:

A 2-year oral gavage study was undertaken in rats in which a number of reproductive organs (ovary, testis, epididymis, seminal vesicle and uterus) were examined using histological techniques (NTP, 1991). No treatment related adverse effects were reported in these tissues studies under haematoxylin and eosin staining. The male reproductive organs were studies in detail, with the epididymis being examined for spermatocele. The seminal vesicle was examined for atrophy and inflammation. The testes was examined for hypospermia, inflammation of the arteriole and interstitial cell hyperplasia. No adverse effects were reported in any of these tissues when compared with the same tissues from control animals. This study gives a good indication that long-term treatment with Sodium azide did not cause any changes to the morphology of the reproductive organs of experimental animals.

 

The NTP study reports of a study in rats in which there were no changes to the oestrous cycle following 1 -year treatment via the oral route (unspecified) of administration with Sodium azide at concentrations up to 5 mg/kg bw/day (reference held on-line at NIEHS - cited in NTP, 1991). No further details about this study were available for review.

 

A study by Faqi (2008) where dams treated with Sodium azide by oral gavage showed that maternal deaths occurred at the top dose only. No deaths or clinical signs of toxicity or bodyweight effects were reported at the other doses. No histopathological investigations were reported to have been undertaken in this study. The pregnancy index in this study was 100% in the treated animals, which was comparable with the controls at 96%. This indicates that the administration of Sodium azide to pregnant animals did not modify the ability of the dams to deliver pups. Although clinical toxicity was observed at the top dose no other adverse effects were observed at the other doses to the dams.

Effects on developmental toxicity

Description of key information

In a study to determine the maternal and developmental toxicity of Sodium azide in rats, sperm-positive Sprague-Dawley rats were treated with Sodium azide via oral gavage once daily from Gestation Day (GD) 6 through 19 at respective dose levels of 0, 1, 5, and 17.5 mg/kg/day. From GD 10-12, the high-dose was reduced to 10 mg/kg/day due to maternal mortality. Overt maternal and developmental toxicity was observed at a dosage level of 17.5/10 mg/kg/day, which can be considered as LOAEL. No adverse effects were observed in the lower dose groups and therefore the NOAEL is considered to be 5 mg/kg bw/day (Faqi 2008).

Link to relevant study records

Referenceopen allclose all

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline study with acceptable restrictions (reporting)
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
no
Limit test:
no
Specific details on test material used for the study:
- Name of test material (as cited in study report): Sodium azide
- Analytical purity: no data
- Impurities (identity and concentrations): no data
Species:
rat
Strain:
Crj: CD(SD)
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Portage, Michigan, USA
- Age at study initiation: 8-10 weeks
- Weight at study initiation: 208-210 g mean body weight
- Fasting period before study:
- Housing: individually in suspended, stainless steel, wire-mash type cages in an environmentally controlled room.
- Diet (e.g. ad libitum): Lab Diet Certified Rodent Diet #5002, PMI Nutrition International Inc., ad libitum
- Water (e.g. ad libitum): no data
- Acclimation period: 6 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-26 °C
- Humidity (%): 30-70%
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
other: distilled water, buffered to pH 9.5 with NaOH
Details on exposure:
VEHICLE
- Justification for use and choice of vehicle (if other than water): not given
- Concentration in vehicle: 0 mg/kg
- Amount of vehicle (if gavage): 5 mL/kg bw
Analytical verification of doses or concentrations:
no
Details on mating procedure:
- Impregnation procedure: purchased timed pregnant
Duration of treatment / exposure:
Control and test article administration began on GD 6 and continued to include GD 19 for all animals. The test article was administered to the treated groups by oral gavage once per day at approximately the same time each day at dosage levels of 1, 5, and 17.5 mg/kg/day at a dosage volume of 5 mL/kg based on the body weight. From GD 10-12, surviving animals at 17.5 mg/kg/day began receiving a reduced dosage level of 10 mg/kg/day at a dosage volume of 2.86 mL/kg.
The control animals received the vehicle, distilled water (buffered at pH 9.5 with sodium hydroxide), at a volume of 5 mL/kg and dosing regimen as the treated animals.
Frequency of treatment:
once a day
Duration of test:
gestation day (GD) 6 to 19: 13 days
No. of animals per sex per dose:
25
Control animals:
yes, concurrent vehicle
Details on study design:
The high-dose (17.5 mg/kg/day) was reduced to 10 mg/kg/day due to severe maternal mortality.
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: not given


