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Administrative data

Key value for chemical safety assessment

Toxic effect type:
dose-dependent

Effects on fertility

Description of key information

No specific study on fertility is available, but the two developmental studies give data on effects of DETU on fertility.
There is no alert in these two studies : no effects were observed on reproductive organ and on fertility.

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

Oral developmental study on rats (Saillenfait 1991) / read across with DMTU :

In this study, rats were exposed to DMTU at 0, 15, 25, 50, 100 or 200 mg/kg bw/day from GD 6-20.

Incidences of pregnancy were comparable among groups. Moreover, no significant effect of DMTU was noted on the mean numbers of implantation sites, viable fetuses, and percentage of resorptions and on fetal sex ratio.

Developmental study on DETU by dermal route (Culik 1973)

DETU was suspended in DMSO and a single dose was applied on the clipped back skin of primigravida Charles River-CD rats on day 12 of gestation at dose levels of 450, 670, 1000, 1500 and 2250 mg/kg bw.

In this study, all animals (at all levels) delivered normal litters. All parameters used to measure the outcome of pregnancy were similar to those of the control DMSO-treated females.

Effects on developmental toxicity

Description of key information
A reliable study on developmental toxicity study on rats in available on Dimethylthiourea (DMTU). 
Foetoxicity was observed in this study at all doses but this toxicity is due to the maternal toxicity (decrease of maternal bodyweight at all doses).
The LOAEL for developmental toxicity was 15 mg/kg/day based on decrease of fetal body weight gain at all doses. No teratogenic effects were observed in this study.
A read-across between DMTU and DETU is justified for the reproduction endpoint, because DETU and DMTU are two thioureas having a high structural similarity. Moreover DETU and DMTU have the same physicalchemical properties, and are harmful by oral route (acute toxicity). The read-across between DMTU and DETU is more justified in the Section 13 of the IUCLID.
Link to relevant study records

Referenceopen allclose all

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Comparable to guideline study [OECD 414] A read-across between DMTU (dimethylthiourea) and DETU (diethylthiourea) is justified because theirs structures differ by a methyl fonction only. DETU has a molecular weight more higher than DMTU and therefore DETU is probably less toxic than DMTU.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
no
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: From IFFA CREDO Breeding Laboratories (St Germain sur l'arbresle, France)
- Age at study initiation: no data
- Weight at study initiation: males = 350 g ; females = 200-220 g
- Fasting period before study: no data
- Housing: Bred females were individually housed in clear polycrbonate cages with hardwood shavings as bedding.
- Diet (e.g. ad libitum): UAR Alimentation Villemoisson, ad libitum
- Water (e.g. ad libitum): filetred tap water, ad libitum
- Acclimation period: 1 or 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- °C
- Humidity (%): 55 +/- 5%
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): a light cycle from 7AM to 7 PM
Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
Administered volume = 5 ml/kg bw
The actual volume administered was based on body weight taken on GD6.
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1M / 3 F
- Length of cohabitation: overnight
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy
Duration of treatment / exposure:
gestation days 6 to 20
Frequency of treatment:
daily, at approximately the same time each time
Duration of test:
1 month
Remarks:
Doses / Concentrations:
0, 15, 25, 50, 100 and 200 mg/kg bw/day
Basis:
actual ingested
No. of animals per sex per dose:
20-23 animals/dose
Control animals:
yes, concurrent vehicle
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes, daily
DETAILED CLINICAL: no data
BODY WEIGHT : Yes, on day 0 and every 3 days from days 6 to 21 of gestation.
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 21
- Organs examined: uterus
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No data
- Number of corpora lutea: No data
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Live and dead fetuses
Fetal examinations:
Fetal body weight & Fetal malformations
live fetuses were removed, weighed, sexed and examined.
- External examinations: Yes: all per litter (including those of the oral cavity)
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes:half per litter
- Head examinations: Yes: No data
Statistics:
Whenever possible, the data were presented as means ± SD. Implantation sites, live fetuses, and various body weights were analyzed by the one-way analysis of variance, followed by Dunnett's test if differences were found. The frequency of nonsurviving implants, resorptions, and anomalies among litters was evaluated with the Dixon-Massey test after an arc-sine-square root transformation. Rates of pregnancy and fetal sex ratio were analyzed using Fisher's exact test. Where applicable, least-squares analysis was carried out. The reported level of statistical significance was p < 0.05.
Indices:
no data
Historical control data:
no data
Details on maternal toxic effects:
No maternal deaths, morbidity, or treatment-related clinical signs were observed during this study. Significant reduction of maternal body weight gain was observed in tha last third of gestation at 15 mg/kg bw/d and throughout treatment at higher dose levels. The maternal weight gain during days 6 to 21 of gestation and the absolute weight gain were significantly reduced at all doses (p<0.01) (table 1). Incidences of pregnancy were comparable among groups (table 2).
Dose descriptor:
NOAEL
Effect level:
< 15 mg/kg bw/day
Basis for effect level:
other: maternal toxicity
Details on embryotoxic / teratogenic effects:
No significant effect of DMTU was noted on the mean numbers of implantation sites, viable fetuses, and percentage of resorptions and on fetal sex ratio. fetal body weights were significantly reduced at all doses tested, showing a dose-depenent relationship. The 9% decrease at 15 mg/kg bw/d reached 34% at 200 mg/kg bw/d (Table 2). The decrease in maternal weight was considered severe aand the fetal effects caused by DMTU were probably secondary to the toxicity incurred by the mothers.
No animalies were seen upon external examination of the fetuses (table 3). Dilated ureter and extra lumbar ribs occurred significantly more often among litters of rats given 200 mg/kg bw/d (p<0.01 and p<0.05, respectively). No other visceral and skeletal variants were significantly affected at any tested dose. In the control group, one fetus exhibited a forelimb syndactiyly and onother a bilateral microphtalmia.
Dose descriptor:
NOAEL
Effect level:
< 15 mg/kg bw/day
Sex:
male/female
Basis for effect level:
fetal/pup body weight changes
Dose descriptor:
NOAEL
Effect level:
> 200 mg/kg bw/day
Basis for effect level:
other: teratogenicity
Abnormalities:
not specified
Developmental effects observed:
not specified

