Registration Dossier
Registration Dossier
Data platform availability banner - registered substances factsheets
Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.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.
Diss Factsheets
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: 308-072-8 | CAS number: 97862-28-7
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Endpoint summary
Administrative data
Key value for chemical safety assessment
Effects on fertility
Link to relevant study records
- Endpoint:
- screening for reproductive / developmental toxicity
- Remarks:
- based on test type (migrated information)
- Type of information:
- migrated information: read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Study period:
- 2013
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: The study was conducted according to GLP and valid methods and is considered relevant and reliable for classification.
- Reason / purpose for cross-reference:
- reference to same study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
- Species:
- rat
- Strain:
- other: CD® / Crl:CD(SD)
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- - Source: Charles River Laboratories Research, Models and Services Germany GmbH, Sandhofer Weg 7, 97633 Sulzfeld, Germany
- Age at start of dosing : Males 55 days; Females: 48 days
- Weight range at start of dosing: Males: 281.0 to 308.0 g; Females: 68.9 to 195.7 g
- Fasting period before study: Ad libitum with exception of the night before the day of blood withdrawal for laboratory examination.
- Housing: With exception of the mating period, the animals were kept singly in MAKROLON
cages (type III plus) with a basal surface of approx. 39 cm x 23 cm and a height of approx. 18 cm. Granulated textured wood (Granulat A2, J. Brandenburg, 49424 Goldenstedt/ Arkeburg, Germany) is used as bedding material in these cages. The cages were cleaned and changed once a week.
- Diet (e.g. ad libitum): ssniff® R/Z V1324 (ssniff Spezialdiäten GmbH, 59494 Soest, Germany, ad libitum with exception of the night before the day of blood withdrawal for laboratory examination.
- Water (e.g. ad libitum): Tap water is offered daily ad libitum.
- Acclimation period: At least 5 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22°C ± 3°C (maximum range)
- Humidity (%): 55% ± 15% (maximum range)
- Air changes (per hr): Not provided
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES:
Males From: August 27, 2012 To: October 2, 2012
Females From: August 27, 2012 To: October 19, 2012 - Route of administration:
- oral: gavage
- Vehicle:
- other: tap water
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
Application volume: 5 mL/kg bw/day. The test item was dissolved in the vehicle tap water to concentrations of 20, 60 and 200 mg test item /mL tap water and was administered orally at a constant volume once daily. The amount of the test item was adjusted to the animal's current body weight daily. The test item-vehicle mixture was freshly prepared every day. - Details on mating procedure:
- - M/F ratio per cage: 1/1 (1 male and 1 female animal were placed in one cage during the dark period)
- Length of cohabitation: The female was placed with the same male until pregnancy occurred or 2 weeks had elapsed.
- Proof of pregnancy: vaginal plug / sperm in vaginal smear referred to as day 0 of pregnancy
- After approx. 14 days of unsuccessful pairing replacement of first male by another male with proven fertility.
- Further matings after two unsuccessful attempts: yes. This mating-procedure was repeated until at least 8 pregnant dams were available for each group.
- After successful mating each pregnant female was caged (how): singly in MAKROLON cages (type III plus) with a basal surface of approx. 39 cm x 23 cm and a height of approx. 18 cm. On the other side of the animal room than the males with each dose group separated by an empty row. - 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 5 mL were taken at the following time points and stored at ≤ -20°C until analysis at LPT.
*Start of treatment period: Analysis of stability and concentration: 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 = 9 samples
*End of treatment period: Concentration: During treatment with the test item always before administration to the last animal/dose level group: 3 samples
The samples were labelled with the study number, test item, test species, type of sample, aliquot number, concentration, test day, sampling time and date.
The validation of the analytical method is part of LPT study No. 28344 (14-day dose-range-finding).
The measured actual concentrations of the test item in the test item vehicle mixtures were between 99.99% and 102.96% of the nominal concentrations (table 26). - Duration of treatment / exposure:
- Males: 2 weeks prior to mating, during the mating period and approx. 2 weeks post mating at least until the minimum total dosing period of 28 days has been completed (up to and including the day before sacrifice).
Females: 2 weeks prior to mating and continuing up to, and including, day 3 post-partum or the day before sacrifice. - Frequency of treatment:
- daily
- Details on study schedule:
- - Age at mating of the mated animals in the study:10 weeks
- Remarks:
- Doses / Concentrations:
0, 100, 300 and 1000 mg/kg bw/day
Basis:
actual ingested - No. of animals per sex per dose:
- 10
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale:
The dose levels have been selected in agreement with the Sponsor based on the results of a 14-day dose-range-finding study in rats dosed at 100, 300 and 1000 mg act. ingr./kg bw by oral gavage (LPT Study No. 28344). None of the animals died prematurely. None of the male and female rats treated orally with 100 or 300 mg act. ingr./kg bw/day revealed any changes in behaviour, external appearance or faeces. Salivation was noted for 2 of 5 male animals treated at 1000 mg/kg bw/day on 1 or 3 test days starting on test day 9 and increased faeces was noted for 3 of 5 male and 2 of 5 female high dosed animals on 6 or 9 test days starting on test day 5. No test item-related changes on body weight and body weight gain were noted for the male and female rats up to 1000 mg act. ingr./kg bw/day. No test item-related changes on food consumption were noted for the male and female rats treated orally with 100 or 300 mg act. ingr./kg bw/day. The food consumption of the male and female animals treated with 1000 mg act. ingr./kg bw/day was slightly increased by 9% for the males and by 10% for the females in test week 2 (statistically significant at p ≤ 0.01 for both sexes). No test item-related influence was noted for the drinking water consumption at any of the tested dose levels. None of the male and female rats treated orally with 100, 300 or 1000 mg act. ingr ./kg bw/day revealed changes at macroscopic inspection at necropsy or organ weights. - Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Throughout the test period, each animal was observed for clinical signs at least once daily. Mortality was recorded twice daily. 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.
