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Diss Factsheets

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

The parent compound Vanadium-tris-acetylacetonate is rapidly hydrolysed to 2,4 -pentanedione (CAS no. 123 -54- 6) and Vanadyl acetylacetonate (CAS no. 3153 -26 -2) in the presence of water or moisture (> 80% hydrolysis after 1h at pH 1.2, 4, 7 and 9). Hence, the half life is < 1 h under neutral and acidic conditions. Accordingly, reliable data of the hydrolysis products 2,4-Pentadione (Cas no. 123-54-6) and Vanadyl acetylacetonate (3153-26-2) or comparable inorganic Vanadium compounds are used to address the endpoint, which is entirely appropriate to draw conclusions on the toxicity to reproduction of Vanadium-tris-acetylacetonate.

NaVO3, rat, oral, 28 d (females)/60 d (males), reproductive performance: NOAEL (P) > 20 mg/kg bw/day, EC (F1) = 5 mg/kg bw/day - VAA NOAEL (P) > 57.1 mg/kg bw/day, EC (F1) = 14.3 mg/kg bw/day

V2O5, mouse, ip, 60 d, reproductive function (males): EC (P + F1) = 2.7 mg/kg bw/day - VAA EC (P + F1) = 10.84 mg/kg bw/day

V2O5, rat, whole body, 6 hr/day, 5 days per week, 90 days (OECD TG 413, GLP): LOAEC = 8 mg/m3- VAA LOAEC = 30.6 mg/m3 (please refer to '7.8.3 other studies')

Acetylacetonate, rat, inhalation, 6 h per day, 5 d, dominant lethal effects (spermatid stage of spermatogenesis) (males): NOEL (P) = 411.84 mg/m3

Link to relevant study records

Referenceopen allclose all

Endpoint:
fertility, other
Remarks:
Fertility Assessment Test (Sperm assessment)
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Justification for type of information:
please refer to Read-across statement attached in section 13
Reason / purpose for cross-reference:
read-across source
Clinical signs:
not examined
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
The final body weight of V2O5-treated animals during 60 days was lower than controls, while differences were not observed in those animals sacrificed at days 10, 20, 30, 40, or 50 after the beginning of the treatment
Food efficiency:
not examined
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:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
not examined
Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
effects observed, treatment-related
Description (incidence and severity):
The sperm count diminished significantly in V2O5-treated animals during 20 days or longer. A marked reduction in sperm motility was observed with the advancement of treatment in mice treated with V2O5.
A significant increase of the percentage of morphologic abnormalities in spermatozoa obtained from vanadium-treated animals was observed after 50 and 60 days of treatment.
Reproductive performance:
effects observed, treatment-related
Description (incidence and severity):
The fertility rate was significantly lower in V2O5-treated mice than in controls (10/30; 33 % vs. 34/40; 85 %, P < 0.05, "z"-test). The number of implants and pups was lower in females mating with V2O5-treated males, while the incidence of resorptions was increased in these females. The body weight of fetuses born from dams impregnated by V2O5-treated mice was lower than controls.
please refer to "Any other information on results incl. tables"
Dose descriptor:
dose level: decrease in fertility rate, implantations, live fetuses, and fetal weight, and an increase in the number of resorptions/dam. Sperm count, motility, and morphology were impaired with the advancement of treatment.
Effect level:
32.5 other: µg/g bw/0.3 d
Based on:
test mat.
Sex:
male
Basis for effect level:
organ weights and organ / body weight ratios
reproductive function (sperm measures)
reproductive performance
Key result
Dose descriptor:
dose level: decrease in fertility rate, implantations, live fetuses, and fetal weight, and an increase in the number of resorptions/dam. Sperm count, motility, and morphology were impaired with the advancement of treatment
Effect level:
10.84 mg/kg bw/day
Based on:
test mat.
Sex:
male
Basis for effect level:
organ weights and organ / body weight ratios
reproductive function (sperm measures)
reproductive performance
Critical effects observed:
yes
Lowest effective dose / conc.:
10.84 mg/kg bw/day (nominal)
System:
male reproductive system
Organ:
germ cells
testes
Treatment related:
yes
Dose response relationship:
no
Relevant for humans:
yes
Remarks on result:
not measured/tested
Clinical signs:
not examined
Mortality / viability:
mortality observed, treatment-related
Description (incidence and severity):
the number of live fetuses of V2O5-treated males is significantly reduced when compared to the controls
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
The body weight of fetuses bom from dams impregnated by V2O5 treated mice was lower than controls.
Food efficiency:
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not examined
Histopathological findings:
not examined
Other effects:
not examined
Behaviour (functional findings):
not examined
Developmental immunotoxicity:
not examined
please refer to "Any other information on results incl. tables"
Dose descriptor:
dose level: decrease in live fetuses, and fetal weight
Generation:
F1
Effect level:
32.5 other: µg/g bw/0.3 d
Based on:
test mat.
Sex:
male/female
Basis for effect level:
viability
body weight and weight gain
Key result
Dose descriptor:
dose level: decrease in live fetuses, and fetal weight
Generation:
F1
Effect level:
10.84 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
viability
body weight and weight gain
Critical effects observed:
no
Remarks on result:
not measured/tested
Reproductive effects observed:
yes
Lowest effective dose / conc.:
10.84 mg/kg bw/day
Treatment related:
yes
Relation to other toxic effects:
reproductive effects in the absence of other toxic effects
Dose response relationship:
no
Relevant for humans:
yes

Table 1: Effects of Vanadium Pentoxide on Reproductive Function of CD-1 Male Mice

 

Control

Vanadium pentoxide (8.5µg/g)

Males (n)

20

13

Mated females (n)

40

Id

Pregnant (n)

34

10

Fertility (%)a

85

33

Implantation sitesb

10.88 ± 1 60

5.80 ± 1.33**

Resorptionsb

0.24 ± 0.42

2.00 ± 1.67*

Live fetusesb

10.53 ± 1.42

3.40 ± 0.49**

Dead fetusesb

0.12 ± 0.32

0.40±0.49

Fetal weight (mg)b

145 ± 4.0

121± 7.0*

a(Pregnant/females mated) x 100

bMean ± SD

* P < 0.05

** P<0.01

Table 2: Effects of Vanadium Pentoxide on Body and Testis Weight, Sperm Count, Sperm Motility and Sperm Morphology (Mean ± SD)

Vanadium pentoxide (8.5 µg/g)

 

Control

10 days

20 days

30 days

40 days

50 days

60 days

Males (n)

20

5

5

5

5

5

20

Initial weight(g)

28.04 ± 0.61

26.74 ± 0.71

27 19 ±0.34

27.33 ± 0.51

28.00 ± 0.25

28.14 ± 0.30

27.44 ± 0.49

Final weight(g)

31.20 ± 1.09

27.14 ± 0.71

27.00 ± 0.43

20.83 ± 0.66

27.14 ± 0.90

26.81 ± 1.03

24.64 ± 1.34*

Testis weight (mg)

135.90 ± 16.80

131.80 ± 24.30

134.10 ± 21.90

129.70 ± 23.30

130.10 ±20.10

124.00 ± 26.00*

118.72 ± 22.33**

Sperm count (x 106/ml)

29.19 ± 2.43

23.50 ± 7.53

19.80 ± 5.31**

16.67 ± 3.68**

16.67 ± 2.68**

19.91 ± 1.28**

7.27 ± 2.31**

Motility (%)

73.10 ± 19.40

40.60 ± 10.10**

35.50 ± 11.70**

18.10 ± 13.40**

14.20 ± 9.30**

4.30 ± 8.80**

4.01 ± 2.91**

Abnormalsperm (%)

6.40 ± 1.80

5.50 ± 3.90

3.80 ± 4.30*

4.70 ± 5.10

6.90 ± 5.10

8.10 ± 4.10*

10.83 ± 3.70**

* P < 0.05

** P < 0.01

Conclusions:
V2O5 treatment resulted in a decrease in fertility rate, implantations, live fetuses, and fetal weight, and an increase in the number of resorptions/dam. Sperm count, motility, and morphology were impaired with the advancement of treatment. The applied dose corresponds to 32.5 µg/g bw/0.3 d (ca. 10.84 mg/kg bw/d) of vanadium-tris-acetylacetonate. For details on the calculation, please refer to "Overall remarks".
Executive summary:

Effects of vanadium pentoxide (V2O5) treatment on reproductive function in male mice were investigated. V2O5 was administered intraperitoneally at a dose of 8.5 µg/g bw every three days for 60 days. Reproductive functions were evaluated with fertility rate, implants, resorptions, sperm counts, motility, and morphology. V2O5 treatment resulted in a decrease in fertility rate, implantations, live fetuses, and fetal weight, and an increase in the number of resorptions/dam. Sperm count, motility, and morphology were impaired with the advancement of treatment. The applied dose corresponds to 32.5 µg/g bw/0.3 d (ca. 10.84 mg/kg bw/d) of vanadium-tris-acetylacetonate.

Endpoint:
screening for reproductive / developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Justification for type of information:
please refer to Read-across statement attached in section 13
Reason / purpose for cross-reference:
read-across source
Clinical signs:
not specified
Mortality:
no mortality observed
Body weight and weight changes:
not specified
Food efficiency:
not specified
Ophthalmological findings:
not examined
Haematological findings:
not examined
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:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
not specified
Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
no effects observed
Description (incidence and severity):
The oral administration of vanadium had no significant adverse effects on the following parameters: number of corpora lutea, number of implantations, number of live and dead fetuses and number of resorptions. Although the administration of 10 and 20 mg/kg/day NaVO3 resulted in an increase in the number of dead fetuses as in the number of resorptions when compared to the control group, these increases were not significant (P > 0.05).
Key result
Dose descriptor:
NOAEL
Remarks:
converted to VAA
Effect level:
> 57.1 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
reproductive performance
Critical effects observed:
no
Remarks on result:
not measured/tested
Clinical signs:
not specified
Mortality / viability:
mortality observed, non-treatment-related
Description (incidence and severity):
The number of litters, living and dead young per litter in the treated rats, as well as the average body weight per litter did not show any significant differences with the control group on days 1 and 4 of nursing. Some significant decrease could be observed on day 21 of nursing. However, no effect dose-response may be induced.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Body weight showed significant decreases during the whole the period of lactation in both males and females, when compared with the control values.
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Ophthalmological findings:
not specified
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Sexual maturation:
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
There were significant decreases in the relative organ weights of spleen, liver and kidneys observed in the pups killed after 21 days of lactation. As can be seen, slight effect dose-response may be induced.
Gross pathological findings:
not specified
Histopathological findings:
not specified
Other effects:
effects observed, treatment-related
Description (incidence and severity):
Body length and tail length of animals in the treated groups showed significant decreases during all the period of lactation in both males and females, when compared with the control values.
Behaviour (functional findings):
not specified
Developmental immunotoxicity:
not examined
Key result
Dose descriptor:
dose level: toxic for the offspring
Remarks:
converted to VAA
Generation:
F1
Effect level:
14.3 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
organ weights and organ / body weight ratios
Remarks on result:
not measured/tested
Key result
Reproductive effects observed:
yes
Lowest effective dose / conc.:
5 mg/kg bw/day
Treatment related:
yes
Relation to other toxic effects:
reproductive effects in the absence of other toxic effects
Dose response relationship:
yes
Relevant for humans:
yes

