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Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

No specific study on fertility is available on DPTU.

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
DPTU was not teratogenic in rats in test conditions but embryolethal and fetotoxic at 100 and 200 mg/kg/d. The NOAEL for developmental toxicity is 50 mg/kg bw.
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)
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Details on test animals or test system 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 polycarbonate cages with hardwood shavings as bedding.
- Diet (e.g. ad libitum): UAR Alimentation Villemoisson, ad libitum
- Water (e.g. ad libitum): filtered 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:
corn oil
Details on exposure:
- Total volume applied: 5 ml/kg body wt
- Control group: received the vehicle alone (20 animals)
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:
from gestational days 6 to 20
Frequency of treatment:
daily, at approximately the same time each time
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:
20 or 21 females
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:
- On day 21 of gestation, the females were killed by an intrapulmonary injection of T61.
- Examination of 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:
- Examination of fetuses: 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.
Indices:
- absolute weight gain + gravide uterus weight
- pregnancy rate
- mean live fetuses per litter
- mean percentage of nonsurvviving implants per litter (resorption + dead fetuses)
- mean resorption sites per litter
- fetal sex ratio M:F
- mean fetal body weight per litt
Historical control data:
yes
Clinical signs:
no effects observed
Description (incidence and severity):
No clinical signs attributed to treatment and no deaths were observed among treated females, in any dosed group.
Description (incidence and severity):
n/a
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
No significant effect on maternal body weight gain was noted in females given 25 or 50 mg/kg/day.
Maternal absolute weight gain was significantly decreased at 100 mg/kg/day compared to control.
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 examined
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
no effects observed
Early or late resorptions:
effects observed, treatment-related
Description (incidence and severity):
Significant increases in the mean percentage of nonsurviving implants and early embryonic resorptions were observed at 200 mg/kg/day (p < 0.05), concomitant with a non-significant decrease in the mean number of live fetuses per litter.
Dead fetuses:
not specified
Changes in pregnancy duration:
not specified
Changes in number of pregnant:
no effects observed
Description (incidence and severity):
Pregnancy rates were equivalent across groups: around 90% in both treated and control groups.
Details on maternal toxic effects:

Treatment did not alter significantly the mean numbers of implantation sites, at any dose.
Dose descriptor:
NOAEL
Effect level:
> 200 mg/kg bw/day
Based on:
test mat.
Remarks on result:
not determinable due to absence of adverse toxic effects
Abnormalities:
no effects observed
Fetal body weight changes:
effects observed, treatment-related
Description (incidence and severity):
Test substance induced a dose-related reduction in both male and female fetal weights which were significantly different from the control at 100 and 200 mg/kg/day (p < 0.05 and p < 0.01, respectively). Indeed, DPTU produced foetoxicity which characterized by significant decreases in fetal weight in a dose-related manner.
Description (incidence and severity):
n/a
Changes in sex ratio:
no effects observed
Description (incidence and severity):
The male-to-female sex ratio was comparable across groups (around 1 in both treated and control groups).
Changes in litter size and weights:
effects observed, treatment-related
Description (incidence and severity):
n/a
External malformations:
not specified
Skeletal malformations:
no effects observed
Description (incidence and severity):
no specific pattern of malformation was distinguished and the incidences of the skeletal variants were comparable to that of controls.
Visceral malformations:
effects observed, treatment-related
Description (incidence and severity):
A treatment-related increase in the incidence of subcutaneous cranial hemorrhage occurred at 200 mg/kg/day.
Apart from hemorrhage, single occurrences of craniorachischisis and gastroschisis, omphalocele, anophthalmia or microphthalmia, and diaphragmatic hernia were observed in treated groups.
Dose descriptor:
NOAEL
Remarks:
(fetotoxicity)
Effect level:
50 mg/kg bw/day
Basis for effect level:
reduction in number of live offspring
Dose descriptor:
NOAEL
Remarks:
(embryotoxicity)
Effect level:
100 mg/kg bw/day
Basis for effect level:
fetal/pup body weight changes
Dose descriptor:
NOAEL
Remarks:
(teratogenicity)
Effect level:
> 200 mg/kg bw/day
Remarks on result:
not determinable due to absence of adverse toxic effects
Abnormalities:
not specified
Developmental effects observed:
not specified
Conclusions:
DPTU was not teratogenic in rats in test conditions but embryolethal and fetotoxic at the doses of 100 and 200 mg/kg bw /day in absence of maternotoxicity.
The NOAEL for developmental toxicity is 50 mg/kg bw.
Executive summary:

Groups of 20 female rats were exposed at 0, 25, 50, 100 and 200 mg/kg of DPTU by gavage from Days 6 to 20 of gestation.