- Individual animals were observed before and after dosing at each time of dosing for any signs of behavioural changes, reaction to treatment or illness. 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.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: 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, pilo-erection, 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. self-mutilation, walking backwards) were also recorded.
BODY WEIGHT: Yes. Body weights were recorded individually for each adult animal.
- Time schedule for examinations:
Males and females were weighed on the first day of dosing, weekly thereafter and at termination. During gestation, females were weighed on days 0, 7, 14 and 20 and within 24 hours of parturition (day 0 or 1 post-partum) and day 4 post-partum.
FOOD CONSUMPTION: Yes
The quantity of food left by individual animals was recorded on a weekly basis throughout the experimental period with the execution of the mating period. Food intake per rat (g/rat/week) was calculated using the total amount of food given to and left by each rat in each group on completion of a treatment week.
WATER CONSUMPTION:
- Time schedule for examinations: Water consumption was monitored daily by visual appraisal throughout the study.
HAEMATOLOGY: see Section 7.5.1
CLINICAL CHEMISTRY: See Section 7.5.1
NEUROLOGICAL OBSERVATIONS: see Section 7.5.1
REPRODUCTIVE PARAMETERS:
Number of pregnant females
Pre-coital time
Gestation length calculated from day 0 of pregnancy
Corpora lutea
lmplantation sites
Number of (viable) pups day0/4
REPRODUCTIVE INDICES:
Gestation Index
Fertility Index
Birth Index
Live Birth Index
Viability Index
Pre-implantation loss [%]
Post-implantation loss [%] - Sperm parameters (parental animals):
- Parameters examined in P male parental generations:
testis weight, epididymis weight
At the time of sacrifice or death during the study, the adult animals were examined macroscopically for any abnormalities or pathological changes. Special attention was paid to the organs of the reproductive system.
The following organs or parts of organs of all male adult animals were fixed in 7% formalin; testes and epididymides were fixed in Bouin' s fixative:
Epididymis (2), Gross lesions, Prostate, Seminal vesicle, Testicle (2).
Detailed histopathologic examination was performed on one testicle and one epididymis (with special emphasis on the qualitative stages of spermatogenesis and histopathology of interstitial testicular structure) of all adult males of groups 1 to 4 following H-E and PAS staining. - Litter observations:
- STANDARDISATION OF LITTERS
- screening study: Dead pups and pups sacrificed at day 4 post-partum, or shortly thereafter, were carefully examined externally for gross abnormalities.
PARAMETERS EXAMINED
Number of pups absolute (total/live)
Number of pups per dam (total/live)
Number of male and female pups (total/live)
Number of stillbirths
Mean pup weight
GROSS EXAMINATION OF DEAD PUPS:
yes, for external and internal abnormalities; possible cause of death was not determined for pups born or found dead. - Postmortem examinations (parental animals):
- SACRIFICE
- Male animals: All surviving animals: The male animals are sacrificed after a minimum total dosing period of 28 days if no longer needed for further mating.
- Maternal animals: All surviving animals: Dams with offspring are sacrificed on day 4 postpartum, or shortly thereafter. Females showing no evidence of copulation are sacrificed 24 days after the last day of the mating period.
GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.
HISTOPATHOLOGY / ORGAN WEIGHTS
Microscopic examination and organ weights of all adult male animals identified as left or right: Epididymis (2) ,Testicle (2)
The following organs or parts of organs of all adult animals are fixed in 7% formalin; testes and epididymides will be fixed in Bouin' s fixative:
Epididymis (2), Gross lesions, Mammary gland, Ovary (2), Prostate, Seminal vesicle, Testicle (2), Uterus (incl. cervix and oviducts), Vagina. - Postmortem examinations (offspring):
- SACRIFICE
- The F1 offspring were sacrificed at 4 days of age.
- These animals were subjected to postmortem examinations macroscopic examination) as follows:
Dead pups and pups sacrificed at day 4 post-partum, or shortly thereafter, were carefully examined externally for gross abnormalities.
The animals were sacrificed under ether anaesthesia by cutting the aorta abdominalis, exsanguinated, weighed, dissected and inspected macroscopically. All superficial tissues were examined visually and by palpation and the cranial roof removed to allow observation of the brain, pituitary gland and cranial nerves. After ventral midline incision and skin reflection all subcutaneous tissues were examined. The condition of the thoracic viscera were noted with due attention to the thymus, lymph nodes and heart.
The abdominal viscera were examined before and after removal; the urinary bladder was examined externally and by palpation. The gastro-intestinal tract was examined as a whole and the stomach and caecum were incised and examined.