Table 1. Effects of NaVO3 given orally to rats killed on day 14 of gestation (a)

 

DosesNaVO3(mg/kg/day)

 

0

5

10

20

No. of pregnant rats

6

8

7

6

Corpora lutea

15.5±3.0

16.0±2.6

16.0±1.8

13.8±1.7

Total implants

12.7±2.7

13.6±1.9

14.0±2.6

12.7±1.0

Live fetuses

11.7±1.8

12.5±1.9

12.3±2.9

9.8±1.3

Dead fetuses

0.3±0.2

0.4±0.2

0.7±0.3

0.8±0.4

resorptions

0.7±0.3

0.7±0.3

1.0±0.4

2.1±0.8

a The results are expressed as mean values±SE

Table 2. Summary of data rat pups nursed by vanadium-treated mothers during a period of 21-days

Doses NaVO3 (mg/kg/day)

 

Day

0

5

10

20

No. of litters

1

11

10

12

9

4

11

10

11

8

21

11

10

9

7

No. of living young

1

117

115

139

95

4

116

115

111

79

21

108

109

55

76

No. of dead young

1

0

8

5

5

4

1

0

28

16

21

8

6

56

3

Dead/living

ratio(x100)

1

0.0

6.9

3.6

5.2

4

0.8

0.0

20.1

16.8

21

6.8

5.2

50.4

3.7

Male/female

ratio

1

1.16

0.98

1.24

1.02

4

1.18

0.98

1.31

1.02

21

1.11

1.05

1.75

1.00

Living young/litter(X±SE)

1

12.2±2.2

11.5±3.5

11.5±2.8

10.2±3.3

4

12.0±2.9

11.5±3.3

9.3±4.1

8.8±4.0

21

11.0±1.9

10.9±3.4

4.6±2.03

8.6±4.5

Dead young/litter(X±SE)

1

0.1±0.0

0.9±0.4

0.7±0.3

1.3±0.7

4

0.2±0.1

0.0±0.0

2.2±1.0

1.4±0.8

21

1.0±0.6

0.6±0.3

4.7±2.1°

0.2±0.1

Average body

weight/litter

(g±SE)

1

94.1±18.1

78.2±24.2

91.1±44.5

64.8±21.2

4

138.8±23.8

119.5±53.3

106.5±32.6

87.5±33.7a

21

466.9±95.2

365.6±85.4

252.7±150.9°

312.5±110.8a

a,b significantly different tot he control group, P < 0.05 or P < 0.01, respectively

Table 3. Average body weight, body length and tail length of rat pups nursed by vanadium-treated mothers

 

 

 

Doses NaVO3[mg/kg/day)

 

 

Day

0

5

10

20

Bodyweight (g±SE)

M

1

7.9±0.9 (63)

7.0±1.1(57)c

6.5±0.9(77)c

6.7±0.6(48)c

4

11.7±1.3 (63)

9.6±1.8(57)c

9.7±1.2(63)c

8.9±0.8(40)c

21

42.0±8.3 (57)

34.3±7.9(56)c

33.7±10.8(35)c

33.6±7.6(38)c

F

1

7.6±0.9 (54)

6.8±1.0 (58)c

6.4±0.9 (62)c

6.5±0.6 (43)c

4

11.2±1.9 (53)

9.5±1.6 (58)c

9.3±1.4 (48)c

8.8±1.1 (39)c

21

41.0±6.7 (51)

32.5±6.3 (53)c

29.7±7.2 (20)c

32.1±8.8 (38)c

Body length

(mm±SE)

M

1

56.8±3.5

54.2±3.6a

53.4±3.4b

53.1±3.0b

4

67.1±3.4

62.0±4.4C

64.7±3.6c

62.2±2.5c

21

119.1±6.1

108.0±10.0c

102.8 7 16.2c

104.8±10.8c

F

1

55.5±3.4

53.6±3.7c

52.4±3.9c

52.0±2.6c

4

65.5±3.0

61.4±3.8c

63.0±3.7c

61.5±3.3c

21

119.7±6.9

105.5±11.3c

100.9±11.7c

104.4±11.3c

Tail length

(mm±SE)

M

1

19.2±2.2

18.7±2.3

18.5±2.6

19.2±1.7

4

30.4±2.4

Z3.9±3.4c

25.8±3.8c

23.6±2.3c

21

66.6±7.0

65.8±7.0

70.7±12.0

62.4±8.6

F

1

19.6±2.7

19.1±2.0

18.3±2.5b

19.6±1.6

4

30.7±2.4

25.1±3.1

26.2±3.8c

24.3±2.5c

21

70.4±8.0

66.3±7.0c

68.9±9.5

61.0±6.0c

a, b, c Significantly different from the control group, P< 0.05, P < 0.01 or P < 0.001 respectively

M = male; F = female

In parentheses the number of animals studied

Table 4. Relative organ weights of rat pups nursed by vanadium treated mothers (g per 100 g body weight±SE)

Doses NaVO3 (mg/kg/day)

 

0

5

10

20

Heart

M

0.79±0.21

0.71±0.12

0.72±0.16

0.64±0.13a

F

0.80±0.23

0.72±0.17

0.92±0.27

0.71±0.10

Lung

M

1.34±0.36

1.42±0.26

1.60±0.55

1.53±0.26

F

1.38±0.34

1.32±0.37

1.76±0.67

1.49±0.13

Spleen

M

0.51±0.18

0.40±0.17

0.54±0.14

0.38±0.17a

F

0.56±0.25

0.39±0.23a

0.53±0.14

0.35±0.11

Liver

M

5.12±0.58

4.72±0.56a

4.63±0.40a

4.57±0.54a

F

5.53±0.45

5.04±0.80a

5.01±0.75a

4.72±0.63

Kidneys

M

1.48±0.26

1.30±0.19a

1.41±0.19

1.39±0.18

F

1.56±0.17

1.38±0.22a

1.45±0.20a

1.32±0.16b

Testicles

M

0.68±0.16

0.62±0.09

0.68±0.08

0.63±0.13

M = males; F = females; a, b significantly different to the control group, P < 0.05 or P < 0.01 respectively

Conclusions:
The doses of NaVO3 administered in this study, which correspond approximately with 1/5, 1/10 and 1/20 of the oral LD50 of mother rats did not produce significant adverse effects on the fertility, reproduction and parturition in the vanadium-treated rats. The highest dose of 20 mg/kg bw/day corresponds to 57.1 mg vanadium-tris-acetylacetonate/kg bw/day.
Executive summary:

Sodium metavanadate was tested for its effects on fetal development, reproduction, gestation and lactation in Sprague Dawley rats. Male rats were administered NaVO3 orally at doses of 0, 5, 10 and 20 mg/kg/day for 60 days before mating with females which had received the same doses from 14 days previous to mating. These females received 0, 5, 10 and 20 mg NaVO3/kg/day during the periods of gestation and lactation. The doses of NaVO3 administered in this study, which correspond approximately with 1/5, 1/10 and 1/20 of the oral LD50 of mother rats did not produce significant adverse effects on the fertility, reproduction and parturition in the vanadium-treated rats. No significant adverse effects could be observed on: number of corpora lutea, implantations, live and dead fetuses, and resorptions. Thus the NOAEL for the parental animals is > 20 mg NaVO3/kg bw/day. The dose of 20 mg/kg bw/day corresponds to 57.1 mg vanadium-tris-acetylacetonate/kg bw/day.

Endpoint:
screening for reproductive / developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Justification for type of information:
please refer to Read-across statement attached in section 13
Reason / purpose for cross-reference:
read-across source
Oestrous cyclicity (parental animals):
not examined
Postmortem examinations (offspring):
not examined
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Prior to exposure, weights were equivalent across all groups. Compared with the air-alone group, there was weight loss for all 2,4-PD exposure groups for the exposure period which was statistically significant at 412 and 694 ppm. During postexposure week 1, males of the 412 and 694 ppm groups had statistically significantly reduced body weight. During postexposure week 2 only males of the 694 ppm group had statistically significant reduced body weights. For the periods week 1-2, 2-3 and weeks 1 -9, males of the 694 ppm group had significantly greater body weight gains than did controls; this was related to the much greater loss in absolute weight during the first week (0-1).
Food efficiency:
not examined
Ophthalmological findings:
effects observed, treatment-related
Description (incidence and severity):
Red ocular discharge and red perioral encrustation were observed in 5 animals. Corneal cloudiness was seen in 4 animals over days 4 to 64, with ulceration in one for the period 27-64 days. At 412 ppm, one male had corneal cloudiness from the fourth day and 3 had corneal ulceration from the 27th day. At 99 ppm 2 animals had corneal cloudiness from the fourth day. These corneal changes were not concentration related.
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
effects observed, treatment-related
Description (incidence and severity):
In males exposed to 694 ppm there was aggressive behavior in 5 of the 20 animals on the first exposure day.
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
There were no histopathological findings in the brain, thymus or testes from the 694 and 0 ppm groups.
Histopathological findings: neoplastic:
no effects observed
Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
effects observed, treatment-related
Description (incidence and severity):
dominant lethal effects (spermatid stage of spermatogenesis)
Reproductive performance:
effects observed, treatment-related
Description (incidence and severity):
Pooled reproductive and gestational data over the 8 week postexposure mating period showed no effects on any reproductive (Table 5) or gestational (Table 6) parameters. However, inspection of the data for animals on a weekly basis showed biologically significant effects as follows. For week 2, at 694 ppm, there was a reduction in the number of corpora lutea, a reduction in total and viable implants per dam, a slight increase in preimplantation loss, and the FL % was slightly increased. For week 3, at both 412 and 694 ppm the number of pregnant females was slightly reduced causing a lowered female fertility index. For week 4, at 694 ppm there was a slight reduction in the number of total and viable implants per litter, a significant increase in preimplantation loss, and the FL % was slightly increased.
In this study 2,4-PD-exposed animals of the 412 and 694 ppm groups showed a transient reduction in body weight and body weight gain. This may have represented a toxic effect, but may also have been a result of the stress from exposure to high concentrations of a pungent odiferous material. The only other clinical finding was corneal opacification and ulceration. However, there was no clear relationship with vapor concentration. Histopathological effects were not seen in the brains of the male rats exposed 6 hours per day for 5 consecutive days to 694 ppm 2,4-PD vapour. Slight reproductive and gestational effects were observed only during weeks 2,3 and 4 of the mating period. Thus, at 2 and 4 weeks there was a reduction, not statistically significant, in total and viable implants per litter (694 ppm), increased preimplantation loss (694 ppm), and the dominant lethal factor, FL%, was slightly increased. At week 3 there was a lowered female fertility index at 412 and 694 ppm.
Dose descriptor:
NOEL
Effect level:
99 ppm
Based on:
test mat.
Sex:
male
Basis for effect level:
other: dominant lethal effects (spermatid stage of spermatogenesis)
Key result
Dose descriptor:
NOEL
Effect level:
411.84 mg/m³ air
Based on:
test mat.
Sex:
male
Basis for effect level:
other: dominant lethal effects (spermatid stage of spermatogenesis)
Remarks on result:
not measured/tested
Key result
Reproductive effects observed:
yes
Lowest effective dose / conc.:
412 ppm
Treatment related:
yes
Relation to other toxic effects:
reproductive effects in the absence of other toxic effects
Dose response relationship:
yes
Relevant for humans:
yes

