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Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information
No available data.
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
Short description of key information:
No specific study on fertility is available on DPTU. However in the developmental study, no effect on implantation sites was observed.
A self classification on reproduction is proposed based on foetotoxicity of DPTU, therefore no other study on reproduction must be performed.

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:
other: see 'Remark'
Remarks:
Comparable to guideline study [OECD 414] Almost all the test conditions were respected except the exposure period. Females were exposed from day 6 of gestation to day 20 instead of day 6 to 15 as it was advised in the guidelines. Moreover, some results are not very precise (table 2) since the standard deviations of the mean-percentages of both nonsurviving implants and resorption sites per litter are very high (sometimes higher than the means).
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:
other: dissolved and suspended in 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
Duration of test:
1 month
Remarks:
Doses / Concentrations:
25, 50, 100 and 200 mg/kg/day
Basis:
actual ingested
No. of animals per sex per dose:
- Number of animals per group: 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
Details on maternal toxic effects:
Maternal toxic effects:no effects

Details on maternal toxic effects:
- 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 (table 1).
- Pregnancy rates were equivalent across groups: around 90% in both treated and control groups (table 2).
Dose descriptor:
NOAEL
Effect level:
> 200 mg/kg bw/day
Basis for effect level:
other: maternal toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
- 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.

EMBRYO-FETAL TOXICITY (table 2):
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.

TYPE OF EMBRYOFETAL MALFORMATIONS (table 3):
- 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.
- The male-to-female sex ratio was comparable across groups (around 1 in both treated and control groups).
Dose descriptor:
NOAEL
Effect level:
50 mg/kg bw/day
Basis for effect level:
other: fetotoxicity
Dose descriptor:
NOAEL
Effect level:
100 mg/kg bw/day
Basis for effect level:
other: embryotoxicity
Dose descriptor:
NOAEL
Effect level:
> 200 mg/kg bw/day
Basis for effect level:
other: teratogenicity
Abnormalities:
not specified
Developmental effects observed:
not specified
Conclusions:
DPTU was not teratogenic in rats in test conditions but embryolethal and fetotoxic.
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.

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 effet is 200 mg/kg bw because no mojor 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 effet is 200 mg/kg bw because no mojor 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 selection of Effect on developmental toxicity: via oral route:
Only one reliable study is available on DPTU.

Justification for classification or non-classification

Proposed self-classification

- Regulation (EC) No 1272/2008

Repro. Cat 2 - H361d as "Suspected of damaging the unborn child".

 

- Directive 67/548/EEC

Repro. Cat 3 - R63 (Possible risk of harm to the unborn child)