The lungs were removed and all pleural surfaces examined under suitable illumination.
The liver and the kidneys were examined. Any abnormalities in the appearance and size of the gonads, adrenals, uterus, intra-abdominal lymph nodes and accessory reproductive organs were recorded.
GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera. - Statistics:
- Toxicology and Pathology data were captured, whenever possible, using the departmental computerized systems (Provantis®8 Integrated preclinical software, Instem LSS Ltd.). Raw data not fully compatible with the computerized systems were maintained on paper according to appropriate SOPs.
The test item-treated groups (2 - 4) were compared with the control group (1 ).
The following statistical methods were used:
STUDENT' s t-test: All numerical functional tests (p ≤0.01)
Multiple t-test based on DUNNETT, C. W., New tables for multiple comparisons with a control, Biometrics, 482-491 (Sept 1 964): Body weight I Food consumption I Haematology I Clinical chemistry I Absolute and relative organ weights: (p ≤ 0.05 and ≤0.01)
For all numerical values (e.g. body weight, food consumption and organ weight data) homogeneity of variances was tested by using the BARTLETT chi2-test.
lf the variances are homogeneous, the DUNNETT test (p ≤ 0.01) was used to compare the experimental groups with the control group.
In case of heterogeneity of variances, the STUDENT's t-test was carried out; limit of significance is p ≤ 0.01.
Exact test of R. A. FISHER: Histopathology, if applicable (p≤0.05)
For the comparison of classification measurements (for example the fertility index) the FISHER's exact test, n < 100 or chi2-test with Yates' correction for continuity, n ≥ 100 (p ≤0.05 and p ≤0.01) were employed.
These statistical procedures were used for all data. Significantly different data were indicated in the tables of the report.
The mean values and standard deviations were calculated to the highest possible degree of accuracy and then rounded to the reported number of decimal places. Hence, deviations to the last decimal place of up to ± 1 may occur caused by rounding. - Reproductive indices:
- Gestation Index
Fertility Index
Pre-implantation loss [%]
Post-implantation loss [%] - Offspring viability indices:
- Birth Index
Live Birth Index
Viability Index - Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- slightly increased salivation in one male rat dosed at 1000 mg/kg bw/day
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- slight reduction iin male and female rats dosed at 1000 mg/kg bw/day
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- slight reduction iin male and female rats dosed at 1000 mg/kg bw/day
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Other effects:
- no effects observed
- Reproductive function: oestrous cycle:
- not examined
- Reproductive function: sperm measures:
- not examined
- Reproductive performance:
- no effects observed
- Dose descriptor:
- NOAEL
- Remarks:
- reproductive toxicity
- Effect level:
- >= 1 000 mg/kg bw/day (actual dose received)
- Based on:
- act. ingr.
- Sex:
- male/female
- Clinical signs:
- not examined
- Mortality / viability:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Sexual maturation:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- no effects observed
- Histopathological findings:
- not examined
- Reproductive effects observed:
- not specified
- Conclusions:
- NOAEL (no-observed-adverse-effect level) for reproductive toxicity: >= 1000 mg/kg bw/day, p.o.
- Executive summary:
The aim of the study was to obtain information on possible effects of the test item on general toxicity, reproduction and/or development according to OECD guideline 422. The test item was administered orally by gavage to rats at dose levels of 100, 300 and 1000 mg active ingredient/kg bw/day. The application started two weeks before mating on test day one and ended on the day or one day before sacrifice. Day of sacrifice was on test day 37 for the male rats and between lactation day 4 and 7 for the female rats.
Effects on the parental generation (general toxicity)
No test item-related premature death was noted in any treatment group (100, 300 and 1000 mg test item/kg bw/day).No signs of clinical toxicity were noted for the male and female rats of the low and intermediate dose groups (100 and 300 mg test item/kg bw/day). A slightly increased salivation was noted in one male rat, no further signs of clinical toxicity were noted for the male and female rats of the high dose group (1000 mg test item/kg bw/day). A slight reduction in body weight was noted for the male and female rats of the high dose group (1000 mg test item/kg bw/day). For the male rats the reduction in body weight was noted from test day 8 (4.4%) until test day 36 (5.5%) and for the female rats from gestation day 0 (7.6%) until lactation day 4 (9.5%). The body weight at autopsy was reduced accordingly.
Effects on reproduction parameters and organs
No test item-related influence was noted on the reproduction parameters in any treatment group (100, 300 and1000 mg/kg bw/day).
Microscopic examination revealed no changes in the reproductive organs from the male and female rats of the high dose group (1000 mg/kg bw/day).
Effects on the F0-generation
NOAEL (no-observed-adverse-effect level): 300 mg/kg bw/day, p.o.
Effects on reproductive toxicity
NOAEL (no-observed-adverse-effect level): >=1000 mg/kg bw/day, p.o.
Reference
No test item-related premature death was noted in any treatment group (100, 300 and 1000 mg/kg bw/day).
No signs of clinical toxicity were noted for the male and female rats of the low and intermediate dose groups (100 and 300 mg/kg bw/day).
A slightly increased salivation was noted in one male rat, no further signs of clinical toxicity were noted for the male and female rats of the high dose group (1000 mg/kg bw/day). No test item related influence was noted for the male and female rats of all treatment groups (100, 300 and 1000 mg/kg bw/day) during the observational and functional (grip strength and spontaneous motility) neurological screenings.
BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
A slight reduction in body weight was noted for the male and female rats of the high dose group (1000 mg/kg bw/day). For the male rats the reduction in body weight was noted from test day 8 (4.4%) until test day 36 (5.5%) and for the female rats from gestation day 0 (7.6%) until lactation day 4 (9.5%). The body weight at autopsy was reduced accordingly.
A slightly statistically significant (p ≤ 0.01) increase in relative food consumption by 10.3% was noted in the high dose males during the 2nd test week. This was caused by the reduced body weight of the rats of the high dose group.
No influence on food consumption was noted in any treatment group in the females.
REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
Pre-coital time: No test item-related influence was noted.
Gestation length: No test item-related influence was noted.
Evaluation of reproduction parameters of the dams:
No test item-related differences were noted in the number of corpora lutea, the number of implantation sites and the number of pups between the dams from the control group and those from the treatment groups.
ORGAN WEIGHTS (PARENTAL ANIMALS)
No test item-related influence was noted.
For other organs: see Section 7.5.1.
GROSS PATHOLOGY (PARENTAL ANIMALS)
No effects on the reproductive organs.
For other organs: see Section 7.5.1.
HISTOPATHOLOGY (PARENTAL ANIMALS)
No effects on the reproductive organs.
For other organs: see Section 7.5.1.
No test item-related influence was noted on the survival rate of the pups.
BODY WEIGHT (OFFSPRING)
No test item related influence was noted on the mean and the total body weight of the pups on lactation day 1 and 4.
GROSS PATHOLOGY (OFFSPRING)
No visible gross abnormalities were noted between the control and the treatment groups
Table 1. Fertility and Reproductive parameters Parental generation
Parameter |
Group 1 Control |
Group 2 100 mg/kg |
Group 3 300 mg/kg |
Group 4 1000 mg/kg |
No. of females evaluated for pre-coital time |
10 |
10 |
10 |
10 |
Mean precoital interval (days) |
4.5 |
3.4 |
3.9 |
2.6 |
No. of females evaluated for fertility |
10 |
10 |
10 |
10 |
Number of pregnant dams |
8 |
9 |
9 |
10 |
Fertility index (%) |
80 |
90 |
90 |
100 |
No. of females evaluated for gestation length |
8 |
9 |
9 |
10 |
Gestation length (days) |
22.0 |
22.2 |
22.2 |
22.1 |
Number of dams with live pups |
8 |
9 |
9 |
10 |
Gestation Index (%) |
100 |
100 |
100 |
100 |
Corpora lutea(total) |
110 |
137 |
129 |
142 |
Corpora lutea(mean) |
13.8 |
15.2 |
14.3 |
14.2 |
Implantation sites (total) |
110 |
131 |
128 |
139 |
Implantation sites (mean) |
13.8 |
14.6 |
14.2 |
13.9 |
Number of pups at birth (total) |
96 |
125 |
123 |
127 |
Number of pups at birth (mean) |
12.0 |
13.9 |
13.7 |
12.7 |
Birth Index (mean %) |
90.4 |
95.5 |
95.9 |
90.1 |
Birth Index (total# %) |
87 |
951 |
96 1 |
90.1 |
Number of stillbirths |
0 |
0 |
1 |
0 |
No. of dams with stillborn pups |
0 |
0 |
1 |
0 |
Number of live born pups (total) |
96 |
125 |
123 |
126 |
Number of live born pups (mean) |
12.0 |
13.9 |
13.7 |
12.6 |
Live birth index (mean %) |
100.0 |
100.0 |
100.0 |
97.5 |
Live birth index (total#1 %) |
100 |
100 |
100 |
99 |
Pre-implantation loss (mean %) |
0.0 |
4.4 |
0.7 |
1.9 |
Pre-implantation loss (total#2 %) |
0.0 |
4.42 |
0.8 |
2.1 |
Post-implantation loss (mean %) |
9.6 |
4.5 |
4.1 |
11.2 |
Post-implantation loss (total#3 %) |
12.7 |
4.62 |
3.92 |
9.4 |
Number of runts |
0 |
0 |
0 |
0 |
Number of malformed pups |
0 |
0 |
0 |
0 |
# based on the total No. of implantation sites and total No. of pups at birth (alive and dead)
#1 based on the total No. live born pups and total No. of pups at birth (alive and dead)
#2 based on the total No. corpora lutea and total No. of implantation sites
#3 based on the total No. implantation sites and toal number of live born pups
1 p≤0.05 Chi2-test
2 p<0.05 Chi2-test
Effect on fertility: via oral route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 1 000 mg/kg bw/day
- Study duration:
- subacute
- Species:
- rat
- Quality of whole database:
- Reliable quality (Klimisch2)
Effect on fertility: via inhalation route
- Endpoint conclusion:
- no study available
Effect on fertility: via dermal route
- Endpoint conclusion:
- no study available
Additional information
Reproductive
screening
No
test data were available for current substance, however read across data
were available from 'Butanedioic acid, 2(or 3)-sulfo-,
4-[2-[(1-oxo(C12-C18(even numbered) and
C18unsaturated)alkyl))amino]ethyl]esters, disodium salts'. Justification
for read across within the subgroups of N-containing sulphosuccinates is
documented in a separate document attached in Section 13.
