Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

No data on fertility is available on 1,3 -dibutylthiourea.

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

Effects on developmental toxicity

Description of key information
In a developmental study in rat, DBTU was foetotoxic in the absence of distinctive maternal effects. However no teratogenic effects related to administration of DBTU were observed at dose levels up to 200 mg/kg/day, a level which was toxic to the dams.
Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study
Reference:
Composition 0
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
not specified
GLP compliance:
not specified
Test material information:
Composition 1
Species:
rat
Strain:
Sprague-Dawley
Details on test animals and environmental conditions:
- Source: IFFA CREDO Breeding Laboratories (Saint-Germain-sur-L'Arbresle, France)
- Age: no data
- Weight at study initiation: Males: around 350 g ; Females: 200-220 g
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
- Total volume applied: 5 ml/kg body wt
- Control group: received the vehicle alone (23 females)
Analytical verification of doses or concentrations:
no
Details on mating procedure:
- Females were placed with untreated males (1 male: 3 females) overnight and were examined by vaginal smear for the presence of sperm the following morning.
- Sperm-positive females were considered to be in Day 0 of gestation.
Duration of treatment / exposure:
15 days (from Gestational Day 6 to GD 20).
Frequency of treatment:
daily
Duration of test:
around 35 days (1 or 2 weeks' quaranting, mating and gestation)
Dose / conc.:
15 mg/kg bw/day (actual dose received)
Dose / conc.:
25 mg/kg bw/day (actual dose received)
Dose / conc.:
50 mg/kg bw/day (actual dose received)
Dose / conc.:
100 mg/kg bw/day (actual dose received)
Dose / conc.:
200 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
21 or 23 females per group
Control animals:
yes, concurrent vehicle
Maternal examinations:
- Maternal observations: daily, for evidence of treatment-related effects.
- Maternal body weight: recorded on day 0 and every 3 days from days 6 to 21 of gestation.
- Food consumption: recorded on days 6, 11, 16 and 21.
Ovaries and uterine content:
The uterus were removed and weighed. The uterine horns were then opened and the numbers of implantation and resorption sites and of live and dead fetuses were recorded.
Fetal examinations:
Live fetuses were removed, weighed, sexed, and examined for external anomalies including those of the oral cavity.
. Half of the viable fetuses from each litter were randomly selected, fixed in Bouin's solution, and examined microscopically as described by Barrow and Taylor for soft tissue anomalies.
. The remaining half of the fetuses were fixed in 70% ethanol and subsequently eviscerated, macerated in 1 % KOH, stained with Alizarin red S, and examined microscopically for skeletal anomalies.
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.
Clinical signs:
no effects observed
Description (incidence and severity):
No signs of altered behavior or general demeanor were observed among bred rats during gestion.
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
No effect on maternal weight gain was discerned among dams given 15 or 25 mg/kg bw/day. maternal weight gain was significantly depressed over the first 3 days of treatment 50 mg/kg /day, and throughout treatment at 100 and 200 mg/kg bw/day.
Weight gain between Days 6 and 21 of gestation and absolute weight gain were significantly reduced at 50, 100 and 200 mg/kg bw/day.
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
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:
not examined
Gross pathological findings:
not specified
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not examined
Other effects:
not examined
Details on results:
The pregnancy rates were similar in all groups.
Number of abortions:
no effects observed
Pre- and post-implantation loss:
not examined
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
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): not examined
Changes in number of pregnant:
no effects observed
Description (incidence and severity):
Pegnancy rates were similar in all groups: around 80-90% .
Other effects:
not examined
Details on maternal toxic effects:
There were no differences among the groups in the mean numbers of implantations and live feuses and in fetal sex ratio when comparent to the control.
There were appearent decreases in the incidences of nonsurviving implants at 25 mg/kg bw/day and of resorptions at 15 and 25 mg/kg bw/day. Review of the control values revealed that these decreases were spuriois and decidely resultated from the high incidences of the concurrent control group.
Key result
Dose descriptor:
NOAEL
Effect level:
25 mg/kg bw/day
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):
DBTU induced a dose-related reduction of fetal weight which was significantly different from the control in females at 15 mg/kg bw/day (6%, reduction, p <0.05), and in males and females at higher dose levels (30% reduction at 200 mg/kg/day) (p< 0.01).
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
no effects observed
External malformations:
no effects observed
Skeletal malformations:
no effects observed
Description (incidence and severity):
The incidences of skeletal variations (primarily reduced ossification of vertebrae and sternebrae and extra lumbar ribs) were similar in all groups of fetuses.
Visceral malformations:
no effects observed
Description (incidence and severity):
The incidences of visceral variations (primarily dilated renal pelvis and ureter) were similar in all groups of fetuses.
Single instances of omphalocele were observed at 25, 50 and 100 mg/kg/day. The occurrence of this malformation was consistent with the range of incidences seen in historical control litters.
One fetus from control had a diaphragmatic hernia.
Other effects:
not examined
Details on embryotoxic / teratogenic effects:
No differences among the groups in the mean numbers of implantations and live fetuses and in fetal sex ratio when compared to the control.
Dose descriptor:
NOAEL
Remarks:
teratogenicity
Effect level:
> 200 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: No teratogenic effect was observed at any doses.
Remarks on result:
not determinable due to absence of adverse toxic effects
Dose descriptor:
LOAEL
Remarks:
foetotoxicity
Effect level:
15 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
fetal/pup body weight changes
Abnormalities:
not specified
Developmental effects observed:
not specified