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: not given


BODY WEIGHT: Yes
- Time schedule for examinations: not given


FOOD CONSUMPTION: Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes


POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 20
- Organs examined: complete necropsy including uterine examination
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
- Other: Number of live and dead fetuses
Fetal examinations:
- External examinations: Yes: [all per litter]
- Soft tissue examinations: No data
- Skeletal examinations: Yes: [half per litter]
- Head examinations: No
- Visceral examinations: Yes: [half per litter]
Statistics:
Mean and SDs were calculated for all measured parameters. Gestation body weights, gestation body weight gains, and gestation food consumption were analyzed by ANOVA followed, where appropriate, by Dunnett's test. Comparison of litter (fetal) body weight data was analyzed by ANOVA; the litter was the unit of observation. For reproductive parameters, a one factor (i.e. treatment group) ANOVA was used for mean corpora lutea, mean total, live and non-live (resorptions and death) implants, mean percent live and non-live implants, and mean percent preand post implantation loss. Visceral and skeletal data were analyzed by Fisher's Exact Test. Sex ratio (% male/litter) was transformed using Arcsin square-root transformation. The transformed data was then analyzed using Dunnett's adjusted t-test and or Welch's f-test with a Bonferroni correction as appropriate. A minimum significance level of p = 0.05 was used for all comparisons.

Indices:
no data
Historical control data:
The mean values of implantation sites and mean viable fetuses at 17.5/10 mg/kg/day were within the laboratory's historical background of the species of rats used in the study.
No data on comparison of other treatment groups to historical controls are made.
Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
A total of 20 out of 25 dams in the high-dose group (17.5 mg/kg/day) died between GD 8 and GD 10. From GD 10-12, the dosage level for the surviving animals (n = 5) was then reduced to 10 mg/kg/day. Two out of the 5 surviving animals died after the dose was reduced to 10 mg/kg/day. All the animals died between GD 8 and GD 12 of the study. No death was observed in the low- (1 mg/kg/day) and mid-dose group (5 mg/kg/day).
Treatment-related clinical signs of toxicity were observed in the high-dose group (17.5/10 mg/kg/day), which included decreased activity, prostration, loss of righting reflex, lacrimation, impaired limb function, swelling (head and face), moribundity, and difficult/slow/shallow breathing. Although the mortality was sodium azide induced, no sodium azide-related macroscopic lesions were observed in dams at necropsy.
Gestation body weight and gestation body weight changes were significantly decreased in the animals receiving the high-dose (17.5/10 mg/kg/day; Tables 1 and 2) when compared to the control animals. Gestation body weight and gestation body weight changes were not affected in the animals receiving 1 and 5 mg/ kg/day. Similarly, gestation food consumption was significantly impacted in the animals of the high-dose group (Table 3). Corrected final GD 20 body weight and corrected weight change (GD 0-20) were significantly decreased at 17.5/10 mg/kg/day in comparison to the control animals.
Dose descriptor:
NOAEL
Effect level:
5 mg/kg bw/day (nominal)
Basis for effect level:
other: maternal toxicity
Dose descriptor:
LOAEL
Effect level:
17.5 mg/kg bw/day (nominal)
Basis for effect level:
other: maternal toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
The pregnancy index was 96% (24 of 25 animals) in the control and 100% (25/25 animals) in the treatment groups.
A total of 22 animals died at 17.5/10 mg/kg/ day.
Resultant number of dams with viable fetuses at GD 20 was 24, 25, 25, and 3 in the control, 1 mg/kg/day, 5 mg/kg/day, and 17.5 (10) mg/kg/day groups, respectively. Implantation sites, viable fetuses, and litter size per dam were significantly higher in the high-dose group (17.5/10 mg/kg/day) in comparison to the control group.
This was considered to be due to the small number of surviving dams (n = 3) available on GD 20 for this group. All other uterine parameters examined during the study were comparable among the groups (Table 4). Fetal body weights (Table 4) were significantly affected in the three remaining litters at 17.5/10.
However, no effects of treatment were evident from fetal external, visceral or skeletal examinations at any of the dose levels evaluated.
Dose descriptor:
NOAEL
Effect level:
5 mg/kg bw/day (nominal)
Basis for effect level:
other: developmental toxicity
Dose descriptor:
LOAEL
Effect level:
17.5 mg/kg bw/day (nominal)
Basis for effect level:
other: developmental toxicity decreased fetal body weight. Reduction of dose to 10 mg/kg/day at days 10-12.
Abnormalities:
not specified
Developmental effects observed:
not specified

