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Diss Factsheets

Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
screening for reproductive / developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2012-08-29 - 2013-04-24
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2013
Report date:
2013

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
GLP compliance:
yes (incl. QA statement)
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Sodium O,O-diisobutyl dithiophosphate
EC Number:
258-508-5
EC Name:
Sodium O,O-diisobutyl dithiophosphate
Cas Number:
53378-51-1
Molecular formula:
C8H18NaO2PS2
IUPAC Name:
sodium O,O-diisobutyl dithiophosphate
Test material form:
other: 51 % w/w solution in water, stabilized with X % NaOH
Details on test material:
- Substance type: Liquid
- Physical state: Light brown liquid
- Molecular formula (if other than submission substance): C8H18NaO2PS2
- Molecular weight (if other than submission substance): 264
- Smiles notation (if other than submission substance): CC(C)COP(=S)([S-])OCC(C)C.[Na+]
- InChl (if other than submission substance): InChI=1/C8H19O2PS2.Na/c1-7(2)5-9-11(12,13)10-6-8(3)4;/h7-8H,5-6H2,1-4H3,(H,12,13);/q;+1/p-1

Test animals

Species:
rat
Strain:
other: Crl: CD(SD)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories,Research Models and Services, Germany GmbH, Sandhofer Weg 7, 97633 Sulzfeld, Germany
- Age at study initiation: Males/females: Both 59 days
- Weight at study initiation: Males: 272.2 g to 299.9 g, Females: 210.4 g to 233.6 g


- Fasting period before study: 16 hours
- Housing: kept individually in MAKROLON cages (type III plus)
- Diet (e.g. ad libitum): Commercial ssniff® R/M-H V1534 (ssniff Spezialdiäten GmbH, 59494 Soest, Germany; served as food ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least 6 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22°C ± 3°C
- Humidity (%): 55% ± 15%
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light): 12 hours light / 12 hours dark

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
VEHICLE
- Amount of vehicle (if gavage): 10 ml/kg b.w./day
Details on mating procedure:
Sexually mature male and female rats were randomly paired for mating. Matingwas monogamous: 1 male and 1 female animal were placed in one cage during the dark period. The female was placed with the same male until pregnancy had occurred or 2 weeks had elapsed. Each morning the females were examined for the presence of sperm or a vaginal plug. If findings were negative, mating was repeated.
The day of conception (day 0 of gestation) was considered to be the day on which sperm was found. In case pairing was unsuccessful, re-mating of females with proven males of the same group was considered. This procedure was repeated until at least 8 pregnant dams were available for each group.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
For the analysis of the test item-vehicle mixtures samples of approx. 2 x 1 mL were taken at the following time points and stored at ≤ minus 20°C until analysis at LPT:

Start of treatment period:
Concentration and stability:
Immediately after preparation of the test item vehicle mixtures as well as 8 and 24 hours after storage of the test item preparations at room temperature:
3 samples/dose level group (groups 2 to 4)
Number of samples: 3 x 3 = 9
Homogeneity:
At start of administration, during (middle) administration and before administration to the last animal of each dose level group:
3 samples/dose level group (groups 2 to 4).
Number of samples: 3 x 3 = 9

End of treatment period:
Concentration:
During treatment with the test item always before administration to the last animal/dose level group:
1 sample/dose level group (groups 2 to 4).
Number of samples: TD 26 (1 x 3) = 3
Number of samples: TD 39 (1 x 3) = 3
Sum of all samples: 24
Sum of all aliquots: 48

The samples were labelled with the study number, test item, test species, type of sample, aliquot number, concentration, test day, sampling time and date.
Duration of treatment / exposure:
Males
The daily administration of the test item started two weeks before mating and lasted until the day before sacrifice (considering a minimum total dosing period of at least 28 days).
Females
The daily administration of the test item started two weeks before mating and lasted up to at least day 3 of lactation.
Frequency of treatment:
once daily
Details on study schedule:
- Age at mating of the mated animals in the study: 10-11 week
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
0 mg/kg bodyweight/day (control)
Basis:
actual ingested
Remarks:
Doses / Concentrations:
60 mg/kg bodyweight/day
Basis:
actual ingested
Remarks:
Doses / Concentrations:
200 mg/kg bodyweight/day
Basis:
actual ingested
Remarks:
Doses / Concentrations:
600 mg/kg bodyweight/day
Basis:
actual ingested
No. of animals per sex per dose:
80 animals (40 male and 40 female rats), 10 animals/sex/group.
A sufficient number to grant at least 8 pregnant females per group for evaluation of the F0 generation
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: See supporting study: 14-DAY DOSE-RANGE-FINDING STUDY OF IBP1-Na (DANAFLOATTM 245) BY ORAL ADMINISTRATION TO RATS