TABLE 4 Terminal Body Weights and Organ Weights for Control (Air-alone) and 2,4-Pentanedione Exposed Male Fischer 344 Rats

 

Weightsfor Various Exposure Groups as Mean±SDa

0 ppm

99 ppm

412 ppm

694 ppm

Absolute Weights

Final body weight (g)

331.2±12.59

331.0±10.38

324.1 ±10.83

330.3±10.67

Brain weight (g)

1.910±0.061

2017±0.284

1.896±0.050

1.907 ±0.076

Thymus weight (g)

0.365±0.056

0.459±0.358

0.377 ±0.059

0.350±0.055

Testes weight (g)b

3.040±0.179

3.076±0.121

2.873 ±0.501

3.064 ±0.121

Relative Weights

Brain as % body weight

0.577 ±0.020

0.609 ±0.079

0.585±0.023

0.578±0.027'

Thymus as % body weight

0.110±0.015

0.138±0.104

0.116±0.017

0.106±0.016

Thymus as % brain weight

19.115 ±2.835

21.505 ±9.913

19.857 ±2.900

18.403 ±3.200

Testes as % body weight

0.919±0.058

0.930±0.037

0.888 ±0.157

0.928 ±0.043

Testes as % brain weight

159.295 ±10.447

154.188±13.979

151.560±26.207

160.975 ±10.601

bN=20 for each group

a Weight for both testes

TABLE 5: Reproductive Parameters Combined for all 8 Weeks in Dominant Lethal Assay in Fischer 344 Rats

 

Values for Various 2,4-PentanedioneGroups

 0ppm

99ppm

412ppm

694ppm

No. females at start of study

320

320

320

320

No. males at start of study

20

20

20

20

No. mating pairs

160

160

160

160

No. males that producedplug/sperm-positive females

20

20

20

20

No. fertile males

 

20

20

20

20

No. plug/sperm-positivefemales

283

288

274

289

No. pregnant females

273

274

256

270

No. females with one or moreresorptions (percent)

69 (25.3)

68 (24.8)

68 (26.6)

70 (25.9)

No. females with two or moreresorptions (percent)

13 (4.8)

5 (1.8)

7(2.7)

7 ( 2.6)

Mating Index

Female

88.4

90.0

85.6

90.3

Male

100.0

100.0

100.0

100.0

Fertility index

Female

96.5

95.1

93.4

93.4

Male

100.0

100.0

100.0

100.0

TABLE 6: Gestational Parameters Combined for all 8 Weeks in Dominant Lethal Assayin Fischer 344 Rats

 

Values forVarious 2,4-Pentanedione Groupsa

0ppm

99ppm

412ppm

694ppm

Corpora lutea/dam

11.4±1.6 (273)

11.5±1.7 (274)

11.7±1.7 (253)b

115±1.7(269)c

Total implants/litter

8.7±3.2(273)

8.7±3.2 (274)

9.1±3.2 (256)

8.7 ±3.3(270)

Pre-implantationloss/litter (%)d

24.4±24.8 (273)

25.6±24.8(274)

21.8±23.6 (256)

25.4 + 24.6 (270)

Viable implants/litter

8.4±3.2(273)

8.4±3.2(274)

8.7 ±3.2(256)

8.4 ±3.2(270)

Non-viable implants/litter

0.3±0.6(273)

0.3 ±0.5(274)

0.3 ±0.7(256)

0.3±0.6(270)

Early resorptions/litter

0.2±0.5 (273)

0.2 ±0.4 (274)

0.2 ±0.7 (256)

0.2±0.5(270)

Late resorptions/litter

0.1±0.3 (273)

0.1 ±0.3 (274)

0.1±0.3 (256)

0.1+0.3 (270)

Post-implantation loss/litter(%)e

3.4±7.1 (273)

3.2±6.6 (274)

45 ±13.2 (256)

4.4+12.3 (270)

Ratio [Dead implants/ Total implants]

0.03±0.07(273)

0.03 ±0.07 (274)

0.04±0.13(256)

0.04±0.12(270)

% live implants/litter

96.6±7.1 (273)

96.8±6.6(274)

95.5±13.2 (256)

95.6 ±12.3 (270)

FL(%)

0.0

0.0

-3.6

0.0
Conclusions:
Although not statistically significant, the effects at weeks 2,3, and 4 are clearly dose-related, and are considered to be biologically significant. The time period for these reproductive and gestational effects corresponds to utilization of sperm which were at the spermatid stage of spermatogenesis over the 2,4-PD vapour exposure period. Thus, the results are compatible with a transient weak dominant lethal effect at the spermatid stage of spermatogenesis, and accord with the in vitro increases in sister chromatid exchanges and clastogenic effects in CHO cells, and positive in vivo micronucleus tests. The "no-observable effect level" for all effects was 99 ppm. The results, although not statistically significant, are dose-related and compatible with a transient slight dominant lethal effect at the spermatid stage of spermatogenesis. This result is also valid for the target substance vanadium-tris-acetylacetonate, since the source substance acetylacetonate is a hydrolysis product of vanadium-tris-acetylacetonate.
Executive summary:

Male Fischer 344 rats, 20 per group, were exposed to 2,4-PD vapour concentrations (mean ± SD) of 0, 99.1 ± 2.2, 412 ± 12.6 and 694 ± 9.1 ppm, for 6 hr/day for 5 consecutive days. The day following the final exposure they were bred to unexposed female Fischer 344 rats, 2 per week for 8 consecutive weeks. Weight loss occurred with males during 2,4-PD exposure for the 412 and 694 ppm groups, with compensatory increased weight at 694 ppm, for the first two weeks postexposure. No histopathological change was seen in brain, testes or thymus from high concentration males sacrificed after eight weeks of mating. Minor transient reproductive and gestational effects were present at 412 and 694 ppm. At week 2 there was a reduction, not statistically significant, in the number of corpora lutea and total and viable implants per dam at 694 ppm, and a slight increase in preimplantation loss. At week 3 the number of pregnant females was slightly reduced at 412 and 694 ppm, causing a lowered female fertility index. At week 4 there was a slight reduction in the number of total and viable implants per litter and a significant preimplantation loss at 694 ppm. The dominant lethal factor (FL%) was increased slightly at 694 ppm for weeks 2 and 4. Thus, the "no observable effect" level for dominant lethal effects was 99 ppm. The results, although not statistically significant, are dose-related and compatible with a transient slight dominant lethal effect at the spermatid stage of spermatogenesis.

This result is also valid for the target substance vanadium-tris-acetylacetonate, since the source substance acetylacetonate is a hydrolysis product of vanadium-tris-acetylacetonate.

Effect on fertility: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
57.1 mg/kg bw/day
Study duration:
subacute
Species:
mouse
Effect on fertility: via inhalation route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LOAEC
30.6 mg/m³
Study duration:
subacute
Species:
mouse
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Vanadium compounds

Hazard values of the vanadium containing source substances were converted to the target substance vanadium acetylacetonate. The hazard values for vanadium acetylacetonate were calculated as follows:

Effect concentration of vanadium in source substance (EC (V))

MW (source substance) = 116.98 g/mol

MW (Vanadium) = 50.94 g/mol

ratio of Vanadium in source substance = n* 50.94 / MW (source substance)

EC (V) = EC(source substance) x ratio of vanadium in source substance

Effect concentraion of target substance vanadium acetylacetonate (VAA)

MW V in VAA = 50.94 g/mol

MW VAA = 348.27 g/mol

EC (VAA) in target = EC (V) in source / 50.94 x 348.27

Sodium metavanadate was tested for its effects on fetal development, reproduction, gestation and lactation in Sprague Dawley rats. Male rats were administered NaVO3 orally at doses of 0, 5, 10 and 20 mg/kg/day for 60 days before mating with females which had received the same doses from 14 days previous to mating. These females received 0, 5, 10 and 20 mg NaVO3/kg/day during the periods of gestation and lactation. The doses of NaVO3 administered in this study, which correspond approximately with 1/5, 1/10 and 1/20 of the oral LD50 of mother rats did not produce significant adverse effects on the fertility, reproduction and parturition in the vanadium-treated rats. No significant adverse effects could be observed on: number of corpora lutea, implantations, live and dead fetuses, and resorptions. Thus the NOAEL for the parental animals is > 20 mg NaVO3/kg bw/day. The dose of 20 mg/kg bw/day corresponds to 57.1 mg vanadium-tris-acetylacetonate/kg bw/day (Domingo 1986).

Effects of vanadium pentoxide (V2O5) treatment on reproductive function in male mice were investigated. V2O5 was administered intraperitoneally at a dose of 8.5 µg/g bw every three days for 60 days. Reproductive functions were evaluated with fertility rate, implants, resorptions, sperm counts, motility, and morphology. V2O5 treatment resulted in a decrease in fertility rate, implantations, live fetuses, and fetal weight, and an increase in the number of resorptions/dam. Sperm count, motility, and morphology were impaired with the advancement of treatment. The applied dose corresponds to 32.5 µg/g bw/0.3 d (ca. 10.84 mg/kg bw/d) of vanadium-tris-acetylacetonate (Altamirano-Lozano 1996).

Conclusion

While in the study by Domingo et al. (1986) no significant adverse effects on the fertility and reproduction were observed in male and female rats, Altamirano-Lozano (1996) found a decrease in fertility rate, implantations, live fetuses, and fetal weight, and an increase in the number of resorptions/dam. In addition, sperm count, motility, and morphology were impaired with the advancement of treatment (Altamirano-Lozano, 1996). This is supported by the findings in a 3 months inhalation study (NTP, 2002). In this study also effects on sperm motility were observed (please refer to 'other information').