Table 1: Gestation body weight (g)

Gestation days

Control

1 mg/kg/day

5 mg/kg/day

17 mg/kg/day

0

207.9 ± 13.5
(n = 24)

208.9 ± 10.7
(n =25)

210.5 ± 11.8
(n =25)

209.6 ± 11.8
(n = 25)

6

250.0 ± 15.8
(n = 24)

248.3 ± 12.5
(n = 25)

249.5 ± 13.1
(n = 25)

249.6 ± 14.3
(n = 25)

9

266.3 ± 18.0
(n = 24)

262.7 ± 13.5
(n = 25)

265.6 ± 14.1
(n = 25)

247.8 ± 17.4**
(n = 20)

12

282.8 ± 12.3
(n = 24)

280.3 ± 15.7
(n = 25)

282.8 ± 13.7
(n = 25)

219.1 ± 32.6**
(n = 4)

15

301 ± 22.5
(n = 24)

301.4 ± 18.1
(n = 25)

302.7 ± 15.7
(n = 25)

248.7 ± 39.1**
(n = 3)

18

338.7 ± 25.2
(n = 24)

337.6 ± 25.2
(n = 25)

339.8 ± 18.1
(n = 25)

295.1 ± 53.7*
(n = 3)

20

371.6 ± 27.2
(n = 24)

370.6 ± 27.7
(n = 25)

374.2 ± 20.2
(n = 25)

326.5 ±42.1*
(n = 3)

Note: Data are means ± SD; from GD 10-12, the high-dose was reduced to 10 mg/kg/day;
n = corresponds to the number of animals.

* Significantly different from control (p < 0.05)

** Significantly different from control (p < 0.01)

 

Table 2: Gestation body weight gain (g)

Gestation interval (days)

Control

1 mg/kg/day

5 mg/kg/day

17 mg/kg/day

0-6

42.1 ± 6.5
(n = 25)

39.3 ± 7.9
(n = 25)

39.0 ± 5.8
(n = 25)

40.1 ±6.2
(n = 25)

6-9

16.3 ± 5.6
(n = 24)

14.4 ± 4.9
(n = 25)

16.1 ± 6.0
(n =25)

-1.6 ± 11.4**
(n =25)

9-12

16.59 ± 5.2
(n =24)

17.6 ± 6.5
(n = 25)

17.2 ± 4.0
(n =25)

-27.0 ± 15.2**
(n = 20)

12-15

18.2 ± 7.8
(n = 24)

21.1 ± 5.7
(n = 25)

19.9 ± 5.5
(n =25)

16.6± 15.9
(n = 4)

15-18

37.7 ± 7.9
(n = 24)

36.2 ± 10.4
(n = 25)

37.0 ± 6.6
(n =25)

46.4 ± 15.4
(n = 3)

18-20

32.9 ± 6.5
(n = 24)

33.0 ± 5.2
(n = 25)

34.4 ± 5.2
(n =25)

31.4± 12.3
(n = 3)

6-20

121.6 ± 16.8
(n =24)

122.3 ± 19.7
(n = 25)

124.7 ± 16.4
(n =25)

79.8 ± 15.7**
(n = 3)

0-20

163.7 ± 19.5
(n = 24)

161.6 ±23.7
(n = 25)

163.7 ± 17.0
(n =25)

122.0 ± 17.9**
(n = 3)

Note: Data are means ± SD; from GD 10-12, the high-dose was reduced to 10 mg/kg/day;
n = corresponds to the number of animals.

