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Toxicological information

Specific investigations: other studies

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Administrative data

Endpoint:
specific investigations: other studies
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study well documented, meets generally accepted scientific principles, acceptable for assessment.

Data source

Reference
Reference Type:
publication
Title:
Goitrogenic effects of ethylenethiourea on rat thyroid.
Author:
O'Neil WM and Marshall WD.
Year:
1984
Bibliographic source:
Pest. Biochem. Physiol. 21: 92-101

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Two 90-day feeding trials were conducted in which rats were treated with 75 or 100 ppm ethylenethiourea (ETU) in the diet. Parameters of thyroid function; serum T4, T3, and TSH; T3 uptake;131I uptake into thyroid; and thyroid to body weight ratios were measured at Days 46 and 91.
GLP compliance:
not specified
Type of method:
in vivo
Endpoint addressed:
repeated dose toxicity: oral

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Other name : Ethylenethiourea (ETU)

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: no data
- Age at study initiation: no data
- Weight at study initiation: 75 +/- 10g
- Fasting period before study: no data
- Housing: in wire rodent cage
- Diet (e.g. ad libitum): Powdered Purina rat chow, ad libitum
- Water (e.g. ad libitum): not precised, ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21°C
- Humidity (%): no data
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: feed
Details on exposure:
no
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The amended feed sample was initially defatted with hexane and the toxicant was removed by extraction with ethyl acetate. Purification on a 10-cm column of Florisil directly preceded quantitation.
Duration of treatment / exposure:
90 days
Frequency of treatment:
daily
Doses / concentrations
Remarks:
Doses / Concentrations:
75 or 100 ppm (approx. 5 and 7 mg/kg bw/day)
Basis:
nominal in diet
No. of animals per sex per dose:
12 animals/sexe/dose
Control animals:
yes
Details on study design:
A 0.2-ml dose of 0.9% saline containing 20 µCi of 131I as sodium iodide (NEN Canada Ltd.) was administered to 12 subject rats. The rats were fasted for 24 hr and sacrificed by exsanguination, and blood samples were stired on ice to await analysis. The thyroid gland was removed with the aid of a dissecting microscope and placed on saline-moistened filter paper.

Examinations

Examinations:
The parameters studied were thyroxine (T4), triiodothyronine (T3) and TSH levels, T3 uptake, 131-iodine uptake by the thyroid gland and relative thyroid weight.
Positive control:
no

Results and discussion

Details on results:
The males and females receiving 75 ppm and the females in the 100 ppm group had normally functioning thyroid glands, while the males in the 100 ppm group were hypothyroid (TSH increased, T4 reduced, T3 increased, T3 uptake reduced, 131-iodine uptake by the thyroid gland decreased).

Any other information on results incl. tables

Table 1 : Means of relative thyroid weight, total serum T4, serum T3, T3 uptake, Free thyroxine index, and thyrotropin for SD rats fed ETU for 45 or 90 days

Relative thyroidweight

(mg/100 g bodywt)

Total serumT4

(µg/100 ml)

SerumT3

(ng/ml)

Day 46

Day 91

Day 46

Day 91

Day 46

Day 91

100-ppm trial

Male ETU

5.58 ± 0.65

4.09 ± 1.12

1.49 ± 0.61e

2.54±0.56e

0.65 ± 0.03

0.68 ± 0.24g

Male control

4.73 ± 1.43g

3.50 ± 0.39

3.82 ± 1.21e

4.34 ± 0.87e

0.53 ± 0.11

0.43 ± 0.07g

Female ETU

7.82 ± 1.18g

5.62 ± 0.65

1.82 ± 0.44

0.63 ±0.21Female

1.82 ± 0.71

0.63 ± 0.20

0.63 ± 0.21g

Female control

6.49 ± 0.56g

5.16 ± 0.50

1.91 ± 0.40

2.55 ± 0.50

0.60 ± 0.22

0.44 ± 0.05g

T3uptake (%)

Free thyroxine index

[T4(µg/100 ml) x %T3uptake]

Thyrotropin (TSH)

(µg/100 ml)

Day 46

Day 91

Day 46

Day 91

Day 46

Day 91

100 -ppm trial

Male ETU

51.34 ± 0.89a

53.72 ± 1.20d

2.19 ± 0.90d

3.92 ± 0.95d

-

195.73 ± 61.73g

Male control

55.55 ±0.81a

61.10± 3.88d

6.08±1.91d

7.52 ± 1.51d

-

88.85 ± 42.22g

Female ETU

53.27 ± 2.07

56.15 ± 1.91

2.76 ± 0.60

2.91 ± 1.11

-

94.76 ± 84.16

Female control

52.85 ± 2.13

57.16 ± 2.59

2.87 ± 0.53

4.17 ± 0.88

-

66.16 ± 53.42

Total serum T4

(µg/100 ml)

Day 46

Day 91

75 -ppm trial

Male ETU

1.43 ± 0.08g

j

3.03 ± 1.29f

 gSf

Male control

1.92 ± 0.48g

5.20 ± 1.22f

Female ETU

1.24 ± 0.07g

3.02 ±0.82Female

3.02 ± 0.82g

Female control

1.48 ± 0.27g

3.92 ± 1.26g

Note.Differences significant at :

aP<0.0001 ;bP = 0.0001;cP = 0.0005 ;dP=0.001 ;eP= 0.005 ;fP = 0.01 ;gP= 0.05


Table 2 : Means +/- SE of 131 I uptake and speciation of

131 I uptake by thyroid

(% of131administered)

131 I- in thyroid

(% of label in thyroid)

131Iincorporated into

MIT prohormoneresidue

(% of label inthyroid)

 

