Registration Dossier
Registration Dossier
Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.
The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.
Use of this information is subject to copyright laws and may require the permission of the owner of the information, as described in the ECHA Legal Notice.
EC number: 620-365-5 | CAS number: 9016-72-2
Toxicological information
Developmental toxicity / teratogenicity
Currently viewing:
Administrative data
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 25 August to 10 October 1986
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 988
- Report date:
- 1986
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.31 (Prenatal Developmental Toxicity Study)
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- polymeric zinc 1,2-propylenebis(dithiocarbamate)
- EC Number:
- 620-365-5
- Cas Number:
- 9016-72-2
- IUPAC Name:
- polymeric zinc 1,2-propylenebis(dithiocarbamate)
- Test material form:
- solid
- Remarks:
- Powder
Constituent 1
- Specific details on test material used for the study:
- LH 30/Z [Propineb], purity 83.9%, batch number 231 501 115
Test animals
- Species:
- rabbit
- Strain:
- Chinchilla
- Remarks:
- Kfm: CHIN, Chinchilla/rabbit hybrid
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: KFH
- Age at study initiation: 4-7 months
- Weight at study initiation: 2630 - 4227 g
- Fasting period before study: none
- Housing: individually in stainless steel cages
- Diet: ad libitum pelleted standard diet (Kliba 341)
- Water: ad libitum
- Acclimation period: at least 7 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-25
- Humidity (%): 40-70
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: From: 26 Aug 1986 To: 10 Oct 1986
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- other: distilled water with 0.5% Cremophor EL
- Details on exposure:
- The test material was dissolved in distilled water with 0.5% Cremophor EL and administered orally by gavage, once daily in the morning from GD6-18. All groups received a dose volume of 4 mL/kg bw with a daily adjustment of individual volume to the actual body weight. Control animals were similarly dosed with the vehicle alone.
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- The test material/vehicle mixtures were prepared daily prior to administration. Stability and homogeneity of the test material/vehicle mixtures were determined prior to the first administration. Samples were taken immediately after preparation. and again after 2 hours. During the treatment period, additional samples for confirmation of homogeneity, concentration and stability were taken once.
- Details on mating procedure:
- After at least seven days of acclimatisation, the females were housed with males (1:1) until mating has been observed. After mating, the females were removed and caged individually. The day of mating was recorded as Gestation Day (GD) 0.
- Duration of treatment / exposure:
- 13 days (GD6-18)
- Frequency of treatment:
- Daily
- Duration of test:
- Rabbits were gavaged on GD6-18 and terminated on GD28
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 mg/kg bw/day
- Remarks:
- Vehicle control (0.5% aqueous Cremophor EL; 4 mL/kg bw); daily adjustment of individual volume to the actual body weight
- Dose / conc.:
- 10 mg/kg bw/day
- Remarks:
- Daily adjustment of individual volume to the actual body weight
- Dose / conc.:
- 30 mg/kg bw/day
- Remarks:
- Daily adjustment of individual volume to the actual body weight
- Dose / conc.:
- 100 mg/kg bw/day
- Remarks:
- Daily adjustment of individual volume to the actual body weight
- No. of animals per sex per dose:
- 16
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- Mated female rabbits were dose by gavage on GD6-18. Dams were sacrificed and fetuses removed by caesarean section on GD28.
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: The animals were observed twice daily for mortality and clinical signs
BODY WEIGHT: Yes
- Time schedule for examinations: bodyweights were recorded daily from GD0-28
FOOD CONSUMPTION: Yes
- Time schedule for examinations: food consumption was recorded on GD 6, 11, 15, 19, 24 and 28
WATER CONSUMPTION: No
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on Gestation Day 28
- Organs examined: gross macroscopic examination of all internal organs - Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes - Fetal examinations:
- - External examinations: Yes: all per litter
- Soft tissue examinations: Yes: all per litter
- Skeletal examinations: Yes: all per litter
- Head examinations: Yes: all per litter
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- At 100 mg/kg bw/d, treatment of mated female rabbits caused severe signs of maternal toxicity.