** Significantly different from control (p < 0.01)

 

Table 3: Gestation food consumption (g)

Gestation interval (days)

Control

1 mg/kg/day

5 mg/kg/day

17 mg/kg/day

0-6

19.9 ± 3.0
(n = 24)

20.7 ± 1.8
(n = 25)

21.0 ± 2.4
(n = 25)

20.7 ± 1.5
(n = 25)

6-9

23.6 ± 2.8
(n = 24)

22.8 ± 2.1
(n = 25)

22.6 ± 3.3
(n = 25)

15.7 ± 5.9**
(n = 20)

9-12

24.4 ± 2.2
(n = 24)

24.0 ± 2.4
(n= 25)

24.6 ± 1.9
(n = 25)

9.1 ± 4.4**
(n = 4)

12-15

25.1 ± 3.5
(n = 24)

26.1 ± 2.5
(n – 25)

25.5 ± 3.4
(n = 25)

14.7 ± 4.2**
(n - 3)

15-18

27.9 ± 2.8
(n = 24)

27.5 ± 3.6
(n - 25)

27.5 ± 2.8
(n = 25)

23.6 ± 5.7
(n = 3)

18-20

28.6 ± 3.9
(n = 24)

27.9 ± 3.2
(n = 25)

28.3 ± 2.4
(n = 25)

26.2 ± 0.8
(n = 3)

6-20

25.7 ± 2.1
(n = 24)

25.5 ± 2.5
(n = 25)

25.6 ± 2.1
(n = 25)

17.9 ± 1.9**
(n = 3)

0-20

23.9 ± 2.1
(n = 24)

24.0 ± 2.2
(n =25)

24.3 ± 2.0
(n = 25)

18.3 ± 1.0**
(n = 3)

Note: Data are means ± SD; from GD 10-12, the high-dose was reduced to 10 mg/kg/day;
n = corresponds to the number of animals.

** Significantly different from control (p < 0.01)

 

Table 4: Summary of maternal and uterine data

Endpoints

Control

1 mg/kg/day

5 mg/kg/day

17 mg/kg/day

No. females on study

25

25

25

25

Number pregnant

24

25

25

25

Number not pregnant

1

0

0

0

Pregnancy index (%)

96

100

100

100

Number died pregnant

0

0

0

22

Number females with viable fetuses

24

25

25

3

Number of corpora lutea/animal

13.0 ± 1.85
(n = 24)

13.6 ± 1.82
(n = 25)

13.9 ± 1.87
(n = 25)

13.9 ± 1.87
(n = 3)

Implantation sites per animal

12.2 ± 1.55
(n = 24)

12.6 ± 1.58
(n = 25)

13.1 ±2.31
(n = 25)

15.0 ± 1.73*
(n = 3)

Pre-implantation loss per animal

10.84 ± 10.460
(n = 24)

7.49 ± 7.897
(n = 25)

5.87 ± 12.795
(n = 25)

4.07 ± 3.572
(n = 3)

Viable fetuses per animal

11.7 ± 1.65
(n = 24)

12.0 ± 1.70
(n =25)

12.8 ± 2.38
(n = 25)

14.7 ± 2.08*
(n = 3)

Post-implantation loss (% implants per animal)

3.77 ± 5.728
(n = 24)

4.11 ±6.499
(n = 25)

2.22 ± 3.710
(n =25)

2.38 ± 4.124
(n =3)

Nonviable fetuses/animal

0.0 ± 0.0
(n = 24)

0.0 ± 0.0
(n = 25)

0.0 ± 0.0
(n = 25)

0.0 ± 0.0
(n = 3)

Resorptions (early + late)

0.5 ± 0.7
(n = 24)

0.5 ± 0.8
(n = 25)

0.3 ± 0.5
(n =25)

0.3 ± 0.6
(n = 3)