Table 1 : change in weight during gestation in SD rats treated daily by gastric intubation with DMTU on days 6 to 20 of gestation and sacrified on day 21a

Compound

Dose

Body weight (g) on GD6

Body weight gain (g)

Absolute weight gain (g)b

GD 6-9

GD 9-12

GD 12/15

GD 15-18

GD 18-21

GD 6-21

Distilled water (ml/kg/d)

5

257+/-14

18+/-5

16+/-6

24+/-5

48+/-7

59+/-10

162+/-19

46+/-17

 

DMTU

(mg/kg/d)

15

255+/-16

15+/-4

15+/-5

19+/-6

40+/-9*

46+/-11**

135+/-24**

33+/-10**

25

255+/-14

12+/-6*

16+/-5

17+/-6**

38+/-9**

41+/-10**

126+/-24**

28+/-13**

50

256+/-11

6+/-5**

19+/-6

15+/-5**

35+/-11**

34+/-9**

109+/-21**

19+/-10**

100

253+/-15

3+/-10**

11+/-7*

14+/-7**

25+/-8**

35+/-9**

88+/-20**

3+/-10**

200

257+/-16

-1+/-4**

14+/-7

8+/-6**

22+/-8**

27+/-9**

71+/-14**

-2+/-11**

Data are expressed as means +/- SD

aIncludes all dams pregnant at sacrifice. GD = gestational day.

b(day 21 bw) – (gravid uterus weight) – (day 6 bw)

* and ** denote significant differences from the vehicle control value using Dunnett’s test, p<0.05 and p<0.01, respectively.

 

 

Table 2 : Reproductive parameters in SD rats treated daily by gastric intubation with DMTU on days 6 to 20 of gestation and sacrified on day 21a

Compound

Dose

No. of deaths per number of treated females

% of females pregnant

Number of examined litters

Mean implantation sites per litter

Mean live fetuses per litter

Mean % nonsurviving implants per litterb

Mean % resorption sites per litter

Distilled water (ml/kg/d)

5

0/20

95.0

19

15.26+/-1.94

14.95+/-1.96

2.02+/-3.70

2.02+/-3.70

 

DMTU (mg/kg/d)

15

0/21

85.7

18

14.39+/-3.47

14.06+/-3.45

2.24+/-4.08

2.24+/-4.08

25

0/21

95.2

20

14.50+/-3.32

14.15+/-3.59

3.63+/-6.44

3.63+/-6.44

50

0/21

90.5

19

13.79+/-3.85

13.26+/-3.75

3.49+/-5.55

3.49+/-5.55

100

0/23

95.6

22

14.81+/-3.17

14.04+/-2.90

4.73+/-6.14

4.73+/-6.14

200

0/23

87.0

20

14.40+/-2.85

13.70+/-2.87

4.68+/-7.19

4.27+/-7.20

Data are expressed as means +/- SD

aIncludes all dams pregnant at sacrifice. GD = gestational day.

bResorption plus dead fetuses

* and ** denote significant differences from the vehicle control value using Dunnett’s test, p<0.05 and p<0.01, respectively.