Symptoms were noted in 5 of the 16 animals. In three females, one of which died prior to the last dose, dyspnoea, ventrolateral recumbency, inability to sit or stand, abnormal head position (opisthonoid) and inability to move the extremities (cataleptoid) were observed. The symptoms were first observed on GD15, 17 and 21, respectively, and continued until death (one female died on GD18 post coitum) or until termination of the study in the surviving animals. In the other two females, signs of abortion were noted on GD21 and 27, respectively. - Dermal irritation (if dermal study):
- not examined
- Mortality:
- mortality observed, treatment-related
- Description (incidence):
- One rabbit at 100 mg/kg bw/d died prior to the last dose
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Mean body weight gain showed a dose-related reduction at 30 and 100 mg/kg bw/d but differences from the control value only attained statistical significance at 100 mg/kg bw/d.
Additionally, calculation of body weight gain corrected for uterus weight showed treatment -related statistically significant reductions in dams at 100 mg/kg bw/d. - Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- Evaluation of food consumption data showed dose-related and statistically significant reductions at 30 and 100 mg/kg bw/d. At 30 mg/kg bw/d, statistical significance was attained between GD15-24 and at 100 mg/kg bw/d, statistical significance was attained between GD6-19.
- 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
- Endocrine findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Description (incidence and severity):
- Gravid uterus weight was unaffected by treatment
- Gross pathological findings:
- no effects observed
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- not examined
- Histopathological findings: neoplastic:
- not examined
Maternal developmental toxicity
- Number of abortions:
- effects observed, treatment-related
- Description (incidence and severity):
- Signs of abortion were noted on GD 21 and 27 in two dams at 100 mg/kg bw/d
- Pre- and post-implantation loss:
- effects observed, treatment-related
- Description (incidence and severity):
- Evaluation of the reproduction parameters showed dose-related increased post-implantation losses at 30 and 100 mg/kg bw/d compared with the vehicle control group. At 30 mg/kg bw/d, the losses were caused by total resorption in two females and the incidences of 9.9% were
within the laboratory historical control data range (0.7-10.4%; covering studies carried out from 1984-1986). At 100 mg/kg bw/d, the increased incidence of post-implantation loss was caused by total resorption or abortion in six females and resulted in a significantly reduced number of live fetuses in this group. - Total litter losses by resorption:
- effects observed, treatment-related
- Description (incidence and severity):
- Total resorption was noted for four dams at 100 mg/kg bw/d
- Early or late resorptions:
- effects observed, treatment-related
- Description (incidence and severity):
- Total resorption was noted for four dams at 100 mg/kg bw/d
- Dead fetuses:
- no effects observed
- Changes in pregnancy duration:
- not examined
- Changes in number of pregnant:
- no effects observed
Effect levels (maternal animals)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 10 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- body weight and weight gain
- clinical signs
- food consumption and compound intake
- mortality
- pre and post implantation loss
Maternal abnormalities
- Key result
- Abnormalities:
- no effects observed
Results (fetuses)
- Fetal body weight changes:
- no effects observed
- Reduction in number of live offspring:
- effects observed, treatment-related
- Description (incidence and severity):
- At 100 mg/kg bw/d, the increased incidence of post -implantation loss caused by total resorption or abortion in six females resulted in a significantly reduced number of live fetuses in this group.
- Changes in sex ratio:
- no effects observed
- Changes in litter size and weights:
- no effects observed
- Anogenital distance of all rodent fetuses:
- not examined
- Changes in postnatal survival:
- not examined
- External malformations:
- no effects observed
- Skeletal malformations:
- no effects observed
- Visceral malformations:
- no effects observed
- Details on embryotoxic / teratogenic effects:
- Fetal parameters (except for the number of live fetuses in the 100 mg/kg bw/d group), as assessed by sex ratios, mean fetal body weights, external and visceral fetal examinations, examination of fetal heads and skeletal examination were not adversely affected by treatment with propineb.