 

 

 

 

 

Fetal weight (g)

 

 

 

 

Male (M)

4.08 ± 0.250
(n = 24)

4.13 ± 0.286
(n = 25)

4.10 ± 0.293
(n = 25)

3.57 ± 0.269
(n = 3)

Female (F)

3.89 ± 0.263
(n =24)

3.88 ± 0.289
(n = 25)

3.88 ± 0.245
(n = 25)

3.36 ± 0.224*
(n = 3)

Combined (M + F)

3.89 ± 0.263
(n = 24)

4.01 ± 0.273
(n = 25)

4.00 ± 0.251
(n = 25)

3.44 ± 0.203*
(n = 3)

Sex ratio (mean % of males/litter)

50.8 ± 15.8
(n = 24)

55.8 ± 15.7
(n = 25)

44.8 ± 12.3
(n = 25)

45.4 ± 24.2
(n = 3)

Note: Data are means ± SD
n = corresponds to the number of litters examined; from GD 10-12, the high-dose was reduced to 10 mg/kg/day.

* Significantly different from control (p < 0.05).

Conclusions:
Overt maternal and developmental toxicity was observed at a dosage level of 17.5/10 mg/kg/day, which can be considered as LOAEL. No adverse effects were observed in the lower dose groups and therefore the NOAEL is considered to be 5 mg/kg bw/day.
Executive summary:

Sodium azide is being proposed for use as an active ingredient to control a broad spectrum of soil borne pathogens including insects, weeds, nematodes, fungi, and bacteria. The purpose of this study was to determine the maternal and developmental toxicity of Sodium azide in rats. Sperm-positive Sprague-Dawley rats were treated with Sodium azide via oral gavage once daily from Gestation Day (GD) 6 through 19 at respective dose levels of 0, 1, 5, and 17.5mg/kg/day. From GD 10-12, the high-dose was reduced to 10 mg/kg/day due to maternal mortality. Cesarean section was performed on GD 20 and implantation and resorption sites, live and dead fetuses were counted. Fetuses were weighed, sexed externally and processed for gross external, visceral and skeletal examinations. A high rate of maternal mortality; reduced gestation body weight, gestation body weight changes and food consumption; decreased corrected body weight and corrected weight gain were observed at 17.5/10mg/kg/day.

Fetal weight was also reduced at 17.5/10mg/kg/day. There were no maternal deaths, clinical signs or body weight effects that were considered related to sodium azide at 1 and 5mg/kg/day. No increase in the incidence of malformations and variations were observed at any of the doses evaluated. Based on the results of this study, the No Observed Adverse Effect Level (NOAEL) and the Lowest Observed Adverse Effect Level (LOAEL) for maternal and developmental toxicity of Sodium azide in rats were considered to be 5 and 10 mg/kg/day, respectively.

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
other: Unsuitable test system
Qualifier:
no guideline followed
Principles of method if other than guideline:
Sodium azide was applied to hatching eggs of hens prior to incubation.
Signs of hatchability (occurence of clear eggs, embryonal mortality and hatchability) were investigated.
GLP compliance:
not specified
Species:
other: hatching eggs
Strain:
other: hens: Rhode Island white (RIW)
Details on test animals or test system and environmental conditions:
The experiment contained 30 strains of the hen breed RIW (Rhode Island White), 15 strains being experimental and 15 control ones. 4 094 hatching eggs were obtained from the experimental hens and 5 757 hatching eggs from the control ones. The hens were kept separately in cages. For the production of hatching eggs an artificial insemination was used.
Route of administration:
infusion
Vehicle:
physiological saline
Analytical verification of doses or concentrations:
not specified
Control animals:
yes
Remarks on result:
not determinable because of methodological limitations
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
In experimental and control group occurred relatively high but equal number of non-fertilized eggs or eggs having an early embryonal mortality (the so—called "clear eggs"), these amounting to 28 and 29 % in experimental and control group, respectively. A different situation was manifested in the total embryonal mortality, this being 21.89 % of the hatching eggs in case of the experimental and 10.48 % in case of the control group. This difference was mostly caused by the mortality until the 5th day of incubation and after the 15th day of incubation, even if the other periods evaluated revealed higher losses. The hatchability was lower in the experimental group by 9 % with respect to the hatching eggs (51 and 60 %) and by 15 % with respect to fertilized eggs (71 and 86 %).
Remarks on result:
not determinable because of methodological limitations
Abnormalities:
not specified
Developmental effects observed:
not specified