2,4 -pentanedione

In a dominant lethal assay male Fischer 344 rats, 20 per group, were exposed to 2,4-PD vapour concentrations (mean ± SD) of 0, 99.1 ± 2.2, 412 ± 12.6 and 694 ± 9.1 ppm, for 6 hr/day for 5 consecutive days. The day following the final exposure they were bred to unexposed female Fischer 344 rats, 2 per week for 8 consecutive weeks. Minor transient reproductive and gestational effects were present at 412 and 694 ppm. At week 2 there was a reduction, not statistically significant, in the number of corpora lutea and total and viable implants per dam at 694 ppm, and a slight increase in preimplantation loss. At week 3 the number of pregnant females was slightly reduced at 412 and 694 ppm, causing a lowered female fertility index. At week 4 there was a slight reduction in the number of total and viable implants per litter and a significant preimplantation loss at 694 ppm. The dominant lethal factor (FL%) was increased slightly at 694 ppm (2900 mg/m3) for weeks 2 and 4. Thus, the "no observable effect" level for dominant lethal effects was 99 ppm (412 mg/m3 air). The results, although not statistically significant, are dose-related and compatible with a transient slight dominant lethal effect at the spermatid stage of spermatogenesis (Tyl, 1989). The statistical significant occurence of preimplanatation, but not postimplanatation losses indicates that unfertilized ova are the reason for these effects. This suggests toxic effects on sperm cells (e.g. reduction of number, inability to penetrate the ovum). Effective germ cell mutagenes, on the other hand, lead to the increase of postimplantation losses. Therefore, this study shows toxic effects, but not mutagenic effects on germ cells (MAK 2007).

Effects on developmental toxicity

Description of key information

oral

NaVO3 rat, OECD TG 421, toxicity to offspring at a parental dose level of 5 mg/kg bw/day (not toxic to parental animals) - VAA dose level = 14.3 mg/kg bw/day

Na3VO4 mouse, gestational day 6 -15: NOAEL (P) = 7.5 mg/kg bw/day, NOAEL (F1) =15 mg/kg bw/day - VAA: NOAEL (P) = 14.2 mg/kg bw/day, NOAEL (F1) = 28.4 mg/kg bw/day

inhalation

Acetylacetonate, rat, gestational day 6 -15: NOEC = 220 mg/m3

Link to relevant study records

Referenceopen allclose all

Endpoint:
developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Justification for type of information:
please refer to Read-across statement attached in section 13
Reason / purpose for cross-reference:
read-across source
Clinical signs:
not specified
Mortality:
no mortality observed
Body weight and weight changes:
not specified
Food efficiency:
not specified
Ophthalmological findings:
not examined
Haematological findings:
not examined
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:
not examined
Gross pathological findings:
not examined
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
not specified
Details on results:
There were no signs of maternal toxicity during the study.
Number of abortions:
no effects observed
Description (incidence and severity):
Although the administration of 10 and 20 mg/kg/day NaVO3 resulted in an increase in the number of dead fetuses as in the number of resorptions when compared to the control group, these increases were not significant (P > 0.05).
Please refer to Table 1.
Pre- and post-implantation loss:
no effects observed
Description (incidence and severity):
Please refer to Table 1.
Total litter losses by resorption:
no effects observed
Description (incidence and severity):
Please refer to Table 1.
Early or late resorptions:
not specified
Dead fetuses:
no effects observed
Description (incidence and severity):
Please refer to Table 1.
Changes in pregnancy duration:
not specified
Changes in number of pregnant:
no effects observed
Description (incidence and severity):
Please refer to Table 1.
Other effects:
not specified
Details on maternal toxic effects:
The doses of NaVO3 administered in this study, which correspond approximately with 1/5, 1/10 and 1/20 of the oral LD50 of mother rats did not produce significant adverse effects on the fertility, reproduction and parturition in the vanadium-treated rats. In a previous study, the effect concentration (fetuses) of 5 mg/kg bw/day NaVO3 in mother rats did not have toxic results for adult rats.
Dose descriptor:
NOAEL
Effect level:
> 57.1 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
dead fetuses
early or late resorptions
other: number of implantations
Abnormalities:
no effects observed
Fetal body weight changes:
effects observed, treatment-related
Description (incidence and severity):
Body weight showed significant decreases during the whole the period of lactation in both males and females, when compared with the control values.
Reduction in number of live offspring:
no effects observed
Description (incidence and severity):
The number of living and dead young per litter in the treated rats did not show any significant differences with the control group
Changes in sex ratio:
not specified
Changes in litter size and weights:
effects observed, treatment-related
Description (incidence and severity):
The number of litters in the treated rats did not show any significant differences with the control group. The average body weight per litter did not show any significant differences with the control group on days 1 and 4 of nursing. Some significant decrease could be observed on day 21 of nursing. However, no effect dose-response may be induced.
Changes in postnatal survival:
no effects observed
External malformations:
not specified
Skeletal malformations:
not specified
Visceral malformations:
not specified
Other effects:
effects observed, treatment-related
Description (incidence and severity):
The body length and tail length of animals in the treated groups showed significant decreases during all the period of lactation in both males and females, when compared with the control values. There were significant decreases in the relative organ weights of spleen, liver and kidneys observed in the pups killed after 21 days of lactation. As can be seen, slight effect dose-response may be induced.
Details on embryotoxic / teratogenic effects:
The body length and tail length of animals in the treated groups showed significant decreases during all the period of lactation in both males and females, when compared with the control values. There were significant decreases in the relative organ weights of spleen, liver and kidneys observed in the pups killed after 21 days of lactation. As can be seen, slight effect dose-response may be induced. Body weight showed significant decreases during the whole the period of lactation in both males and females, when compared with the control values.
Dose descriptor:
dose level: toxic to offspring
Effect level:
14.3 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
fetal/pup body weight changes
other: body length and tail length, relative organ weights of spleen, liver and kidneys
Remarks on result:
other: converted to VAA
Abnormalities:
effects observed, treatment-related
Localisation:
other: body length and tail length, relative organ weights of spleen, liver and kidneys
Developmental effects observed:
yes
Lowest effective dose / conc.:
14.3 mg/kg bw/day
Treatment related:
yes
Relation to maternal toxicity:
developmental effects in the absence of maternal toxicity effects
Dose response relationship:
yes
Relevant for humans:
yes

Table 1. Effects of NaVO3 given orally to rats killed on day 14 of gestation (a)

 

Doses NaVO3 (mg/kg/day)

 

0

5

10

20

No. of pregnant rats

6

8

7

6

Corpora lutea

15.5±3.0

16.0±2.6

16.0±1.8

13.8±1.7

Total implants

12.7±2.7

13.6±1.9

14.0±2.6

12.7±1.0

Live fetuses

11.7±1.8

12.5±1.9

12.3±2.9

9.8±1.3

Dead fetuses

0.3±0.2

0.4±0.2

0.7±0.3

0.8±0.4

resorptions

0.7±0.3

0.7±0.3

1.0±0.4

2.1±0.8

a The results are expressed as mean values±SE

Table 2. Summary of data rat pups nursed by vanadium-treated mothers during a period of 21-days

Doses NaVO3 (mg/kg/day)

 

Day

0

5

10

20

No. of litters

1

11

10

12

9

4

11

10

11

8

21

11

10

9

7

No. of living young

1

117

115

139

95

4

116

115

111

79

21

108

109

55

76

No. of dead young

1

0

8

5

5

4

1

0

28

16

21

8

6

56

3

Dead/living

ratio(x100)

1

0.0

6.9

3.6

5.2

4

0.8

0.0

20.1

16.8

21

6.8

5.2

50.4

3.7

Male/female

ratio

1

1.16

0.98

1.24

1.02

4

1.18

0.98

1.31

1.02

21

1.11

1.05

1.75

1.00

Living young/litter (X±SE)

1

12.2±2.2

11.5±3.5

11.5±2.8

10.2±3.3

4

12.0±2.9

11.5±3.3

9.3±4.1

8.8±4.0

21

11.0±1.9

10.9±3.4

4.6±2.03

8.6±4.5

Dead young/litter (X±SE)

1

0.1±0.0

0.9±0.4

0.7±0.3

1.3±0.7

4

0.2±0.1

0.0±0.0

2.2±1.0

1.4±0.8

21

1.0±0.6

0.6±0.3

4.7±2.1°

0.2±0.1

Average body

weight/litter

(g±SE)

1

94.1±18.1

78.2±24.2

91.1±44.5

64.8±21.2

4

138.8±23.8

119.5±53.3

106.5±32.6

87.5±33.7a

21

466.9±95.2

365.6±85.4

252.7±150.9°

312.5±110.8a

a,b significantly different tot he control group, P < 0.05 or P < 0.01, respectively

Table 3. Average body weight, body length and tail length of rat pups nursed by vanadium-treated mothers

 

 

 

Doses NaVO3 (mg/kg/day)

 

 

Day

0

5

10

20

Bodyweight (g±SE)

M

1

7.9±0.9 (63)

7.0±1.1(57)c

6.5±0.9(77)c

6.7±0.6(48)c

4

11.7±1.3 (63)

9.6±1.8(57)c

9.7±1.2(63)c

8.9±0.8(40)c

21

42.0±8.3 (57)

34.3±7.9(56)c

33.7±10.8(35)c

33.6±7.6(38)c

F

1

7.6±0.9 (54)

6.8±1.0 (58)c

6.4±0.9 (62)c

6.5±0.6 (43)c

4

11.2±1.9 (53)

9.5±1.6 (58)c

9.3±1.4 (48)c

8.8±1.1 (39)c

21

41.0±6.7 (51)

32.5±6.3 (53)c

29.7±7.2 (20)c

32.1±8.8 (38)c

Body length

(mm±SE)

M

1

56.8±3.5

54.2±3.6a

53.4±3.4b

53.1±3.0b

4

67.1±3.4

62.0±4.4C

64.7±3.6c

62.2±2.5c

21

119.1±6.1

108.0±10.0c

102.8 7 16.2c

104.8±10.8c

F

1

55.5±3.4

53.6±3.7c

52.4±3.9c

52.0±2.6c

4

65.5±3.0

61.4±3.8c

63.0±3.7c

61.5±3.3c

21

119.7±6.9

105.5±11.3c

100.9±11.7c

104.4±11.3c

Taillength

(mm±SE)

M

1

19.2±2.2

18.7±2.3

18.5±2.6

19.2±1.7

4

30.4±2.4

Z3.9±3.4c

25.8±3.8c

23.6±2.3c

21

66.6±7.0

65.8±7.0

70.7±12.0

62.4±8.6

F

1

19.6±2.7

19.1±2.0

18.3±2.5b

19.6±1.6

4

30.7±2.4

25.1±3.1

26.2±3.8c

24.3±2.5c

21

70.4±8.0

66.3±7.0c

68.9±9.5

61.0±6.0c

a, b, c Significantly different from the control group, P< 0.05, P < 0.01 or P < 0.001 respectively

M = male; F = female

In parentheses the number of animals studied

Table 4. Relative organ weights of rat pups nursed by vanadium treated mothers (g per 100 g body weight±SE)