Examinations

Parental animals: Observations and examinations:
AGE SIDE OBSERVATIONS: Yes
- Time schedule: at least daily, The frequency was increased when signs of toxicity were observed.
Cageside observations included skin/fur, eyes, mucous membranes, respiratory and circulatory systems, somatomotor activity and behaviour patterns. The onset, intensity and duration of any signs observed were recorded.
Individual animals were observed before and after dosing at each time of dosing for any signs of behavioural changes, reaction to treatment or illness.
In addition, animals were checked regularly throughout the working day from 7:00 a.m. to 3:45 p.m. On Saturdays and Sundays animals were checked regularly from 7:00 a.m. to 11:00 a.m. with a final check performed at approximately 3:30 p.m.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: at least daily, The frequency was increased when signs of toxicity were observed.
Additionally, once before the first exposure (to allow within-subject comparisons) and once a week thereafter, detailed clinical observations were made in all animals outside the home cage in a standard arena and at the same time, each time preferably by observers unaware of the treatment. Signs noted included changes in skin, fur, eyes, mucous membranes, occurrence of secretions and excretions and autonomic activity (e.g. lacrimation, piloerection, pupil size, and unusual respiratory pattern). Changes in gait, posture and response to handling as well as the presence of clonic or tonic movements, stereotypies (e.g. excessive grooming, repetitive circling), difficult or prolonged parturition or bizarre behaviour (e.g. selfmutilation, walking backwards) were also recorded.
Dated and signed records of appearance, change, and disappearance of clinical signs were maintained on clinical history sheets for individual animals.

BODY WEIGHT: Yes
- Time schedule for examinations: Males and females were weighed on the first day of dosing, weekly thereafter and at termination of the study. During gestation, females were weighed on days 0, 7, 14 and 20 and within 24 hours of parturition (day 1 post-partum) and day 4 postpartum.
Body weights were recorded individually for each adult animal.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: daily

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
At the intermediate and the high dose level (200 and 600 mg IBP1-Na/kg b.w./day) a slight to extreme salivation was noted in nearly all animals, with a higher incidence at the high dose level. Piloerection and an increased water consumption were noted for a few animals of the intermediate and the high dose group, which is most like related to the alkalinity of the substance.
Mortality:
mortality observed, non-treatment-related
Description (incidence):
No test item-related premature death was noted.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
A slight reduction in body weight was noted until the end of the study on test day 38 for the male rats of the high dose group (600 mg IBP1-Na/kg b.w./day). Body weight at autopsy was reduced accordingly
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
A slight reduction in body weight was noted until the end of the study on test day 38 for the male rats of the high dose group (600 mg IBP1-Na/kg b.w./day). Body weight at autopsy was reduced accordingly
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
The histopathological examination revealed test item related changes in the forestomach from male and female rats of the intermediate and the high dose group (200 and 600 mg IBP1-Na/kg b.w./day) in form of hyperplasia and hyperkeratosis of the squamous cell epithelium, infiltration with neutrophilic granulocytes, granulation tissue and ulcerations.
Additionally, test item-related changes were noted in the liver in the form of a centrilobullar hepatocellular hypertrophy at 600 mg/kg bw/day.

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
no effects observed
Reproductive performance:
no effects observed

Effect levels (P0)

open allclose all
Dose descriptor:
NOAEL
Effect level:
200 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: General health parameters
Dose descriptor:
NOAEL
Effect level:
600 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: Reproductive parameters

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
In the high dose group the mean litter weight of the male and female pups was decreased by 5.6% on lactation day 1 and by 9.6% on lactation day 4 (without statistical significance). No noticeable differences were noted for the total litter weight
Sexual maturation:
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings:
no effects observed

Effect levels (F1)

Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
600 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: systemic effects

Overall reproductive toxicity

Reproductive effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
NOAEL (no-observed-adverse-effect level): 200 mg test item/kg b.w./day, p.o.

Remark: The test solution contains NaOH due to the production method.
Executive summary:

The test was performed according to OECD guideline 422 under GLP compliance. The test substance was administered orally to rats at dose levels of 60, 200 or 600 mg test item/kg b.w./day.


The following no-observed-effect levels were established for systemic effects: NOAEL (no-observed-adverse-effect level): 200 mg test item/kg b.w./day, p.o.


The following no-observed-effect levels were established for reproductive effects: NOAEL (no-observed-adverse-effect level): 600 mg test item/kg b.w./day, p.o.