Table 1 : Change weigh during gestation in Sprague Dawley rats treated daily by gastric intubation with DBTU

Dose

(mg/kg/day)

Bodyweight on GD6

Bodyweight gain (g)

Absolute weight gain (g)

GD 6-9

GD 9-12

GD 12-15

GD 15-18

GD 18-21

GD 6-21

0

252 +/- 16

15 +/-7

19+/-7

23+/-7

43+/-10

55+/-14

156 +/-34

50+/-12

15

251+/-19

15+/-5

15+/-6

22+/-4

45+/-10

53+/-13

150+/-25

48+/-13

25

251+/-19

12+/-4

19+/-5

25+/-4

44+/-8

58+/-10

157+/-21

46+/-13

50

248+/-11

9+/-5**

16+/-4

20+/-4

40+/-6

49+/-8

133+/-13*

33+/-13**

100

250+/-11

6+/-4**

18+/-5

16+/-4**

30+/-9**

45+/-11

116+/-26**

25+/-14**

200

250+/-11

0+/-6**

20+/-9

11+/-5**

24+/-7**

24+/-18**

78+/-29**

-7+/-21**

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

Data expressed as means +/- SD

Absolute weight gain = (day 21 body weight) – (gravid uterus weight) – (day 6 body weight)

 

Table 2: Reproductive parameters in Sprague-Dawley rats treated daily by gastric intubation with DBTU

Dose

(mg/kg/day)

Number of deaths per number of treated females

Percentage of females pregnant

Number of examined litters

Mean implantation sites per litter

Mean live fetuses per litter

Mean % nonsurviving implants per litter

Mean resorptions sites par litter

Fetal sex ratio M:F (%)

Mean fetal body weight (g) per litter

males

females

0

0/23

91.3

21

15.33+/-3.58

14.00+/-4.09

 

 

0.97

5.87+/-0.32

5.64+/-0.28

15

0/23

91.3

21

14.29+/-4.15

13.76+/-4.15

4.62+/-7.91

4.25+/-7.94

0.91

5.60+/-0.46

5.32+/-0.38*

25

0/23

95.6

22

15.77+/-2.43

15.36+/-2.59

2.85+/-3.68*

2.60+/-3.48

1.05

5.44+/-0.26**

5.15+/-0.24**

50

0/21

85.7

18

15.06+/-1.80

14.50+/-1.65

3.46+/-5.68

3.46+/-5.68

0.92

5.10+/-0.29**

4.78+/-0.19**

100

0/21

85.7

18

14.39+/-4.07

13.83+/-3.96

3.63+/-4.66

3.23+/-3.95

1.01

4.94+/-0.46**

4.58+/-0.32**

200

0/21

81.0

17

15.29+/-1.21

14.53+/-1.37

4.89+/-6.49

4.89+/-6.49

1.13

4.12+/-0.45**

3.97+/-0.47**

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

Data expressed as means +/- SD

  

Table 3: Incidence of anomalies in fetuses of Sprague-Dawley rats treated daily by gastric intubation with DBTU

Doses (mg/kg /day)

0

15

25

50

100

200

 

Number of fetuses (litters) examined

External examination

294(21)

289(22)

338(22)

261(18)

249(18)

247(17)

Soft tissue examination

147(21)

145(21)

169(22)

131(18)

125(18)

124(17)

Skeletal examination

147(20)

144(22)

169(22)

130(18)

124(17)

123(17)

 

Numbers of fetuses (litters) affected

External anomalies

 

> omphalocele

0

0

1(1)

1(1)

1(1)

0

> subcutaneous cranial hemorrhage

0

0

0

0

1(1)

3(2)

Soft tissue anomalies

 

> diaphragmatic hernia

1(1)

0

0

0

0

0

> dilated renal pelvis

0

0

0

0

0

8(3)

> dilated ureter

0

0

1(1)

0

1(1)

4(1)

Skeletal anomalies

 

> interparietal and/or occipital not ossified

0

0

0

0

1(1)

2(1)

> vertebral centra dumbbell-shaped or bilobed

1(1)

4(4)

0

1(1)

5(2)