A
key study for repeated dose toxicity was performed by means of an oral
combined repeated dose and reproduction/development screening study
according to OECD guideline 422 (Hansen, 2013e). The test item (liquid
formulation) containing 41.5% active ingredient was administered orally
by gavage to rats at dose levels of 100, 300 and 1000 mg act. ingr./kg
bw/day for for at least 28 days in male rats and at least 39 days in
females. No test item-related premature death was noted in any treatment
group. No signs of clinical toxicity were noted for the male and female
rats of the low and intermediate dose groups (100 and 300 mg/kg bw/day),
whereas slightly increased salivation was noted in one male rat as the
only finding at 1000 mg/kg bw/day. A slight reduction in body weight was
noted for the male and female rats dosed at 1000 mg/kg bw/day. Other
parameters such as neurological observations, haematology and serum
chemistry are discussed in the repeated dose toxicity section.
No test item-related influence was noted on the reproduction toxicity
parameters in any treatment group (100, 300 and 1000 mg/kg bw/day).
Microscopic examination revealed no changes in the reproductive organs
from the male and female rats of the high dose group (1000 mg/kg
bw/day). NOAEL for systemic toxicity was 300 mg/kg bw/day, whereas NOAEL
for reproductive toxicity was >= 1000 mg/kg bw.
Multigeneration
studies
Further
data on reproductive toxicity were available from read across substance
Docusate sodium (CAS No. 577-11-7). Justification for read across with
the category of Di-ester sulphosuccinates is documented in a separate
document attached in Section 13.
-
A key 3-generation toxicity study at dietary dose levels of 0.1, 0.5 and
1.0% in the diet (MacKenzie, 1986) conducted according to OECD caused a
reduction in body weights at the dose levels of 0.5 and 1% in the diet
for parental males of all generations and for F1 and F2 females. Pup
weights at the 0.5% and 1.0% dose levels were lower than those of the
control in all three generations, however this did not interfere with
growth and development or reproductive performance, and had no adverse
effects at levels on the reproductive function of either sex in any
generation up to 1%. There were no other effects on parental or
reproductive parameters. The NOEL for body weights of parental animals
and offspring was 0.1%; the NOEL for reproductive parameters was 1.0%,
which was considered to correspond with approximately 750 mg/kg bw/day.
- In a supporting 2-generation toxicity study in rats, 0.5 and 1% were
given in the diet (Levinskas & Shaffer, 1970). In the first mating of
the F0 generation and the second mating of the F2 generation, pups were
weaned directly onto the diets which were being fed to their parents. In
the other 3 matings of this study, dams were given a control diet on the
day before delivery to avoid a bitter taste of the milk. Pups of all
litters were examined for gross defects. Autopsies were performed,
however, only on pups from the first mating of the F2 animals. Portions
of all major organs were taken for histopathology processing and
examination from one male and female from each litter. The other male
and female were skinned and eviscerated, and the carcasses cleared, and
the skeletons stained and examined for defects. In both the first mating
of the F0 generation and the second mating of the F2 generation, the
fertility and gestation indices were high and comparable. The viability
index was good, albeit slightly down for the F3b pups, while the
lactation index was depressed for both of these matings. In addition,
the mean weight of the pups at weaning decreased with increasing
concentrations of test material in the diet of the dams. In the second
mating of the F0 animals, the viability and lactation indices and the
mean weight of the test pups at weaning still showed decreases relative
to the control values. However, in the 2 subsequent matings, all indices
for the dosed animals were numerically high and compared favorably with
the corresponding control values. Also, the mean weight of the pups at
weaning was essentially similar for all groups. Consequently, it is
concluded that diets containing 1% or less had no adverse effect on the
reproduction and lactation performance of rats. The lowering of the
survival rate and the mean body weight of the F1a and F3b pups is
attributed to an impairment of nutrition as a result of the taste which
is believed to have been secreted into the milk of the dams. Microscopic
study of tissues showed findings which were similar in all groups. In
processing the skeletons, the presence of an extra sternebrae in the
sternum between the 5th and 6th sternebrae was not considered to
parental exposure of test material. It is concluded that feeding of test
material to rats from weaning through reproductive age for successive
generations at levels of 1%, or less, did not produce lesions or
anomalies in the offspring which could be attributed to the compound.
Conclusion
An
oral gavage reproductive screening study with read across substance
Butanedioic acid, 2(or 3)-sulfo-, 4-[2-[(1-oxo(C12-C18(even
numbered)andC18unsaturated)alkyl)) amino]ethyl]esters, disodium salts
showed NOAEL of 300 mg/kg bw for paternal/maternal toxicity, whereas
1000 mg/kg bw was NOAEL for reproductive and developmental toxicity.
Multigeneration studies with read across substance Docusate dodium (CAS 577-11-7) showed slight maternal/paternal toxicity at 0.5 and 1% in the diet, however this was not confirmed in the second study. From both studies, it can be concluded that the substance up to 1% in the diet did not lead to effects on fertility or postnatal development; this concentration corresponds with 750 mg/kg bw/day, which is higher than the NOAEL for paternal/maternal toxicity. Based on the absence of reproductive findings in the screening study, the repeated dose studies and the multigeneration studies with with structurally similar substances, no further testing is needed for registered substance.