No clinical signs attributed to treatment and no deaths were observed among treated females, in any dosed group. No significant effect on maternal body weight gain was noted in females given 25 or 50 mg/kg/day. Maternal absolute weight gain was significantly decreased at 100 mg/kg/day compared to control. The NOAEL for maternal effet is 200 mg/kg bw because no major effect was observed at any dose.


The male-to-female sex ratio was comparable across groups (around 1 in both treated and control groups).


Treatment did not alter significantly the mean numbers of implantation sites, at any dose. Significant increases in the mean percentage of nonsurviving implants and early embryonic resorptions were observed at 200 mg/kg/day (p < 0.05), concomitant with a nonsignificant decrease in the mean number of live fetuses per litter. Test substance induced a dose-related reduction in both male and female fetal weights which were significantly different from the control at 100 and 200 mg/kg/day (p < 0.05 and p < 0.01, respectively). Therefore the NOAEL for foetoxicity effects is 50 mg/kg bw.


Moreover, embryofetal malformations were observed in the treated groups. A treatment-related increase in the incidence of subcutaneous cranial hemorrhage occurred at 200 mg/kg/day. Apart from hemorrhage, single occurrences of craniorachischisis and gastroschisis, omphalocele, anophthalmia or microphthalmia, and diaphragmatic hernia were observed in treated groups. However no specific pattern of malformation was distinguished and the incidences of the skeletal variants were comparable to that of controls.


No sign of teratogenicity was observed in this study (NOAEL for teratogenicity > 200 mg/kg bw).


To sum up, DPTU was not teratogenic in rats in test conditions but embryolethal and fetotoxic. The NOAEL for developmental toxicity is 50 mg/kg bw.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
50 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
The Saillenfait study is a reliable study 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 study available
Additional information

Developmental study of Saillenfait (1991):

Groups of 20 female rats were exposed at 0, 25, 50, 100 and 200 mg/kg of DPTU by gavage from Days 6 to 20 of gestation.

Toxic effects on females and foetus were observed.

No clinical signs attributed to treatment and no deaths were observed among treated females, in any dosed group. No significant effect on maternal body weight gain was noted in females given 25 or 50 mg/kg/day. Maternal absolute weight gain was significantly decreased at 100 mg/kg/day compared to control. The NOAEL for maternal effect is 200 mg/kg bw because no major effect was observed at any dose.

The male-to-female sex ratio was comparable across groups (around 1 in both treated and control groups).

Treatment did not alter significantly the mean numbers of implantation sites, at any dose. Significant increases in the mean percentage of nonsurviving implants and early embryonic resorptions were observed at 200 mg/kg/day (p < 0.05), concomitant with a nonsignificant decrease in the mean number of live fetuses per litter. Test substance induced a dose-related reduction in both male and female fetal weights which were significantly different from the control at 100 and 200 mg/kg/day (p < 0.05 and p < 0.01, respectively). Therefore the NOAEL for foetoxicity effects is 50 mg/kg bw.

Moreover, embryofetal malformations were observed in the treated groups. A treatment-related increase in the incidence of subcutaneous cranial hemorrhage occurred at 200 mg/kg/day. Apart from hemorrhage, single occurrences of craniorachischisis and gastroschisis, omphalocele, anophthalmia or microphthalmia, and diaphragmatic hernia were observed in treated groups. However no specific pattern of malformation was distinguished and the incidences of the skeletal variants were comparable to that of controls.

No sign of teratogenicity was observed in this study (NOAEL for teratogenicity > 200 mg/kg bw).

To sum up, DPTU was not teratogenic in rats in test conditions but embryolethal and fetotoxic. The NOAEL for developmental toxicity is 50 mg/kg bw.

 

Justification for classification or non-classification

Based on the developemental study in rats, DPTU should be classified as Repro. Cat 2 - H361d as "Suspected of damaging the unborn child" according to the Regulation EU n°1272/2008.

Justification : No sign of teratogenicity was observed in the rat study so the Repro Category 1 is not required. However, embryolethal and fetotoxic effects were observed at 100 mg/kg/day in absence of adverse maternal toxicity.

Additional information