11(5)

> ribs wavy

0

1(1)

0

0

2(1)

0

> ribs extra cervical

1(1)

1(1)

1(1)

0

0

1(1)

> ribs extra lumbar

9(7)

13(7)

28(11)

15(11)

9(7)

10(5)

> sternebrae scrambled

0

0

0

1(1)

0

0

> sternebrae fifth not ossified

0

1(1)

0

0

1(1)

3(2)

 

 

 

 

 

 

 

 

 

 

 

Conclusions:
DBTU was foetotoxic in the absence of distinctive maternal effects. However no teratogenic effects related to administration of DBTU were observed at dose levels up to 200 mg/kg/day, a level which was toxic to the dams.
Executive summary:

Sprague-Dawley rats were administered 1,3 -dibutyl-2 -thiourea by gavage from Days 6 to 20 of gestation. Daily dosage levels were 0, 15, 25, 50, 100 and 200 mg/kg/day.

No signs of altered or general demeanor were observed among bred rats given DBTU during gestation. No effect on maternal weoght gain was discerned among dams given 15 or 25 mg/kg/day. maternal weight gain was significantly

DBTU was foetotoxic in the absence of distinctive maternal effects. However no teratogenic effects related to administration of DBTU were observed at dose levels up to 200 mg/kg/day, a level which was toxic to the dams. depressed aver the first 3 days of treatment at 50 mg/kg/day, and throughout at 100 and 200 mg/kg/day (p<0.01).Weight gain between Days 6 and 21 of gestation and absolute weight gain were significantly reduced at 50, 100, and 200 mg/kg/day. Pregnancy rates were similar in all groups. There were no differences among the groups in the mean numbers of implantations and live fetuses and in fetal sex ratio when compared to the control. There were apparent decreases in the incidences of nonsurvaving implants at 25 mg/kg/day and of resorptions at 15 and 25 mg/kg/day. Review of the control values revealed that these decreases were spurious and decidely resulted from the high incidences of the concurrent control group. DBTU induced a dose-related reduction of fetal weight which was significantly different from the control in females at 15 mg/kg/day (6%, reduction, p<0.05), and in males and females at higher dose levels (30% reduction at 200 mg/kg/day, p< 0.01). The incidences of visceral variations (primarely dilated renal pelvis and ureter) and skeletal variaations (primarily reduced ossification of vertebrae and sternebrae and extra lumbar ribs) were similar in all groups of fetuses. Single instances of omphalocele were observed at 25, 50 and 100 mg/kg/day. The occurence of this malformation was consistent with the range of incidences seen in historical control litters. One fetus from control had a diaphragmatic hernia.

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:
the Saillenfait's study is considered to be reliable with a klimisch score of 2.
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

Developmental study in rats (Saillenfait 1991):

Sprague-Dawley rats were administered 1,3 -dibutyl-2 -thiourea by gavage from Days 6 to 20 of gestation. Daily dosage levels were 0, 15, 25, 50, 100 and 200 mg/kg/day.

No signs of altered or general demeanor were observed among bred rats given DBTU during gestation. No effect on maternal weoght gain was discerned among dams given 15 or 25 mg/kg/day. maternal weight gain was significantly depressed aver the first 3 days of treatment at 50 mg/kg/day, and throughout at 100 and 200 mg/kg/day (p<0.01).Weight gain between Days 6 and 21 of gestation and absolute weight gain were significantly reduced at 50, 100, and 200 mg/kg/day. Pregnancy rates were similar in all groups.

There were no differences among the groups in the mean numbers of implantations and live fetuses and in fetal sex ratio when compared to the control. There were apparent decreases in the incidences of nonsurvaving implants at 25 mg/kg/day and of resorptions at 15 and 25 mg/kg/day. Review of the control values revealed that these decreases were spurious and decidely resulted from the high incidences of the concurrent control group. DBTU induced a dose-related reduction of fetal weight which was significantly different from the control in females at 15 mg/kg/day (6%, reduction, p<0.05), and in males and females at higher dose levels (30% reduction at 200 mg/kg/day, p< 0.01).

The incidences of visceral variations (primarely dilated renal pelvis and ureter) and skeletal variaations (primarily reduced ossification of vertebrae and sternebrae and extra lumbar ribs) were similar in all groups of fetuses. Single instances of omphalocele were observed at 25, 50 and 100 mg/kg/day. The occurence of this malformation was consistent with the range of incidences seen in historical control litters. One fetus from control had a diaphragmatic hernia.

DBTU was foetotoxic in the absence of distinctive maternal effects. However no teratogenic effects related to administration of DBTU were observed at dose levels up to 200 mg/kg/day, a level which was toxic to the dams.

Justification for classification or non-classification

Based on the available data, no classification is required for reproduction according to the Regulation EC.N°1272/2008.