Short description of key information:
A key study for reproductive toxicity in rats by was available from an OECD 422 study with a liquid formulation containing 41.5% active ingredient of read across substance Butanedioic acid, 2(or 3)-sulfo-, 4-[2-[(1-oxo(C12-C18(even numbered) and C18unsaturated)alkyl))amino]ethyl]esters, disodium salts, at dose levels of 100, 300 and 1000 mg/kg bw/day. No reproductive toxicity effects were observed up to 1000 mg/kg bw. At the dose of 1000 mg/kg bw, decrease body weight and other systemic effects were observed, therefore NOAEL for systemic toxicity was 300 mg/kg bw/day, whereas NOAEL for reproductive toxicity was 1000 mg/kg bw/day.
Read-across from CAS no. 577-11-7 (Docusate sodium) three-generation study according to OECD TG 416 and GLP showed decreased body weights in P, F1 and F2 generations at 0.5 and 1% dietary concentrations (the latter corresponding with 750 mg/kg bw), however these were not considered adverse and were not associated with any other (reproductive) findings. In a second (supporting) two-generation study the highest concentration of 1% in the diet corresponding with 750 mg act. ingr./kg bw was NOAEL.
Justification for selection of Effect on fertility via oral route:
key study
Effects on developmental toxicity
Description of key information
Developmental toxicity was not observed in the oral combined repeated dose and reproduction/development screening study according to OECD guideline 422 with read across substance Butanedioic acid, 2(or 3)-sulfo-, 4-[2-[(1-oxo(C12-C18(even numbered) and C18unsaturated)alkyl))amino]ethyl]esters, disodium salts. Rats were dosed at 100, 300 and 1000 mg act. ingr./kg bw/day. No test item related influence was noted on the survival rate and the mean and total body weights of the pups. External examination of the pups revealed no visible changes related to the test item. NOAEL for systemic toxicity was 300 mg/kg bw/day, whereas NOAEL for reproductive and developmental toxicity was >= 1000 mg/kg bw.
Prenatal developmental toxicity was tested by dietary administration of read across substance Docusate sodium in rats from day 6 to 15 of gestation. 1% in the diet was a maternal and developmental NOAEL, whereas at 2% in the diet visceral and skeletal anomalies were observed, which were considered secondary to maternal toxicity. This was confirmed in a similar study with Docusate calcium given at subtoxic and toxic dose levels, where the same could be observed.
Based on the absence of developmental findings in the screening study and teratogenicity study with structurally similar substances, no further testing is needed for registered subtance.
Link to relevant study records
- Endpoint:
- developmental toxicity
- Type of information:
- migrated information: read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Study period:
- 1976
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: see 'Remark'
- Remarks:
- only 2 doses tested. Allthough not all details on the study design were provided, the study was performed to the highest standards at the time of conduct. In the current study, a concurrent test article, dioctyl calcium sulfosuccinate (DCS) was also tested at 0.5, 1, 1.5 and 2% in the diet.
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- GLP compliance:
- no
- Limit test:
- no
- Species:
- rat
- Strain:
- Sprague-Dawley
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Breeding Laboratories
- Age at study initiation: About 2 months
- Weight at study initiation: Not provided
- Fasting period before study: Not provided
- Housing: Individually in hanging wire mesh cages
- Diet (e.g. ad libitum): Wayne Lab Meal ad libitum
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: Not provided
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 24 ± 2°C
- Humidity (%): 50 ± 5%
- Air changes (per hr): Not provided
- Photoperiod (hrs dark / hrs light): 12/12 - Route of administration:
- oral: feed
- Vehicle:
- corn oil
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS: 40% solution in corn oil
DIET PREPARATION
- Rate of preparation of diet (frequency): Not provided
- Mixing appropriate amounts with (Type of food): 1.0% and 2.0% admixed in Wayne Lab Meal
- Storage temperature of food: Not provided
VEHICLE
- Justification for use and choice of vehicle (if other than water):
- Concentration in vehicle: 40% solution in corn oil
- Amount of vehicle (if gavage):/
- Lot/batch no. (if required): Not provided
- Purity: Not provided - Details on mating procedure:
- Not provided
- Duration of treatment / exposure:
- gestational days 6 through 15: dosing
- Duration of test:
- gestational days 6 through 15: dosing
gestational day 21: killing of the mothers and removing fetuses by cesarean section - Remarks:
- Doses / Concentrations:
1.0 % DSS , 2.0% DSS
Basis: - No. of animals per sex per dose:
- 22 female rats in dose 1.0% DSS
20 female rats in dose 2.0% DSS - Control animals:
- yes, concurrent vehicle
- Details on study design:
- Not provided
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes (clinical condition and signs of illness)
- Time schedule: each day
- Cage side observations were not included.