Doses NaVO3 (mg/kg/day)

 

0

5

10

20

Heart

M

0.79±0.21

0.71±0.12

0.72±0.16

0.64±0.13a

F

0.80±0.23

0.72±0.17

0.92±0.27

0.71±0.10

Lung

M

1.34±0.36

1.42±0.26

1.60±0.55

1.53±0.26

F

1.38±0.34

1.32±0.37

1.76±0.67

1.49±0.13

Spleen

M

0.51±0.18

0.40±0.17

0.54±0.14

0.38±0.17a

F

0.56±0.25

0.39±0.23a

0.53±0.14

0.35±0.11

Liver

M

5.12±0.58

4.72±0.56a

4.63±0.40a

4.57±0.54a

F

5.53±0.45

5.04±0.80a

5.01±0.75a

4.72±0.63

Kidneys

M

1.48±0.26

1.30±0.19a

1.41±0.19

1.39±0.18

F

1.56±0.17

1.38±0.22a

1.45±0.20a

1.32±0.16b

Testicles

M

0.68±0.16

0.62±0.09

0.68±0.08

0.63±0.13

M = males; F = females; a, b significantly different to the control group, P < 0.05 or P < 0.01 respectively

Conclusions:
The doses of NaVO3 administered in this study, which correspond approximately with 1/5, 1/10 and 1/20 of the oral LD50 of mother rats did produce significant adverse effects on the development of the offspring always significantly decreased from birth and during all the lactation period. All the doses used produced toxic effects in the offspring. Significant decreases in the weights of liver, spleen and kidneys of the pups whose mothers received NaVO3 during the lactation, are due to a reduction in the growth of these animals according to the criterion "organ weight/body weight".
The results of this experiment demonstrate that a dose of at least 5 mg/kg/day NaVO3 in mother rats (corresponding to roughly 2.1 mg vanadium/kg body wt/day) may result in toxicity for the offspring. This corresponds to a dose of 14.3 mg vanadium-tris-acetylacetonate/ kg bw/day. or details on the calculations, please refer to "Overall remarks".
Executive summary:

Sodium metavanadate was tested for its effects on fetal development, reproduction, gestation and lactation in Sprague Dawley rats. Male rats were administered NaVO3 orally at doses of 0, 5, 10 and 20 mg/kg/day for 60 days before mating with females which had received the same doses from 14 days previous to mating. These females received 0, 5, 10 and 20 mg NaVO3/kg/day during the periods of gestation and lactation. No significant adverse effects could be observed on: number of corpora lutea, implantations, live and dead fetuses, and resorptions. Significant decreases were observed in the development of the pups in all the vanadium -treated groups. All the doses used produced toxic effects in the offspring in the absence of maternal toxicity. Toxic effects observed were: The body length and tail length of animals in the treated groups showed significant decreases during all the period of lactation in both males and females, when compared with the control values. There were significant decreases in the relative organ weights of spleen, liver and kidneys observed in the pups killed after 21 days of lactation. As can be seen, slight effect dose-response may be induced. Body weight showed significant decreases during the whole the period of lactation in both males and females, when compared with the control values. The results of this experiment demonstrate that a dose of at least 5 mg/kg/day NaVO3 in mother rats (corresponding to roughly 2.1 mg vanadium/kg body wt/day) results in toxicity for the offspring. This corresponds to a dose of 14.3 mg vanadium-tris-acetylacetonate/ kg bw/day.

Endpoint:
developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Justification for type of information:
please refer to Read-across statement attached in section 13
Reason / purpose for cross-reference:
read-across source
Clinical signs:
not specified
Mortality:
mortality observed, treatment-related
Description (incidence):
The highest dose (60 mg/kg/d) was extraordinarily toxic, since 17 dams (from 19 pregnant females dosed) died during the treatment period. Consequently, the two remaining dams were not included in the teratological evaluation of orthovanadate. At 30 mg/kg/d, four dams (from 18 pregnant females dosed) were found dead during the study, although exposure to 7.5 or 15 mg/kg/d of sodium orthovanadate did not result in any maternal death.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Maternal weight gain was significantly reduced below control values in the 30-mg/kg/d group on gestational days 6-15. At scheduled termination on gestation day 18, there were not significant decreases in body weight, corrected body weight, and change in corrected body weight.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Food consumption exhibited a significant decrease in the 15 and 30 mg/kg/d dose groups on gestational days 0-18 (compound intake is not affected since it is applied by gavage).
Food efficiency:
not specified
Ophthalmological findings:
not examined
Haematological findings:
not examined
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):
There was a decrease in absolute and relative liver weight in the 15-mg/kg/d group and an increase in relative kidney weight at 30 mg/kg/d, which were statistically significant vs controls (Table 2). However, the decreases in liver weight were not dose-related and therefore they were not attributed to treatment. At scheduled termination on gestation day 18, there were not significant decreases in gravid uterine weight.
Gross pathological findings:
not examined
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
not specified
Details on results:
please refer to "Any other information on results incl. tables"
Number of abortions:
effects observed, non-treatment-related
Pre- and post-implantation loss:
effects observed, non-treatment-related
Total litter losses by resorption:
effects observed, non-treatment-related
Early or late resorptions:
effects observed, non-treatment-related
Dead fetuses:
effects observed, non-treatment-related
Changes in pregnancy duration:
not examined
Changes in number of pregnant:
not examined
Other effects:
not specified
Details on maternal toxic effects:
Evaluation of gestational parameters for the mice indicated no treatment-related effects on number of total implantations per litter, number of live and nonlive (dead plus resorbed) fetuses per litter, sex ratio, fetal body weights, and the number of stunted fetuses. No significant differences in the number of early and late resorptions, or in the number of dead and live fetuses, were observed at any dosage level employed in the present study.
please refer to "Any other information on results incl. tables"
Key result
Dose descriptor:
NOAEL
Effect level:
14.2 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
body weight and weight gain
food consumption and compound intake
mortality
Abnormalities:
no effects observed
Fetal body weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
no treatment-related effects on fetal body weights
Reduction in number of live offspring:
effects observed, non-treatment-related
Description (incidence and severity):
no treatment-related effects on number of live and nonlive (dead plus resorbed) fetuses per litter
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
not specified
Changes in postnatal survival:
not examined
External malformations:
no effects observed
Description (incidence and severity):
Sodium orthovanadate did not induce significant incidence of gross and visceral malformations or variations in mouse fetuses.
Skeletal malformations:
effects observed, treatment-related
Description (incidence and severity):
Treatment-related changes were found during the examination of the incidence and type of skeletal anomalies. Significant decreases in the number of ossified sacrococcygeal vertebrae, as well as in the number of ossified forelimb and hindlimb proximal phalanges, were the most conspicuous defects observed. No significant increases in the number of fetuses with reduced ossification of occipital and parietal bones or sternebrae were observed.
Visceral malformations:
no effects observed
Description (incidence and severity):
Sodium orthovanadate did not induce significant incidence of gross and visceral malformations or variations in mouse fetuses.
Other effects:
not specified
Details on embryotoxic / teratogenic effects:
Fetotoxicity was evidenced by an incomplete skeletal ossification process is some districts of fetuses from dams exposed to sodium orthovanadate at 30 mg/kg/d.
Please refer to "Any other information on results incl. tables".
Key result
Dose descriptor:
NOAEL
Effect level:
28.4 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: delay in the ossification process of some skeletal districts
Abnormalities:
effects observed, treatment-related
Localisation:
skeletal: forelimb
skeletal: vertebra
skeletal: hindlimb
Description (incidence and severity):
Significant decreases in the number of ossified sacrococcygeal vertebrae, as well as in the number of ossified forelimb and hindlimb proximal phalanges, were the most conspicuous defects observed
Developmental effects observed:
yes
Lowest effective dose / conc.:
56.8 mg/kg bw/day
Treatment related:
yes
Relation to maternal toxicity:
developmental effects as a secondary non-specific consequence of maternal toxicity effects
Dose response relationship:
no
Relevant for humans:
yes

Table 1: Body Weight Gain and Food Consumption Data of Mice Given Oral Doses of Sodium Orthovanadate on Gestation Days 6-15

Dose, mg/kg/d

 

0

7.5

15

30

Number of dams

18

18

20

14

Body weight gain during gestation daysa

0-6

(pretreatmentperiod)

4.1±1.7

3.3±2.0

4.2±1.6

3.6±1.9

6-9

1.1±3.2

3.2±2.6

1.2±1.7

1.3±1.4

6-12

5.3±3.4

5.4±4.7

5.4±3.8

4.7±2.5

6-15

(treatment period)

11.8±3.6

11.4±3.1

9.6±3.7

8.5±3.7b

15-1

(posttreatment period)

6.6±2.3

5.8±2.8

6.3±3.0

7.0±3.1

Total,0-18

22.5±3.8

20.5±4.1

20.1±5.5

19.1±5.2

Food consumption (g/dam) during gestation daysa

0-6

(pretreatment period)

41.1±18.8

48.0±17.1

26.9±16.4

30.9±12.2

6-9

20.4i2.9

19.3±7.2

17.2±3.9b

15.0±4.7c

6-12

41.2±14.6

39.2±13.3

35.6±10.6

34.2±12.9b

6-15

(treatment period)

63.9±6.8

60.1±15.8

53.8±7.5c

54.0±8.2c

15-18

(posttreatment period)

25.9±5.0

22.0±6.1

21.9±4.2

26.0±4.1

Total,0-18

130.9±24.2

130.1±28.0

102.6± 28.5b

110.9±20.2b

 

aResults are means ± SD.

bSignificantly different from control, p < 0.05.

cSignificantly different from control, p < 0.01.

Table 2: Body and Organ Weights at Sacrifice for Control and Orthovanadate-Treated Pregnant Mice a

Dose, mg/kg/d

 

0

7.5

15

30

Body weight atsacrifice,g

50.1±6.4

50.8±5.8

46.3±7.7

47.1±7.3

Gravid uterine weight,g

18.0±4.1

18.4±3.4

15.5±5.8

14.7±5.6

Corrected body weight,gb

32.1±3.4

32.4±3.8

30.8±4.1

32.4±3.6

Corrected body-weightchange,gc

4.6±3.3

4.1±3.0

4.6±3.4

4.4±2.7

Liver weight,g

2.18±0.23

1.92±0.27

1.79±0.19f

2.24±0.20

Relative liver weight,%d

6.79±0.66

5.93±0.58

5.81±0.54e

6.91±0.72

Kidney weight,g

0.34±0.07

0.35±0.05

0.32±0.05

0.36±0.04

Relative kidney weight,%d

1.06±0.10

1.08±0.08

1.04±0.09

1.11±0.10e

aResults are means±SD.

bCorrected body weight = body weight at sacrifice - gravid uterine weight.cCorrected body-weight change = corrected body weight - body weight at gestation d 0.

dCalculated as percentage of corrected body weight.

eSignificantly different from control, p < 0.05.

fSignificantly different from control, p < 0.01.