Table 1: Hatchability indices after Sodium azide treatment of eggs in domestic fowl

Group

Hatching eggs

Clear eggs

Died (n)

Hatched

n

%

0-5 d

6-10 d

11-15 d

over 15 d

total

n

%

n

%

Experiment

4094

1156

28.23

454

60

38

297

849

21.89

2089

51.02

Control

5757

1685

29.26

305

27

38

220

590

10.48

3482

60.48

Conclusions:
The dose of Sodium azide (0.065 g/L in physiological solution) used resulted in a 10% reduction of the hatchability and a 10% increase of embryonal mortality, particularly in the first five and the last five days of incubation.
Executive summary:

The effect of Sodium azide applied to hatching eggs of the hens, breed RIW, - prior to incubation in the amount of 6.5 x 10-6g on the indices - hatchability (occurence of clear eggs, embryonal mortality and hatchability) was investigated. The dose of Sodium azide used (0.065 g/L in physiological solution) resulted in a 10% reduction of the hatchability and a 10% increase of embryonal mortality, particularly in the first five and the last five days of incubation.

 

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Well documented study meeting general accepted scientific principles
Qualifier:
no guideline followed
Principles of method if other than guideline:
Sodium azide was tested on sea urchin embryos and gametes (Paracentrotus lividus). Developing embryos were exposed to SA (10^-6 to 10^-3 M) up to pluteus larval stage, or for shorter intervals before or after hatching.
GLP compliance:
not specified
Species:
other: Paracentrotus lividus
Remarks on result:
not determinable because of methodological limitations
Remarks on result:
not determinable because of methodological limitations
Abnormalities:
not specified
Developmental effects observed:
not specified
Conclusions:
Data show a slight non-significant increase in developmental defects in the offspring of Sodium azide exposed sea urchin sperm at pH = 8.
Executive summary:

Sodium azide (SA) was tested on sea urchin embryos and gametes (Paracentrotus lividus). Developing embryos were exposed to SA (10-6to 10-3M) up to pluteus larval stage, or for shorter intervals before or after hatching. Developmental defects in SA-exposed embryos consisted mainly of gut abnormalities, without any detectable differences between pre- or post-hatch-exposed embryos. SA-induced damage to gut was exerted during gastrulation, as evident by lectin binding of extracellular matrix. No mitotic damage was observed in SA-exposed embryos, nor could pH-related variations be detected in SA-induced embryotoxicity at pH's ranging from 8 to 6. Concurrently, no effect ensued in the exposure of unfertilized eggs to SA (10 -5 to 10-2 M) both in terms of fertilization success and of offspring quality When sperm were suspended in filtered seawater at pH's ranging from 8 to 6, and SA levels ranging from 10^(-5) to 10^(-2) M, fertilization success of SA-exposed sperm appeared to be modulated by pH, by displaying three distinct dose-response trends at pH 8, 7, or 6. The consequences of sperm pretreatment on offspring quality failed to show any significant SA-induced changes on larval malformations or mortality, but a slight non-significant increase in developmental defects in the offspring of Sodium azide exposed sea urchin sperm at pH = 8 was observed.