 

Compound

Dose

Fetal sex ratio M:F (%)

Mean fetal body weight (g) per litter

Males

Females

Distilled water (ml/kg/d)

5

0.86

6.00+/-0.30

5.68+/-0.29

 

DMTU (mg/kg/d)

15

1.14

5.47+/-0.33**

5.19+/-0.34**

25

0.96

5.29+/-0.30**

5.04+/-0.25**

50

1.15

5.20+/-0.33**

4.80+/-0.36**

100

0.98

4.40+/-0.28**

4.26+/-0.29**

200

0.89

3.94+/-0.28**

3.76+/-0.24**

Data are expressed as means +/- SD

* and ** denote significant differences from the vehicle control value using Dunnett’s test, p<0.05 and p<0.01, respectively.

 

 

Table 3 : Incidence of anomalies in fetuses of SD rats teated daily by gastric intubation with DMTU on days 6 to 20 of gestation and sacrified on day 21

 

 

 

Distilled

Water (ml/kg/d) 

DMTU (mg/kg/d)

 

5

15

25

50

100

200

 

Number of fetuses (litters) examined

External examination

284 (19)

253 (18)

283 (20)

252 (19)

309 (22)

274 (20)

Soft tissue examination

142 (19)

127 (18)

142 (20)

126 (19)

154 (22)

137 (20)

Skeletal examination

142 (19)

126 (18)

141 (20)

126 (19)

155 (22)

137 (20)

 

Number of fetuses (litters) affected

Soft tissue anomalies

 

 

 

 

 

 

Microphtalmiab

1 (1)

0

0

0

0

0

Hydroureter

0

0

0

0

0

3 (2)

Dilated renal pelvis

1 (1)

0

0

0

1 (1)

5 (2)

Dilated ureter

0

0

0

0

1 (1)

18 (11) **

Skeletal anomalies

Interparietal and/or occipital not ossified

0

0

0

0

0

0

Vertebral centra dumbbell-shaped or absent

0

2 (2)

0

2 (2)

3 (3)

4 (3)

Extra lumbar ribs

9 (4)

9 (6)

8 (7)

13 (6)

14 (8)

13 (13)*

Fifth sternebrae

Not ossified

4 (4)

0

1 (1)

0

0

2 (2)

Forelimb syndactilyly

1 (1)

0

0

0

0

0

 

 bConsidered to be a malformation

* and ** denote significant differences from the vehicle control value, p<0.05 and p<0.01, respectively.

 

Conclusions:
DMTU was not teratogenic in rat at 200 mg/kg bw/day, which was maternally toxic. But DMTU was fetotoxic at all doses tested in the presence of maternal toxicity.
Executive summary:

A read-across between these two substances is justified for the reproduction endpoint.

Because DETU and DMTU are two thioureas having a high structural similarity: both structures differ by a carbon by chain.

Moreover DETU and DMTU have the same physicalchemical properties, and are harmful by oral route (acute toxicity).

Saillenfait,et al (1991), tested DMTU in SD rats at 0, 15, 25, 50, 100 or 200 mg/kg/day from GD 6-20.

The only maternal toxicity noted was decreased body weight gain at 15 mg/kg/day and above (NOAEL of maternal toxicity < 15 mg/kg bw/d). The LOAEL for developmental toxicity was 15 mg/kg/day based on decrease of fetal body weight gain at all doses. The decrease in maternal weight was considered severe and the fetal effects caused by DMTU were probably secondary to the toxicity incurred by the mothers. Dilated ureter and extra lumbar ribs were observed at 200 mg/kg bw/d (significant results).

No teratogenic effects related to administration of DMTU were observed at dose levels up to 200 mg/kg bw/d, a level which was toxic to the dams.

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Qualifier:
no guideline followed
Principles of method if other than guideline:
Developmental study was performed on rats by dermal route. Rats were exposed on day 12 of gestation only at dose levels of 450, 670, 1000, 1500 and 2250 mg/kg bw.
GLP compliance:
no
Limit test:
yes
Species:
rat
Strain:
other: Charles River-CD
Details on test animals and environmental conditions:
Primigravida femelles.
Route of administration:
dermal
Vehicle:
DMSO
Details on exposure:
DETU was applied on the clipped back skin of rat.
Analytical verification of doses or concentrations:
no
Details on mating procedure:
no data
Duration of treatment / exposure:
a single exposure on gestation day 12
Frequency of treatment:
a single exposure
Remarks:
Doses / Concentrations:
450, 670, 1000, 1500 and 2250 mg/kg bw
Basis:
nominal conc.
No. of animals per sex per dose:
5 females/group
Control animals:
yes, concurrent vehicle
Details on study design:
The animals were sacrified on the twentieth day of gestation and the observations and determinations were made.
Maternal examinations:
no data
Ovaries and uterine content:
gross examinations of uterus and fetuses, number of implantation sites, number of live fetuses, number of early resorptions, number of late resorptions.
Fetal examinations:
fetal weight and fetal crown-rump length.
All fetuses were saved in appropriate fixatives for possible future determination of skeletal and visceral anomalies.
Statistics:
no data
Indices:
no data
Historical control data:
no data
Details on maternal toxic effects:
Maternal toxic effects:no effects
DETU was not toxic to pregnant rats, no mortality was observed.
Dose descriptor:
NOAEL
Effect level:
> 2 250 mg/kg bw/day
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
> 2 250 mg/kg bw/day
Basis for effect level:
other: developmental toxicity
Details on embryotoxic / teratogenic effects:
DETU was not toxic to pregnant rats, not embryolethal and not teratogenic under the conditions of this test at levels ranging from 450 to 2250 mg/kg bw. All animals (at all levels) delivered normal litters. All parameters used to measure the outcome of pregnancy and fetal development were similar to those of the control DMSO-treated females.