Table 3: Summary of Observations at Time of Cesarean Section of Mice Treated with Orthovanadate on Gestation Days 6-15

Dose, mg/kg/d

 

0

7.5

15

30

Number of litters

18

18

20

14

Total implants/littera

13.0±2.7

13.6±2.5

12.3±4.2

12.9±2.8

Live fetuses/littera

11.9±2.3

12.4±2.0

11.2±4.1

10.4±4.3

Early resorptions/littera

0.6±0.6

0.8±0.8

0.7±0.8

0.7±0.9

Later resorptions/littera

0.2±0.4

0.2±0.6

0.2±0.5

1.8±3.9b

Dead fetuses/littera

0.3±0.7

0.2±0.5

0.2±0.4

0.0±0.0

Fetal body weight(g)a

1.14±0.14

1.12±0.17

1.05±0.11

1.06±0.13

Sex ratio, M/F

0.97

1.02

0.89

0.88

Number of stunted fetusesc

2(2)

3(2)

6(3)

1(1)

 

aResults are means±SD.

bOne litter at 30 mg/kg/d contained no viable implants.

cNumbers in parentheses indicate number of affected litters.

 

Conclusions:
In conclusion, treatment with sodium orthovanadate during the period of organogenesis resulted in slight fetal-growth retardation in mice, but only in the presence of well-defined maternal toxicity. The NOAEL for maternal toxicity induced by sodium orthovanadate was 7.5 mg/kg/d, whereas 15 mg/kg/d represented a NOAEL for developmental toxicity. There was no evidence of embryotoxicity or teratogenicity in mice under the conditions of this study. The NOAEL for maternal toxicity of 7.5 mg/kg bw/day corresponds to 14.2 mg/kg bw/day vanadium-tris-acetylacetonate. The NOAEL for fetal toxicity of 15 mg/kg bw/day corresponds to 28.4 mg/kg bw/day vanadium-tris-acetylacetonate. The lowest dose leading to toxic effects in fetus of 30 mg/kg bw/day corresponds to 56.8 mg/kg bw/day vanadium-tris-acetylacetonate. For details on the calculations, please refer to "Overall remarks".
Executive summary:

Sodium orthovanadate in deionized water was administered once daily by gavage on gestational days 6-15 to mice at doses of 0, 7.5, 15, 30, and 60 mg/kg. Dams were killed on day 18 of pregnancy, and fetuses were examined for external, visceral, and skeletal defects. Maternal toxicity was observed at the highest doses of sodium orthovanadate, as evidenced by a significant number of deaths (60 and 30 mg/kg/d) and reduced weight gain and food consumption (30 and 15 mg/kg/d). Embryolethality and teratogenicity were not observed at maternally toxic doses and below, but fetal toxicity was evidenced by a significant delay in the ossification process of some skeletal districts at 30 mg/kg/d. The no-observed-adverse-effect level (NOAEL) for maternal toxicity was 7.5 mg/kg/d, and 15 mg/kg/d represented a NOAEL for developmental toxicity in mice under the conditions of this study. The NOAEL for maternal toxicity of 7.5 mg/kg bw/day corresponds to 14.2 mg/kg bw/day vanadium-tris-acetylacetonate. The NOAEL for fetal toxicity of 15 mg/kg bw/day corresponds to 28.4 mg/kg bw/day vanadium-tris-acetylacetonate. The lowest dose leading to toxic effects in fetus of 30 mg/kg bw/day corresponds to 56.8 mg/kg bw/day vanadium-tris-acetylacetonate.

Endpoint:
developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Justification for type of information:
please refer to Read-across statement attached in section 13
Reason / purpose for cross-reference:
read-across source
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Reduced body weights at 398 ppm on gd 9, 12, 15 and 18, but not on gd 21. Also, maternal weight gain was reduced at 398 ppm for the intervals gd 6-9, 6¬12,6-15, and 6-18, but no difference was present for the postexposure gd interval, gd 15-21. There was a very slight, nonstatistically significant, reduction in body weights at 202 ppm for gd 6-9, 6-12, and 6-15. At sacrifice on gd 21 there were no effects of 2,4-PD vapour concentration on maternal body weight (total or corrected for gravid uterine weight), or on absolute or relative (to corrected body weight) thymus weight.
Food efficiency:
not examined
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:
effects observed, treatment-related
Description (incidence and severity):
Absolute and relative liver weights were increased at 202 but not 398 ppm.
Gross pathological findings:
no effects observed
Neuropathological findings:
no effects observed
Description (incidence and severity):
Light microscopical examination of maternal brains revealed no evidence of gliosis, and no treatment-related differences in the low incidence of other neuropathological findings.
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
no effects observed
Number of abortions:
not examined
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Changes in pregnancy duration:
not examined
Changes in number of pregnant:
no effects observed
Other effects:
no effects observed
Dose descriptor:
NOEC
Effect level:
53 ppm (analytical)
Based on:
test mat.
Basis for effect level:
body weight and weight gain
Key result
Dose descriptor:
NOEC
Effect level:
220.48 mg/m³ air (analytical)
Based on:
test mat.
Basis for effect level:
body weight and weight gain
Abnormalities:
no effects observed
Fetal body weight changes:
effects observed, treatment-related
Description (incidence and severity):
On gd 21, foetal body weight per litter was significantly reduced at 398 ppm for males, females, and all foetuses and at 202 ppm for males and all foetuses. Female foetal weight was also reduced at 202 ppm, but the difference was not statistically significant relative to that in the air-alone control group.
Reduction in number of live offspring:
not examined
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
effects observed, treatment-related
Description (incidence and severity):
On gd 21, foetal body weight per litter was significantly reduced at 398 ppm for males, females, and all foetuses and at 202 ppm for males and all foetuses. Female foetal weight was also reduced at 202 ppm, but the difference was not statistically significant relative to that in the air-alone control group.
Changes in postnatal survival:
not examined
External malformations:
no effects observed
Description (incidence and severity):
The incidence of external variations was unaffected by treatment.
Skeletal malformations:
no effects observed
Visceral malformations:
no effects observed
Other effects:
effects observed, treatment-related
Description (incidence and severity):
A total of 17 skeletal variations (out of 79 observed) exhibited statistically significant changes in incidence in the 398 ppm group, suggesting a consistent pattern of fetotoxicity at the high concentrations. The incidence of one visceral variation (out of 46 observed), partial foetal atelectasis, was increased at 398 ppm relative to that of the controls. There appeared to be a slightly increased number of foetuses (but not litters) exhibiting visceral and total variations at all 2,4-PD vapour concentrations, but the incidences were not dose related and were not statistically significantly different from those of the control. There were no differences among the groups in the incidence of individual malformations, malformations by category (external, visceral and skeletal), or total malformations.
Dose descriptor:
NOEC
Effect level:
53 ppm (analytical)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
fetal/pup body weight changes
other: skeletal variations
Key result
Dose descriptor:
NOEC
Effect level:
220.48 mg/m³ air (analytical)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
fetal/pup body weight changes
other: skeletal variations
Abnormalities:
no effects observed
Developmental effects observed:
no

TABLE 7 Body Weight of Foetuses Removed on Gestational Day 21 from 2,4-PD Vapour-exposed and Air-alone Control Fischer344 Rats.

Foetal Weight per Littera(g)

2,4-PD Concentration (ppm)

 0

53

202

398

Number of litters

22

20

23

20

All foetuses

4.57 ± 0.20

4.55 ± 0.23

4.42 ± 0.14e

4.10 ± 0.14f

Male foetuses

4.71 ± 0.18b

4.68 ± 0.24c

4.57 ± 0.19e

4.24 ± 0.14d,f

Female foetuses

4.40 ± 0.19b

4.41 ± 0.21

4.28 ± 0.17

3.95 ± 0.14d,f

aValues as means ± S.D.

bN = 21 because one litter contained only femalefoetuses and one litter contained only male foetuses at 0ppm

CN = 19 because onelitter contained only female foetuses at 53 ppm

dN = 19 because one litter contained only female foetuses and one litter contained only male foetuses at 398ppm

ep < 0.05 (compared to controls)

fp < 0.001 (compared to controls)

TABLE 8 Significant Variations Observed in Foetuses and Litters; Dams Exposed to 2,4-PD Vapour on Gestational Days 6 through 15a

Group (ppm)

 

Foetuses

 

 

Litters

 

 

 

0

53

202

398

0

53

202

398

Number examined externallyb

 

 

 

 

 

 

 

 

No significant findings

183

162

195

167

22

20

23

20

Number examined

 

 

 

 

 

 

 

 

viscerallyc

96

87

104

90

22

20

23

20

Partial Foetal

8

15

21

14

5

10

9

12f

atelectasis

8.3

17.2

20.2

15.6

22.7

50.0

39.1

60.0

Number examined

 

 

 

 

 

 

 

 

skeletallyd

87

75

91

77

22

20

23

19

Cervical centrum

2

2

2

10

2

1

2

9f

#6unossified

2.3

2.7

2.2

13.0

9.1

5.0

8.7

47.4

Cervical centrum

18

13

7

1

14

9

6f

 

#6bilobed

20.7

17.3

17.7

1.3

63.6

45.0

26.1

5.3

Cervical centrum

6

5

10

34

6

4

10

16g

#5unossified

6.9

6.7

11.0

44.2

27.3

20.0

43.5

84.2

Cervical centrum

9

6

4

1

8

6

4

1f

#5bilobed

10.3

8.0

4.4

1.3

36.4

30.0

17.4

5.3

Thoracic centrum

0

0

4

7

0

0

4

5f

#1poorly ossified

0.0

0.0

4.4

9.1

0.0

0.0

17.4

26.3

Premaxillary

2

0

2

10

2

0

2

8f

poorly ossified

2.3

0.0

2.2

13.0

9.1

0.0

8.7

42.1

Some proximal

 

 

 

 

 

 

 

 

phalages(forelimb)

41

46

67

72

16

15

21

19f

poorly ossified

47.1

61.3

73.6

93.5

72.7

75.0

91.3

100.0

Majority proximal

 

 

 

 

 

 

 

 

phalages (hindlimb)

46

41

52

13

19

17

19

8g

poorly ossified

52.9

54.7

57.1

16.9

88.4

85.0

82.6

42.1

Some proximal

 

 

 

 

 

 

 

 

phalanges (hindlimb)

58

55

68

16

20

18

21

10f

unossified

66.7

73.3

74.7

20.8

90.9

90.0

91.3

52.6

Majority proximal

 

 

 

 

 

 

 

 

phalanges (hindlimb)

8

11

9

19

5

8

8

11f

unossified

9.2

14.7

9.9

24.7

22.7

40.0

34.8

42.9

All proximal

 

