1,3-dibutyl-2-thiourea

Endpoint summary

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

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

not specified

GLP compliance:

not specified

Species:

rat

Strain:

Sprague-Dawley

Details on test animals or test system 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.