Implantation losses (9.9%) observed at 30 mg/kg bw/d are not considered to be relevant because the incidence was still well within the background incidence (Laboratory historical control data from 1984 to 1986) which were included in the study report: the range of implantation
losses was between 0.7 to 10.4%, with values above 10% observed in the controls from 3 studies). As there were no adverse effects in the developmental parameters at this dose level, the NOAEL for developmental toxicity in the rabbit is considered to be 30 mg/kg bw/d. However, the PPR Meeting 146 concluded that as the incidences of post-implantation loss were borderline with the upper range of historical control data from a limited number of studies, the developmental NOAEL is 10 mg/kg bw/d.
Effect levels (fetuses)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 30 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- reduction in number of live offspring
Fetal abnormalities
- Key result
- Abnormalities:
- no effects observed
Overall developmental toxicity
- Key result
- Developmental effects observed:
- yes
- Lowest effective dose / conc.:
- 30 mg/kg bw/day
- Treatment related:
- yes
- Relation to maternal toxicity:
- developmental effects as a secondary non-specific consequence of maternal toxicity effects
- Dose response relationship:
- yes
- Relevant for humans:
- yes
Any other information on results incl. tables
Maternal findings
| 0 mg/kg bw/d | 10 mg/kg bw/d | 30 mg/kg bw/d | 100 mg/kg bw/d |
Mated (#) | 16 | 16 | 16 | 16 |
Pregnant (#) | 16 | 14 | 16 | 15 |
Mortality (#) | - | - | - | 1 |
Abortion (#) | - | - | - | 2 |
Implantation sites or resorbed fetuses only (#) | - | - | 2 | 4 |
Litters (#) | 16 | 14 | 14 | 8 |
Weight gain (g) GD 6-28 | 401 | 384 | 279 | 167 |
Weight gain (%) GD 6-28 | +12.7 | +11.8 | +8.8 | +5.4 |
Corrected weight gain (%) | +0.5 | -1.8 | +5.0 | -7.6 |
Litter parameters
| 0 mg/kg bw/d | 10 mg/kg bw/d | 30 mg/kg bw/d | 100 mg/kg bw/d |
Pre-implantation loss (#) | 2 | 3 | - | 5 |
Pre-implantation loss (%) | 1.7 | 2.4 | 0.0 | 4.5 |
Post-implantation loss (#) | 5 | 7 | 13 | 47 |
Post-implantation loss (%) | 4.4 | 5.8 | 9.9 | 44.8 |
Live fetuses (#) | 109 | 113 | 118 | 58 |
Applicant's summary and conclusion
- Conclusions:
- The results of this study indicate that the oral administration of two mated female rabbits causes dose-related toxic effects at dose levels of 30 and 100 mg/kg bw/d. At these dose levels, treatment caused reduced food consumption and body weight gain and increased post-implantation loss. Additionally, one out of five females at 100 mg/kg bw/d with severe symptoms died. There was no evidence of teratogenicity in this study.
- Executive summary:
In a pre-natal developmental toxicity study, groups of 16 mated female Chinchilla rabbits were administered propineb (83.9% purity) by oral gavage at dose levels of 0, 10, 30 or 100 mg/kg bw/d from day 6-18 of gestation. Signs of severe maternal toxicity were seen at 100 mg/kg bw/d, including reduced weight gain and food intake in comparison with controls, dyspnoea and ventro-lateral recumbency, and signs of abortion in two females. One dam died. Body-weight gain and food intake were also reduced at 30 mg/kg bw/d. Evaluation of reproduction parameters revealed a dose-related increase in post-implantation loss at 30 and 100 mg/kg bw/d. Fetal parameters, including external, skeletal and visceral examinations, revealed no effects associated with treatment with propineb. A maternal NOAEL of 10 mg/kg bw/d can be determined for this study based on clinical signs, reduced weight gain and food consumption. A developmental NOAEL of 10 mg/kg bw/d can be determined for this study, based on increased post-implantation loss.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