Day 46

Day 91

Day 46

Day 91

Day 46

Day 91

 

100ippm trial

 

Male ETU

6.70 ± 1.55e

j

9.70 ± 3.02

23.36 ± 1.56

21.79 ± 2.67

31.84 ± 0.40d

26.03 ± 2.91f

 

Male control

13.65 ± 3.72e

13.22 ± 3.07

20.66 ± 0.30

22.41 ± 3.02

20.21 ± 0.29d

21.23 ± 2.24f

 

Female ETU

9.65 ± 2.03

9.94 ± 3.73

20.55 ± 0.98

19.68 ± 1.40

31.10 ± 0.23g

26.87 ± 2.84

 

Female control

12.98 ± 5.68

12.78 ± 3.61

21.79 ± 0.59

17.19 ± 2.75

21.94 ± 3.13g

24.91 ± 3.04

 

131I incorporated into

DIT prohormone residue

(% of label in thyroid)

131I incorporated into

T3prohormone residue

(% of label in thyroid)

131I incorporated into

T4prohormone residue

(% of label in thyroid)

 

Day 46

Day 91

Day 46

Day 91

Day 46

Day 91

 

100=ppm trial

 

Male ETU

23.77 ± 4.99

25.26 ± 4.62

10.92 ± 2.74

11.15 ± 0.90

11.99 ± 1.73

15.76 ± 0.87g

 

Male control

25.37 ± 0.87

24.60 ± 2.19

8.25 ± 0.93

9.18 ± 1.75

13.33 ± 1.58

19.92 ± 4.18g

 

Female ETU

15.03 ± 2.47

23.51 ± 2.92

7.21 ± 1.36

12.85 ± 1.73

10.94 ± 0.69g

17.10 ± 2.73

 

Female control

21.72 ± 1.20

26.05 ± 3.16

7.24 ± 1.41

11.40 ± 1.23

15.53 ± 1.40g

20.45 ± 2.65

 

Note.Differences significant at :

aP<0.0001 ;bP = 0.0001;cP = 0.0005 ;dP=0.001 ;eP= 0.005 ;fP = 0.01 ;gP= 0.05


Table 3 :Ratios of Labeled Prohormonal Residues in Thyroids from Rats fed ETU for45or 90 Days

% 131Ias MITResidue

% 131Ias DITResidue

% 131Ias T3Prohormone

% 131Ias T4Prohormone

% 131Ias DITResidue

% 131Ias T4Residue

Day 46

Day 91

Day 46

Day 91

Day 46

Day 91

100 -ppm Trial

Male ETU

1.37 ± 0.27

1.03 ± 0.32

0.88 ± 0.36

0.71 ± 0.04b

1.97 ± 0.13

1.60 ± 0.31

Male control

0.80 ± 0.05

0.86 ± 0.12

0.63 ± 0.16

0.46 ± 0.06b

1.91 ± 0.16

1.27 ± 0.24

Female ETU

2.09 ± 0.35

1.15 ±0.12

0.66 ± 0.10

0.76 ± 0.10g

1.37 ± 0.14

1.42 ± 0.36

Female control

1.02 ± 0.20

0.97 ± 0.19

0.47 ± 0.13

0.58 ± 0.13g

1.41 ± 0.20

1.32 ± 0.34

*T3prohormone

* T4prohormone

Day 46

Day 91

Day 46

Day 91

Male ETU

68.8 ± 21.8g

107.7 ± 32.9

80.4±20.5d

152.7±47.2e

Male control

112.2 ± 35.0g

121.4 ± 45.8

182.6 ± 52.0d

255.3 ± 43.9e

Female ETU

63.8 ± 8.31

122.7 ± 28.4

102.6 ± 18.6

164.0 ± 45.7e

Female control

93.5 ± 37.8

142.9 ± 30.0

202.0 ± 95.5

261.5 ± 49.2e

* T3 prohormone

Serum T3

* T4 prohormone

Serum T4

Day 46

Day 91

Day 46

Day 91

Male ETU

4.23 ± 1.00f

4.83 ± 1.99f

2.15 ± 1.40

2.06 ± 0.64

Male control

6.49 ± 1.55f

8.94 ± 2.55f

1.84 ± 0.67

2.30 ± 0.76

Female ETU

4.58 ± 1.95

7.81 ± 2.61e

3.08± 1.15

4.45 ± 1.86

Female control

7.08 ± 2.95

13.38 ± 2.31e

2.04 ± 1.44

2.69 ± 1.03

Note.Differences significant at :

aP<0.0001 ;bP = 0.0001;cP = 0.0005 ;dP=0.001 ;eP= 0.005 ;fP = 0.01 ;gP= 0.05

Applicant's summary and conclusion

Conclusions:
ETU inhibits MIT utilization and the coupling of DIT residues to form T4. The capacity of serum to bind T3 was reduced; however, no other evidence for extrathyroidal effects of ETU were observed.
Executive summary:

Two 90-day feeding trials were conducted in which rats were treated with 75 or 100 ppm ethylenethiourea (ETU) in the diet. Parameters of thyroid function; serum T4, T3, and TSH; T3 uptake;131I uptake into thyroid; and thyroid to body weight ratios were measured at Days 46 and 91. In addition, a thyroid hydrolysis study (100 ppm trial) was conducted in an effort to trace the fate of incorporated 131I. Treated groups from the lower feeding level and treated females from the higher feeding level were functionally euthyroid whereas treated males (100 ppm) were somewhat hypothyroid despite hyperstimulation. ETU inhibits MIT utilization and the coupling of DIT residues to form T4. The capacity of serum to bind T3 was reduced; however, no other evidence for extrathyroidal effects of ETU were observed. Thus ETU mimics the mode of action of methimazole.