 

 

 

 

 

 

 

phalanges (hindlimb)

9

4

11

42

8

4

9

16g

unossified

10.3

5.3

12.1

54.5

36.4

20.0

39.1

84.2

Some metatarsals

 

 

 

 

 

 

 

 

(hindlimb) poorly

6

1

7

33

5

1

7

15g

ossified

6.9

1.3

7.7

42.9

22.7

5.0

30.4

78.9

Xiphoid process

 

 

 

 

 

 

 

 

(sternebra#6)

7

3

7

30

5

3

7

15g

poorly ossified

8.0

4.0

7.7

39.0

22.7

15.0

30.4

78.9

Number with external

 

 

 

 

 

 

 

 

variations

14

16

20

13

10

10

11

9

Percent with external

 

 

 

 

 

 

 

 

variations

7.7

9.9

10.3

7.8

45.5

50.0

47.8

45.0

Number with soft

 

 

 

 

 

 

 

 

tissue variations

64

70

94

75

20

20

23

19

Percent with soft

 

 

 

 

 

 

 

 

tissue variations

66.7

80.5

904

83.3

90.9

100 0

100 0

95.0

Number with skeletal

 

 

 

 

 

 

 

 

variations

87

75

91

77

22

20

23

19

Percent with skeletal

 

 

 

 

 

 

 

 

variations

100.0

100.0

100.0

100.0

100.0

100.0

100.0

100.0

Total number with

 

 

 

 

 

 

 

 

variations

152

146

186

153

22

20

23

19

Total percent with

 

 

 

 

 

 

 

 

variations

83.1

90.1

95.4

91.6

100.0

100.0

100.0

95.0

aFor all findings,thenumber (of foetuses affected orlitters with one or more affected foetuses) is presentedon top and the percentage of the total (foetuses of litters) examined ispresented beneath. A single foetusmay be represented more than oncein listing individual defects. Only live foetuses were examined.

bAll foetuses were examined externally.

cApproximately 50% of each litter were examined viscerally and for soft tissue craniofacial defects.

dApproximately 50% of each litter were examined for skeletal defects after staining with alizarin red S.

eOne litter consisted of only one live foetus.By convention inthis laboratory, this foetus as examined forvisceral and craniofacial alterations.

fp < 0.05

gp< 0.01

Conclusions:
At 398 ppm (1655.68 mg/m3 air) there was maternal toxicity (reduced body weight) and foetotoxicity (reduced body weight and ossification) and at 202 ppm (840.32 mg/m3 air) there was foetotoxicity (reduced body weight). Embryotoxicity or teratogenicity were not seen at any concentration. The no-observable-effects concentration was 53 ppm (220.48 mg/m3 air) for both maternal and developmental toxicity.This result is also valid for the target substance vanadium-tris-acetylacetonate, since the source substance acetylacetonate is a hydrolysis product of vanadium-tris-acetylacetonate.
Executive summary:

The developmental toxicity of 2,4-Pentanedione (2,4-PD; CAS No. 123-54-6), a widely used industrial chemical, was investigated by vapour exposure, because of its widespread use, and potential for human exposure. Timed-pregnant Fischer 344 rats were exposed on gestational days (gd) 6 to 15 inclusive to analytically measured concentrations (as mean ± SD) of 53 ± 1.6, 202 ± 4.7 and 398 ± 5.7 ppm 2,4-PD vapour. At sacrifice (gd 21) foetuses were examined for external, visceral and skeletal variations and malformations. There was no maternal mortality, and body weight was reduced only at 398 ppm. Histological examination of maternal brains from the 398 ppm group showed no abnormalities. No treatment-related effects were seen on number of corpora lutea; total, nonviable or viable implants per litter; pre-or post-implantation losses; or foetal sex ratio. Reduced foetal body weight per litter was seen at 398 ppm (males and females and all foetuses) and 202 ppm (males and all foetuses). There was no concentration-related, or statistically significant, increase in the incidence of individual malformations, malformations by category (external, visceral or skeletal), or total malformations. Partial foetal atelectasis was increased at 398 ppm, and the increased incidence of 17 skeletal variants (out of 79 observed) indicated a consistent pattern of foetotoxicity at 398 ppm. In summary, at 398 ppm (1655.68 mg/m3 air) there was maternal toxicity (reduced body weight) and foetotoxicity (reduced body weight and ossification) and at 202 ppm (840.32 mg/m3 air) there was foetotoxicity (reduced body weight). Embryotoxicity or teratogenicity were not seen at any concentration. The no-observable-effects concentration was 53 ppm (220.48 mg/m3 air) for both maternal and developmental toxicity. This result is also valid for the target substance vanadium-tris-acetylacetonate, since the source substance acetylacetonate is a hydrolysis product of vanadium-tris-acetylacetonate.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LOAEL
14.3 mg/kg bw/day
Study duration:
subacute
Species:
rat
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

Vanadium compounds

Hazard values of the vanadium containing source substances were converted to the target substance vanadium acetylacetonate. The hazard values for vanadium acetylacetonate were calculated as follows:

Effect concentration of vanadium in source substance (EC (V))

MW (source substance) = 116.98 g/mol

MW (Vanadium) = 50.94 g/mol

ratio of Vanadium in source substance = n* 50.94 / MW (source substance)

EC (V) = EC(source substance) x ratio of vanadium in source substance

Effect concentraion of target substance vanadium acetylacetonate (VAA)

MW V in VAA = 50.94 g/mol

MW VAA = 348.27 g/mol

EC (VAA) in target = EC (V) in source / 50.94 x 348.27

Sodium metavanadate was tested for its effects on fetal development, reproduction, gestation and lactation in Sprague Dawley rats. Male rats were administered NaVO3 orally at doses of 0, 5, 10 and 20 mg/kg/day for 60 days before mating with females which had received the same doses from 14 days previous to mating. These females received 0, 5, 10 and 20 mg NaVO3/kg/day during the periods of gestation and lactation. No significant adverse effects could be observed on: number of corpora lutea, implantations, live and dead fetuses, and resorptions. Significant decreases were observed in the development of the pups in all the vanadium -treated groups. All the doses used produced toxic effects in the offspring in the absence of maternal toxicity. The body length and tail length of animals in the treated groups showed significant decreases during all the period of lactation in both males and females, when compared with the control values. There were significant decreases in the relative organ weights of spleen, liver and kidneys observed in the pups killed after 21 days of lactation. As can be seen, slight effect dose-response may be induced. Body weight showed significant decreases during the whole the period of lactation in both males and females, when compared with the control values. The results of this experiment demonstrate that a dose of at least 5 mg/kg/day NaVO3 in mother rats (corresponding to roughly 2.1 mg vanadium/kg body wt/day) results in toxicity to the offspring. This corresponds to a dose of 14.3 mg vanadium-tris-acetylacetonate/ kg bw/day (Domingo 1986).

Sodium orthovanadate in deionized water was administered once daily by gavage on gestational days 6-15 to mice at doses of 0, 7.5, 15, 30, and 60 mg/kg. Dams were killed on day 18 of pregnancy, and fetuses were examined for external, visceral, and skeletal defects. Maternal toxicity was observed at the highest doses of sodium orthovanadate, as evidenced by a significant number of deaths (60 and 30 mg/kg/d) and reduced weight gain and food consumption (30 and 15 mg/kg/d). Embryolethality and teratogenicity were not observed at maternally toxic doses and below, but fetal toxicity was evidenced by a significant delay in the ossification process of some skeletal districts at 30 mg/kg/d. The no-observed-adverse-effect level (NOAEL) for maternal toxicity was 7.5 mg/kg/d, and 15 mg/kg/d represented a NOAEL for developmental toxicity in mice under the conditions of this study. The NOAEL for maternal toxicity of 7.5 mg/kg bw/day corresponds to 14.2 mg/kg bw/day vanadium-tris-acetylacetonate. The NOAEL for fetal toxicity of 15 mg/kg bw/day corresponds to 28.4 mg/kg bw/day vanadium-tris-acetylacetonate. The lowest dose leading to toxic effects in fetus of 30 mg/kg bw/day corresponds to 56.8 mg/kg bw/day vanadium-tris-acetylacetonate (Sanchez 1991).

Conclusion

While in the study of Domingo (1986), significant toxic effects of NaVO3 in the offspring were observed in the absence of maternal toxicity, Sanchez et al. (1991) found no developmental toxicity of NaVO3 independet from maternal toxicity. However, in the study of Sanchez et al. (1991) only female animals at gestation days 6 -15 were dosed. So, only effects occuring during organogenesis are covered. In the study of Domingo et al. (1986), on the other hand, males and females were dosed for 60 and 14 days before mating and during gestation and lactation. Therefore, this study covers the whole gestation including also the period of gametogenesis of males and females. Because of this, the results of the study of Domingo et al. (1986) are considered more adequate to assess the developmental toxicity. As a conclusion, there is evidence for developmental toxicity of vanadium compounds.

2,4 -pentanedione

The developmental toxicity of 2,4-Pentanedione (2,4-PD; CAS No. 123-54-6), a widely used industrial chemical, was investigated by vapour exposure. Timed-pregnant Fischer 344 rats were exposed on gestational days (gd) 6 to 15 inclusive to analytically measured concentrations (as mean ± SD) of 53 ± 1.6, 202 ± 4.7 and 398 ± 5.7 ppm 2,4-PD vapour. At sacrifice (gd 21) foetuses were examined for external, visceral and skeletal variations and malformations. There was no maternal mortality, and body weight was reduced only at 398 ppm. Histological examination of maternal brains from the 398 ppm group showed no abnormalities. No treatment-related effects were seen on number of corpora lutea; total, nonviable or viable implants per litter; pre-or post-implantation losses; or foetal sex ratio. Reduced foetal body weight per litter was seen at 398 ppm (males and females and all foetuses) and 202 ppm (males and all foetuses). There was no concentration-related, or statistically significant, increase in the incidence of individual malformations, malformations by category (external, visceral or skeletal), or total malformations. Partial foetal atelectasis was increased at 398 ppm, and the increased incidence of 17 skeletal variants (out of 79 observed) indicated a consistent pattern of foetotoxicity at 398 ppm. In summary, at 398 ppm (1655.68 mg/m3 air) there was maternal toxicity (reduced body weight) and foetotoxicity (reduced body weight and ossification) and at 202 ppm (840.32 mg/m3 air) there was foetotoxicity (reduced body weight). Embryotoxicity or teratogenicity were not seen at any concentration. The no-observable-effects concentration was 53 ppm (220.48 mg/m3 air) for both maternal and developmental toxicity (Tyl, 1990)

The observed foetotoxicity at 398 ppm (reduced body weight and ossification) occured at concentration significantly toxic to maternal animals. The reduction of the body weight of female foetuses at 202 ml/m3 is significant but very low. In addition, it can not be concluded if the reduced foetal body weight is connected with the reduced body weight gain of the maternal animals between gestation day 6 and 15. Due to the significant maternal toxicity at 398 ppm, the developmental toxicity effects are considered to be secondary effects (MAK 2007).

