Imidazolidine-2-thione

Specific investigations: other studies

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

Test material information

Constituent 1

Reference substance name:

Imidazolidine-2-thione

EC Number:

202-506-9

EC Name:

Imidazolidine-2-thione

Cas Number:

96-45-7

Molecular formula:

C3H6N2S

IUPAC Name:

imidazolidine-2-thione

Details on test material:

Other name : Ethylenethiourea (ETU)

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system 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 ± 0.61^e	2.54±0.56^e	0.65 ± 0.03	0.68 ± 0.24^g
Male control	4.73 ± 1.43^g	3.50 ± 0.39	3.82 ± 1.21^e	4.34 ± 0.87^e	0.53 ± 0.11	0.43 ± 0.07^g
Female ETU	7.82 ± 1.18^g	5.62 ± 0.65	1.82 ± 0.44 0.63 ±^0.21Female	1.82 ± 0.71	0.63 ± 0.20	0.63 ± 0.21^g
Female control	6.49 ± 0.56^g	5.16 ± 0.50	1.91 ± 0.40	2.55 ± 0.50	0.60 ± 0.22	0.44 ± 0.05^g
	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 ± 0.89^a	53.72 ± 1.20^d	2.19 ± 0.90^d	3.92 ± 0.95^d	-	195.73 ± 61.73^g
Male control	55.55 ±0.81^a	61.10± 3.88^d	6.08±1.91^d	7.52 ± 1.51^d	-	88.85 ± 42.22^g
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 ± 0.08^g ^j	3.03 ± 1.29^f  ^gS^f
Male control	1.92 ± 0.48^g	5.20 ± 1.22^f
Female ETU	1.24 ± 0.07^g 3.02 ±^0.82Female	3.02 ± 0.82^g
Female control	1.48 ± 0.27^g	3.92 ± 1.26^g
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 (% of^131administered)		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 ± 1.55^e ^j	9.70 ± 3.02	23.36 ± 1.56	21.79 ± 2.67	31.84 ± 0.40^d	26.03 ± 2.91^f
Male control	13.65 ± 3.72^e	13.22 ± 3.07	20.66 ± 0.30	22.41 ± 3.02	20.21 ± 0.29^d	21.23 ± 2.24^f
Female ETU	9.65 ± 2.03	9.94 ± 3.73	20.55 ± 0.98	19.68 ± 1.40	31.10 ± 0.23^g	26.87 ± 2.84
Female control	12.98 ± 5.68	12.78 ± 3.61	21.79 ± 0.59	17.19 ± 2.75	21.94 ± 3.13^g	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 ± 0.87^g
Male control	25.37 ± 0.87	24.60 ± 2.19	8.25 ± 0.93	9.18 ± 1.75	13.33 ± 1.58	19.92 ± 4.18^g
Female ETU	15.03 ± 2.47	23.51 ± 2.92	7.21 ± 1.36	12.85 ± 1.73	10.94 ± 0.69^g	17.10 ± 2.73
Female control	21.72 ± 1.20	26.05 ± 3.16	7.24 ± 1.41	11.40 ± 1.23	15.53 ± 1.40^g	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 ± 0.04^b	1.97 ± 0.13	1.60 ± 0.31
Male control	0.80 ± 0.05	0.86 ± 0.12	0.63 ± 0.16	0.46 ± 0.06^b	1.91 ± 0.16	1.27 ± 0.24
Female ETU	2.09 ± 0.35	1.15 ±0.12	0.66 ± 0.10	0.76 ± 0.10^g	1.37 ± 0.14	1.42 ± 0.36
Female control	1.02 ± 0.20	0.97 ± 0.19	0.47 ± 0.13	0.58 ± 0.13^g	1.41 ± 0.20	1.32 ± 0.34
	*T3prohormone		* T4prohormone
	Day 46	Day 91	Day 46	Day 91
Male ETU	68.8 ± 21.8^g	107.7 ± 32.9	80.4±20.5^d	152.7±47.2^e
Male control	112.2 ± 35.0^g	121.4 ± 45.8	182.6 ± 52.0^d	255.3 ± 43.9^e
Female ETU	63.8 ± 8.31	122.7 ± 28.4	102.6 ± 18.6	164.0 ± 45.7^e
Female control	93.5 ± 37.8	142.9 ± 30.0	202.0 ± 95.5	261.5 ± 49.2^e
	* T3 prohormone Serum T3		* T4 prohormone Serum T4
	Day 46	Day 91	Day 46	Day 91
Male ETU	4.23 ± 1.00^f	4.83 ± 1.99^f	2.15 ± 1.40	2.06 ± 0.64
Male control	6.49 ± 1.55^f	8.94 ± 2.55^f	1.84 ± 0.67	2.30 ± 0.76
Female ETU	4.58 ± 1.95	7.81 ± 2.61^e	3.08± 1.15	4.45 ± 1.86
Female control	7.08 ± 2.95	13.38 ± 2.31^e	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.