BODY WEIGHT: Yes
- Time schedule for examinations:
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day #21
- Organs examined: Ovaries and uterine content - Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No
- Number of corpora lutea: No
- Number of implantations: Yes
- Number of resorptions: Yes - Fetal examinations:
- - External examinations: Yes (3336 of conceptuses)
- Soft tissue examinations: No
- Skeletal examinations: Yes (one half of the total number of fetuses)
- Head examinations: No
-Visceral examinations: Yes (one-half of the total number of fetuses were fixed in Bouin’s fluid for a detailed examination of visceral anomalies, using the slicing method of Wilson) - Statistics:
- Maternal body-weight gains, maternal food consumptions and fetal weights were analyzed by Dunnett’s two-sided, multiple comparison test. Frequencies of resorptions and fetal abnormalities among litters were analyzed by the Mann-Whitney U test or the Chi-square test (with Yate’s correction), as appropriate.
- Dose descriptor:
- NOAEC
- Effect level:
- 1 other: %
- Based on:
- act. ingr.
- Remarks:
- in the diet
- Basis for effect level:
- other: maternal toxicity
- Dose descriptor:
- NOAEC
- Effect level:
- 1 other: %
- Based on:
- act. ingr.
- Remarks:
- in the diet
- Basis for effect level:
- other: developmental toxicity
- Dose descriptor:
- NOAEL
- Effect level:
- 1 074 mg/kg bw/day (nominal)
- Based on:
- act. ingr.
- Basis for effect level:
- other: maternal toxicity
- Dose descriptor:
- NOAEL
- Effect level:
- 1 074 mg/kg bw/day (nominal)
- Based on:
- act. ingr.
- Basis for effect level:
- other: developmental toxicity
- Abnormalities:
- not specified
- Developmental effects observed:
- not specified
- Conclusions:
- Subtoxic dietary levels of 1.0% docusate sodium ingested on gestational days 6 through 15 showed no adverse effects on the various maternal or fetal parameters. Near toxic or toxic dietary levels of 2.0% DSS produced significant incidences of resorptions (13.7%) and gross abnormalities either among litters (25.0%) or fetal populations (20.2%) as compared to controls. Interpretation of the results of the present experiments, in which only maternally toxic dose levels induce teratogenicity, indicates no real hazard with the recommended human use of these surfactants.
- Executive summary:
Prenatal developmental toxicity was studied in rats dosed from day 6 to day 15 of gestation by dietary administration of docusate sodium at dose levels of 1.0 and 2.0 % in the diet.Subtoxic dietary levels of 1.0% showed no adverse effects on the various maternal or fetal parameters. Near toxic or toxic dietary levels of 2.0% docusate sodium produced significant depressions in maternal weight-gains and increased incidences of resorptions (13.7%) and gross abnormalities either among litters (25.0%) or fetal populations (20.2%) as compared the controls. These abnormalities consisted primarily of exencephaly of varying degrees with, at times, spina bifida, anophtalmia and associated skeletal defects. The visceral observations confirmed the significance of the exencephalous characteristics and anophtalmia for the group given dietary levels of 2.0%. In this group, skeletal observations revealed a significant incidence of incomplete ossification to absence of the various cranial bones, a curved or open vertebral column, and a variety of defects of the vertebrae and ribs. There were significant depressions in maternal weight gains in the 2.0% DSS-group . Interpretation of the results of the present experiment, in which only maternally toxic dose levels induce teratogenicity, indicates no real hazard with the recommended human use of these surfactants.
The concentration of 1% in the diet is considered as maternal and developmental NOAEL. This dose level corresponded with 1074 mg/kg body weight, as calculated in the study.
Reference
TABLE 1. Maternal and fetal results of pregnant rats given various amounts if DSS in their diets during
gestational days 6 through 15.
Parameter |
Dose: Control |
1.0% DSS |
2.0% DSS |
Maternal |
Groups: (I-A) |
(II-A) |
(II-B) |
No. of pregnant rats |
43 |
22 |
20 |
No. of pregnancies with total resorptions |
0 |
0 |
1 |
No. of pregnancies with viable fetuses |
43 |
22 |
19 |
Average weight gain of dams with viable fetuses(g): |
|
|
|
Days 6 to 15 |
78 |
86 |
52* |
Days 15 to 21 |
66 |
67 |
77 |
Avarage, apparent food intake of dams with viable fetuses (g/rat/day): |
|
|
|
Days 6 to 15 |
22.5 |
24.8 |
21.4 |
Days 15 to 21 |
28.6 |
32.1 |
33.4 |
Calculated compound consumed (mg/kg/day) |
-- |
1074 |
1988 |
Litters |
|
|
|
Total number of: implantations |
411 |
203 |
219 |
Resorptions (% occurence) |
23 (5.6) |
8 (3.9) |
30*a (13.7) |
Dead fetuses (% occurrence) |
3 (0.7) |
0 |
1 (0.5) |
Viable fetuses (% occurrence) |
385 (93.7) |
195 (96.1) |
188 (85.5) |
Fetal weight (g) |
4.6 |
5.2 |
4.7 |
Litters size (viable fetuses) |
8.9 |
8.9 |
9.9 |
External major malformations1: No. of litters affected (% occurrence) |
0 |
0 |
5* (25.0) |
No. of fetuses affected (% occurrence) |
0 |
0 |
36*a (20.2) |
* Significantly different from control (p< 0.05)
a Significance by Chi-square, but not Mann-Whitney U test
1 Primarily, exencephaly varying degrees and associated anomalies (See TABLE 2)
TABLE 2. Morphological observations of fetuses delivered from rats given DSS in their diets on
gestational days 6 through 15.