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Well documented study, meets generally accepted scientific principles
Qualifier:
no guideline followed
Principles of method if other than guideline:
Pairs of osmotic minipumps containing 400 mg/mL (6.15 M) sodium azide in distilled water were subcutaneously implanted in timed pregnancy Syrian golden hamsters. The period of pump implantation which was Days 7 through 9 of gestation. After removal of the pumps the dams were euthanized on Day 13 of gestation, and the uteri were removed for counting of the number of living, malformed, and resorbed fetuses.
GLP compliance:
no
Limit test:
no
Species:
hamster, Syrian
Strain:
not specified
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories North WiIlmington MA U.S.A.
- Age at study initiation: no data
- Weight at study initiation: no data
- Fasting period before study: no data
- Housing: individually housing in cages with pine shave bedding
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: no data


ENVIRONMENTAL CONDITIONS
- Temperature (°C): no data
- Humidity (%): no data
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12-hr dark/12-hr light cycle

Route of administration:
subcutaneous
Vehicle:
water
Details on exposure:
subcutaneous implantation of two osmotic minipumps per animal delivering a calculated maximum dose rate of 60 µmol/kg BW/h for 40-48h. Exposed animals were pregnant dams from day 7 to 9 of gestation.
Controlls received distilled water (vehicle) instead of sodium azide solution.
Analytical verification of doses or concentrations:
no
No. of animals per sex per dose:
13
Control animals:
yes, concurrent vehicle
Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
Two azide-treated dams from a total of 15 died before pump removal, and these animals were not included in the study. In 6 of 13 dams pumps were removed before 48 hr (3 at 40 hr and 3 at 42 hr) because of the severity of the dyspnea, hypothermia, and ataxia. The condition of these animals subsequently improved, and they were included in the study.
Dose descriptor:
NOAEL
Effect level:
84 mg/kg bw/day (nominal)
Basis for effect level:
other: maternal toxicity
Dose descriptor:
LOAEL
Effect level:
93.6 mg/kg bw/day (nominal)
Basis for effect level:
other: maternal toxicity
Abnormalities:
not specified
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
The number of resorption sites and malformations (exclusively in the form of encephaloceles) were counted and pooled under the designation of "adverse reactions." The incidence of such adverse reactions was significantly (p < 0.0065) higher in treated hamsters than in controls as also was the number of resorptions. In contrast, the incidence of malformations alone was not significantly different between control and azide-treated animals (Table 1).
Dose descriptor:
NOAEL
Effect level:
84 mg/kg bw/day (nominal)
Basis for effect level:
other: developmental toxicity
Dose descriptor:
LOAEL
Effect level:
93.6 mg/kg bw/day (nominal)
Basis for effect level:
other: developmental toxicity increased fetus resorption, encephaloceles
Abnormalities:
not specified
Developmental effects observed:
not specified

Table 1: Effect of sodium azide infusions on hamster littersa:

Parameter

Control

Azide

Number of litters

14

13

Total implantationsb

185

176

Total fetuses

183

146

Average No. fetuses per litter

13.1

11.2

Total adverse reactionsc

3

35

Total malformations

1

5d

Percentage affected

9.8

29.6

a   Sodium azide dose rate at 6 x 10-2mmol hr for 40-48 hr (Days 7 through 9 of gestation). Controls received distilled water. Two azide-treated dams died before removal of the pumps and are not included above.

b    The sum of the total fetuses and resorption sites.

c    The sum of the resorptions and malformations (encephaloceles).

d    Distributed among four litters.

 

Conclusions:
Maternal and developmental toxicity was observed at a dosage level of 93.6 mg/kg/day, which can be considered as LOAEL. No adverse effects were observed in the lower dose groups and therefore the NOAEL is considered to be 84.0 mg/kg bw/day.
Executive summary:

Pairs of osmotic minipumps containing 400 mg/mL (6.15 M) Sodium azide in distilled water were subcutaneously implanted in timed pregnancy Syrian golden hamsters. The total delivered dose was calculated as 60 µmol/kg/hr at the maximal pumping rate. Most dams exhibited obvious signs of toxicity during the period of pump implantation which was Days 7 through 9 of gestation. After removal of the pumps the dams were euthanized on Day 13 of gestation, and the uteri were removed for counting of the number of living, malformed, and resorbed fetuses. This dose rate resulted in a significantly increased incidence of resorptions of embryos over that in a control group implanted with pumps delivering only distilled water. The incidence of gross malformations exclusively in the form of encephaloceles was not different between control and azide-infused groups. The extent of nitrosylation of circulating hemoglobin was followed with time and found to involve only about 0.1% of the total blood pigment. Thus, this commercially important and widely distributed chemical with high acute toxicity is not considered to be teratogenic in hamsters, and it produces embryotoxicity only at dose rates that result in toxic signs in the dams. Maternal and developmental toxicity was observed at a dosage level of 93.6 mg/kg/day, which can be considered as LOAEL. No adverse effects were observed in the lower dose groups and therefore the NOAEL is considered to be 84.0 mg/kg bw/day.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
5 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
comparable to guideline study with acceptable restrictions
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