Table of results : Effects of a single topical application of DETU on the outcome of pregnancy and fetal development.

 

Compound

Number of females

Number per pregnant female

Number of fetus with anomalies

pregnant

Not pregnant

Died

Implantation sites

Early Resorption sites

Late resorptions

Live fetuses

DMSO

4

1

0

10.8

0.3

0

10.5

None

DETU

4

1

0

10.0

1.5

0

8.5

None

Mean of all treated-animals (at all doses)

Conclusions:
DETU was not toxic to pregnant rats, not embryolethal and not teratogenic under the conditions of this test at levels ranging from 450 to 2250 mg/kg bw.
Executive summary:

The purpose of this developmental study was to determine the Appropriate lethal dose (ALD) of DETU for pregnant rats and to evaluatae embryotoxic and teratogenic potential. The test material was suspended in DMSO and a single dose was applied on the clipped back skin of primigravida Charles River-CD rats on day 12 of gestation at dose levels of 450, 670, 1000, 1500 and 2250 mg/kg bw. Five pregant females were treated with DMSO and served as controls.

The animals were sacrified on the twentieth day of gestation and the following observations and determinations were made: gross examinations of uterus and fetuses, number of implantation sites, number of live fetuses, number of early resorptions, number of late resorptions, fetal weight and fetal crown-rump length. All fetuses were saved in appropriate fixatives for possible future determination of skeletal and visceral anomalies.

DETU was not toxic to pregnant rats, not embryolethal and not teratogenic under the conditions of this test at levels ranging from 450 to 2250 mg/kg bw. All animals (at all levels) delivered normal litters. All parameters used to measure the outcome of pregnancy and fetal development were similar to those of the control DMSO-treated females.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LOAEL
15 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
A reliable study on developmental toxicity study on rats in available on Dimethylthiourea (DMTU). The study is reliable with a klimisch score of 1.
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
2 250 mg/kg bw/day
Study duration:
subacute
Species:
rat
Additional information

Developmental study on DMTU by oral route (read-across)

Saillenfait et al. (1991), tested DMTU in SD rats at 0, 15, 25, 50, 100 or 200 mg/kg/day from GD 6-20.

The only maternal toxicity noted was decreased body weight gain at 15 mg/kg/day and above (NOAEL of maternal toxicity < 15 mg/kg bw/d). The LOAEL for developmental toxicity was 15 mg/kg/day based on decrease of fetal body weight gain at all doses. The decrease in maternal weight was considered severe and the fetal effects caused by DMTU were probably secondary to the toxicity incurred by the mothers. Dilated ureter and extra lumbar ribs were observed at 200 mg/kg bw/d (significant results).

No teratogenic effects related to administration of DMTU were observed at dose levels up to 200 mg/kg bw/d, a level which was toxic to the dams.

Developmental study on DETU by dermal route

DETU was suspended in DMSO and a single dose was applied on the clipped back skin of primigravida Charles River-CD rats on day 12 of gestation at dose levels of 450, 670, 1000, 1500 and 2250 mg/kg bw. Five pregant females were treated with DMSO and served as controls.

The animals were sacrified on the twentieth day of gestation and the following observations and determinations were made: gross examinations of uterus and fetuses, number of implantation sites, number of live fetuses, number of early resorptions, number of late resorptions, fetal weight and fetal crown-rump length. All fetuses were saved in appropriate fixatives for possible future determination of skeletal and visceral anomalies.

DETU was not toxic to pregnant rats, not embryolethal and not teratogenic under the conditions of this test at levels ranging from 450 to 2250 mg/kg bw. All animals (at all levels) delivered normal litters. All parameters used to measure the outcome of pregnancy and fetal development were similar to those of the control DMSO-treated females.

Justification for classification or non-classification

Proposed self-classification (Regulation (EC) No 1272/2008) :

Not classified.

Justification: No teratogenic effects were observed in the oral developmental study. A foetotoxicity (decrease of fetal bodyweight) was observed but is due to the maternal toxicity.