Toxicity to reproduction: other studies

Description of key information

V2O5 rat, whole body, 6 hr/day, 5 days per week, 90 days (OECD TG 413, GLP): LOAEC = 8 mg/m3- VAA LOAEC = 30.6 mg/m3

Link to relevant study records
Reference
Endpoint:
toxicity to reproduction: other studies
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Justification for type of information:
please refer to Read-across statement attached in section 13
Reason / purpose for cross-reference:
read-across source
Dose descriptor:
LOAEL
Remarks:
mice
Effect level:
30.6 mg/m³ air
Based on:
test mat.
Remarks:
converted to VAA (for details on the calculation please refer to 'overall remarks'
Sex:
male
Basis for effect level:
other: epididymal sperm motility
Remarks on result:
other: The epididymal spermatozoal motility of males exposed to 8 or 16 mg/m3 was significantly decreased
The epididymal spermatozoal motility of male mice exposed to 8 or 16 mg/m3 was significantly decreased (Table 3). No significant differences were noted in estrous cycle parameters between exposed and chamber control female mice (Table 4). In rats no significant changes were observend in sperm motility. The estrous cycle length was significant longer than the chamber control in the 8 mg/m3 doese group, but not in the 16 mg/m3 dose group. (table 1 and 2).

Table 1

Summary of Reproductive Tissue Evaluations for Male Rats in the 3-Month Inhalation Study of Vanadium Pentoxidea

 

Chamber control

2 mg/m3

4 mg/m3

8 mg/m3

n

10

10

10

10

Weights (g)

Necropsy body wt

350±8

339 ± 6

334 ± 7

319±7**

L. Cauda epididymis

0.1742±0.0062

0.1666±0.0042

0.1809±0.0043

0.1768±0.0056

L. Epididymis

0.4967±0.0076

0.4756 ± 0.0081

0.4896 ± 0.0097

0.5075 ± 0.0050

L. Testis

1.4960±0.0292

1.4606 ± 0.0326

1.5077 ± 0.0265

1.4908 ± 0.0183

Spermatid measurements

Spermatid heads (107/g testis)

9.70 ± 0.44

9.89 ± 0.58

9.35±0.39

8.91±0.42

Spermatid heads (107/testis)

14.42 ± 0.49

14.34 ± 0.72

14.08±0.59

13.30±0.69

Spermatid count (mean/10-4mL suspension)

72.10±2.45

71.70±3.59

70.40 ± 2.94

66.50±3.45

Epididymalspermatozoal measurements

Motility(%)

85.68 ± 1.77

85.51 ± 2.21

87.69 ± 1.47

80.14±2.45

Concentration (106/g caudaepididymaltissue)

427 ± 15

463 ± 11

436±28

386±24

** Significantly different (P≤0.01) from the chamber control group by Williams' test

aData are presented as mean ± standard error. Differences from the chamber control group are not significant by Dunnett's test (tissue weights) or Dunn's test (spermatid and epididymal spermatozoal measurements).

Table 2

Estrous Cycle Characterization for Female Rats in the 3-Month Inhalation Study of Vanadium Pentoxidea

 

Chamber Control

4 mg/m3

8 mg/m3

16 mg/m3

n

10

10

10

8

Necropsy body wt

198 ± 3

196 ± 4

189 ± 4

117±5**

Estrous cycle length (days)

5.00 ± 0.00

5.00 ± 0.08

5.50±0.14**b

5.25± 0.25c

Estrous stages (% of cycle)

 

 

 

 

Diestrus

39.2

40.8

49.2

71.9

Proestrus

18.3

16.7

15.8

10.4

Estrus

20.8

19.2

17.5

10.4

Metestrus

21.7

22.5

17.5

7.3

Uncertain diagnoses

0.0

0.8

0.0

0.0

** Significantly different (P≤0.01) from the chamber control group by Williams' test (necropsy body weight) or Shirley's test (estrous cycle length)

aNecropsy body weight and estrous cycle length data are presented as mean ± standard error. By multivariate analysis of variance, exposed females do not differ significantly from the chamber control females in the relative length of time spent in the estrous stages.

bEstrous cycle was longer than 12 days or was unclear in 1 of 10 animals.

cEstrous cycle was longer than 12 days or was unclear in six of eight animals.

Table 3

Summary of Reproductive Tissue Evaluations for Male Mice in the 3-Month Inhalation Study of Vanadium Pentoxidea

 

Chamber Control

4 mg/m3

8mg/m3

16mg/m3

n

10

10

10

9

Weights (g)

Necropsy body wt

35.4±1.1

34.5 ± 0.5

33.4±0.4

32.0±0.6**

L. Cauda epididymis

0.0170±0.0010

0.0174 ± 0.0006

0.0180±0.0006

0.0165±0.0009

L. Epididymis

0.0525±0.0012

0.0505 ± 0.0013

0.0546 ± 0.0013

0.0512±0.0013

L. Testis

0.1209±0.0025

0.1217±0.0014

0.1166±0.0020

0.1163±0.0018

Spermatid measurements

Spermatid heads (107/g testis)

17.97±0.67

15.99 ± 0.71

17.93±0.74

17.67±0.74

Spermatid heads (107/testis)

2.17±0.09

1.94 ± 0.08

2.09 ± 0.09

2.05 ± 0.08

Spermatid count (mean/10-4mL suspension)

67.83±2.68

60.68 ±2.50

62.28 ± 2.89

64.06 ± 2.47

Epididymalspermatozoal measurements

Motility(%)

88.63± 0.90b

86.23 ± 1.64

77.10± 3.15**b

83.11± 2.48*c

Concentration (106/g caudaepididymaltissue)

894 ± 57

915 ± 55

818 ± 39

849 ± 98

* Significantly different (P≤0.05) from the chamber control group by Shirley's test

** Significantly different (P≤0.01) from the chamber control group by Williams' test (necropsy body weight) or Shirley's test (epididymal spermatozoal motility)

aData are presented as mean ± standard error. Differences from the chamber control group are not significant by Dunnett's test (tissueweights) or Dunn's test (spermatid measurements and epididymal spermatozoal concentration).

bn=9

cn=8

Table 4

Estrous Cycle Characterization for Female Mice in the 3-Month Inhalation Study of Vanadium Pentoxidea

 

 

 

 

 

Chamber Control

4 mg/m3

8 mg/m3

16 mg/m3

n

10

10

10

10

Necropsy body wt

31.1±1.0

26.2±0.4**

27.3 ± 0.4**

25.8 ± 0.4**

Estrous cycle length (days)

4.25 ± 0.13

4.29±0.15

4.05 ± 0.05

5.11± 0.51c

Estrous stages (% of cycle)

Diestrus

27.5

40.8

29.2

34.2

Proestrus

21.7

14.2

15.0

18.3

Estrus

29.2

26.7

33.3

30.8

Metestrus

21.7

18.3

22.5

15.8

Uncertain diagnoses

0.0

0.0

0.0

0.8

** Significantly different (P≤0.01) from the chamber control group by Williams' test

aNecropsy body weight and estrous cycle length data are presented as mean ± standard error. Differences from the chamber control group forestrous cycle length are not significant by Dunn's test. By multivariate analysis of variance, exposed females do not differ significantlyfrom the chamber control females in the relative length of time spent in the estrous stages.

bEstrous cycle was longer than 12 days or was unclear in 3 of 10 animals.

cEstrous cycle was longer than 12 days or was unclear in 1 of 10 animals.
Conclusions:
The epididymal spermatozoal motility of male mice exposed to 8 or 16 mg/m3 was significantly decreased. No significant differences were noted in estrous cycle parameters between exposed and chamber control female mice. In male rats no significant changes were observend in sperm motility. The estrous cycle length in female rats was significant longer than the chamber control in the 8 mg/m3 dose group, but not in the 16 mg/m3 dose group. 8 mg/m3 corresponds to a dose of 30.6 mg/m3 when converted to the target substance vanadium acetylacetonate.
Executive summary:

Groups of 10 male and 10 female rats were exposed to particulate aerosols of vanadium pentoxide at concentrations of 0, 1, 2, 4, 8, or 16 mg/m3 by inhalation, 6 hours per day, 5 days per week for 3 months. Reproductive tissues were examined and estrous cycle and sperm measurements were performed. The following effects were observed: The epididymal spermatozoal motility of male mice exposed to 8 or 16 mg/m3 was significantly decreased. No significant differences were noted in estrous cycle parameters between exposed and chamber control female mice. In male rats no significant changes were observend in sperm motility. The estrous cycle length in female rats was significant longer than the chamber control in the 8 mg/m3 dose group, but not in the 16 mg/m3 dose group. 8 mg/m3 corresponds to a dose of 30.6 mg/m3 when converted to the target substance vanadium acetylacetonate.

Additional information

Vanadium

Hazard values of the vanadium containing source substances were converted to the target substance vanadium acetylacetonate. The hazard values for vanadium acetylacetonate were calculated as follows:

Effect concentration of vanadium in source substance (EC (V))

MW (source substance) = 116.98 g/mol

MW (Vanadium) = 50.94 g/mol

ratio of Vanadium in source substance = n* 50.94 / MW (source substance)

EC (V) = EC(source substance) x ratio of vanadium in source substance

Effect concentraion of target substance vanadium acetylacetonate (VAA)

MW V in VAA = 50.94 g/mol

MW VAA = 348.27 g/mol

EC (VAA) in target = EC (V) in source / 50.94 x 348.27

Groups of 10 male and 10 female rats were exposed to particulate aerosols of vanadium pentoxide at concentrations of 0, 1, 2, 4, 8, or 16 mg/m3 by inhalation, 6 hours per day, 5 days per week for 3 months. Reproductive tissues were examined and estrous cycle and sperm measurements were performed. The following effects were observed: The epididymal spermatozoal motility of male mice exposed to 8 or 16 mg/m3 was significantly decreased. No significant differences were noted in estrous cycle parameters between exposed and chamber control female mice. In male rats no significant changes were observend in sperm motility. The estrous cycle length in female rats was significant longer than the chamber control in the 8 mg/m3 dose group, but not in the 16 mg/m3 dose group (NTP 2002).

Justification for classification or non-classification

Based on the available studies there is evidence that vanadium compounds are toxic to reprodution and development. Toxic effects on reproductive function in male mice were observed in two repeated-dose studies (60 and 90 days). Significant toxic effects in the offspring in the absence of maternal toxicity was found in a study similar to OECD TG 421. Therefore, vanadium-tris-acetylacetonate is classified as toxic to reproduction, Category 2 (H361: Suspected of damaging fertility or the unborn child) in accordance with Regulation (EC) No 1272/2008.

Additional information