In a study to determine the maternal and developmental toxicity of Sodium azide in rats, sperm-positive Sprague-Dawley rats were treated with Sodium azide via oral gavage once daily from Gestation Day (GD) 6 through 19 at respective dose levels of 0, 1, 5, and 17.5 mg/kg/day. From GD 10-12, the high-dose was reduced to 10 mg/kg/day due to maternal mortality. Overt maternal and developmental toxicity was observed at a dosage level of 17.5/10 mg/kg/day, which can be considered as LOAEL. No adverse effects were observed in the lower dose groups and therefore the NOAEL is considered to be 5 mg/kg bw/day (Faqi 2008).

 

Pairs of osmotic minipumps containing 400 mg/ml (6.15 M) Sodium azide in distilled water were subcutaneously implanted in timed pregnancy Syrian golden hamsters. The total delivered dose was calculated as 60 µmol/kg/hr at the maximal pumping rate. Sodium azide is not considered to be teratogenic in hamsters, and it produces embryotoxicity only at dose rates that result in toxic signs in the dams (Sana 1990).

 

The effect of Sodium azide applied to hatching eggs of the hens, breed RIW, - prior to incubation in the amount of 6.5 x 10-6g on the indices - hatchability (occurence of clear eggs, embryonal mortality and hatchability) was investigated. The dose of Sodium azide used resulted in a 10% reduction of the hatchability and a 10% increase of embryonal mortality, particularly in the first five and the last five days of incubation (Grolmus 1986).

 

Data show a slight non-significant increase in developmental defects in the offspring of Sodium azide exposed sea urchin sperm at pH = 8 (Pagano 1988).

Toxicity to reproduction: other studies

Link to relevant study records
Reference
Endpoint:
toxicity to reproduction: other studies
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
other: Documentation insufficient for assessment.
Qualifier:
no guideline followed
GLP compliance:
no
Type of method:
in vitro
Species:
mouse
Strain:
not specified
Details on test animals or test system and environmental conditions:
Pronuclear mouse embryos
Conclusions:
Sodium azide has a drastically toxic effect on the in vitro growth of mouse embryos at concentrations of 10^(-4) mol/L in the petri dish or greater.
Executive summary:

In a study conducted by Robertson J.L. and Roudebush W.E. , the toxicity potential of Sodium azide on mouse development was determined in vitro. Embryos were treated with Sodium azide and evaluated following 72 hours of culture. The results show that Sodium azide has a drastically toxic effect on the in vitro growth of mouse embryos at concentrations of 10 -4 mol/L in the petri dish or greater. It was toxic to most, though not all, mouse embryos at 10 -5 mol/L but was not significantly toxic at levels of 10 -6 mol/L or less.

Additional information

In a study conducted by Robertson J.L. and Roudebush W.E. , the toxicity potential of Sodium azide on mouse development was determined in vitro. Embryos were treated with Sodium azide and evaluated following 72 hours of culture.The results show that Sodium azide has a drastically toxic effect on the in vitro growth of mouse embryos at concentrations of 10 -4 mol/L in the petri dish or greater. It was toxic to most, though not all, mouse embryos at 10-5 mol/L but was not significantly toxic at levels of 10 -6 mol/L or less.

Justification for classification or non-classification

Based on the results from a number of repeated dose and developmental toxicity studies, there is no evidence of adverse effects on reproductive organs or tissues or of other concerns in relation with reproductive and developmental toxicity. Although embryotoxicity has been reported, this was only observed in association with maternal toxicity and can be considered a secondary effect.

Additional information