Morphology |
Dose: Control |
1.0% DSS |
2.0% DSS |
External observations1: |
Groups: (I-A) |
(II-A) |
(II-B) |
Total number examined |
388a |
195 |
189 |
Major anomalies: Adactyly |
0 |
0 |
0 |
Hemimelia |
0 |
0 |
0 |
Schistocelia |
0 |
0 |
2 |
Dome shaped head |
0 |
0 |
0 |
Cranial bubble (1-2mm) |
0 |
0 |
9* |
Exencephaly |
0 |
0 |
18* |
Exencephaly (cleft condition) |
0 |
0 |
7* |
Anencephaly |
0 |
0 |
0 |
Spina bifida |
0 |
0 |
6 |
Macroglossia |
0 |
0 |
0 |
Micro- or anophtalmia |
0 |
0 |
3 |
Defects: Hematoma (subcutaneous) |
2 |
0 |
0 |
Edamatous abdomen |
0 |
0 |
0 |
Tail short & curled |
0 |
0 |
0 |
Abducted fifth digit, left Rear foot |
0 |
0 |
1 |
1 Fetuses may have more than one defect
a Fifty-four fetuses examined grossly only. (Shipment c valid as controls only)
*Significantly different from control (p< 0.05) by Chi-square only
TABLE 3. Visceral observations of fetuses delivered from rats given DSS in their diets on gestation days
6 through 15.
Visceral observations |
Dose: Control |
1.0 % DSS |
2.0% DSS |
Groups: (I-A) |
(II-A) |
(II-B) |
|
Total number of fetuses examined |
165a |
98 |
91 |
Defects1: Exencephalous characteristics |
0 |
0 |
11* |
Dilated lateral ventricles |
1 |
3 |
5 |
Microphtalmia |
0 |
1 |
0 |
Anolphtalmia |
0 |
0 |
23* |
Retinal foldings |
0 |
0 |
0 |
Anotia or microtia |
0 |
0 |
0 |
Cleft palate |
0 |
0 |
1 |
Situs transversus – aorta, esophagus & stomach |
1 |
0 |
0 |
Intestinal agenesis |
0 |
0 |
0 |
Arch of aorta absent or right sided |
0 |
0 |
0 |
Diaphragmic hernia |
0 |
0 |
1 |
Dilated renal pelves |
2 |
0 |
3 |
Ectopic kidneys(s) &/or variation in size |
1 |
0 |
0 |
Renal agenesis |
0 |
0 |
2 |
Dilated ureters |
6 |
0 |
3 |
Adrenal agenesis |
0 |
0 |
1 |
Testes – ectopic or enlarged |
1 |
0 |
1 |
Hermaphroditism |
0 |
0 |
3 |
1Fetuses may have more than one defect
aExcludes 1 fetus lost
*Significantly different from control (p<0.05) by Chi-square only
TABLE 4. Skeletal observations of fetuses delivered from rats given DSS in their diets on gestation days
6 through 15.
Skeletal observations |
Dose: Control |
1.0 % DSS |
2.0% DSS |
Groups: (I-A) |
(II-A) |
(II-B) |
|
Total number of fetuses examined |
167a |
97 |
98 |
Defects1: Cranial bones, incomplete to lack of ossification : Nasal |
0 |
0 |
4 |
Frontal |
1 |
0 |
20* |
Parietal |
1 |
1 |
19* |
Interparietal |
1 |
2 |
18* |
Supraoccipital |
0 |
0 |
15* |
Exoccipital |
0 |
0 |
2 |
Atlas |
0 |
0 |
1 |
Zygomatic |
0 |
0 |
1 |
Premaxilla |
0 |
0 |
1 |
Tympanic bullae |
0 |
0 |
5 |
Mandibles |
0 |
0 |
1 |
Hyoid |
0 |
0 |
3 |
Eye orbit, reduction |
0 |
0 |
0 |
Exoccipital, fused to atlas |
0 |
0 |
0 |
Vertebrla column, curved &/or open |
0 |
0 |
5 |
Vertebrae: |
|
|
|
misshapened &/or retarded development |
0 |
0 |
5 |
thoracic, bipartite centra |
2 |
1 |
5 |
lumbar, bipartite centra |
0 |
0 |
2 |
Sternebrae: |
|
|
|
fused |
0 |
0 |
0 |
hypoplastic to absent |
0 |
0 |
1 |
one or two absent |
1 |
0 |
0 |
staircase |
0 |
0 |
3 |
bipartite |
0 |
0 |
2 |
Rib(s): |
|
|
|
accesory |
6 |
5 |
5 |
Absent or less developed |
0 |
0 |
7* |
wavy |
2 |
2 |
0 |
fused |
0 |
0 |
2 |
Pelvic, hypoplastic to absent |
0 |
0 |
0 |
Brachydactyly |
0 |
0 |
0 |
Syndactyly |
0 |
0 |
0 |
Adactyly |
0 |
0 |
0 |
Hemimelia & small scapula |
0 |
0 |
0 |
1Fetuses may have more than one defect
aExcludes 1 fetus destroyed during cleaning process
*Significantly different from control (p<0.05) by Chi-square only
Effect on developmental toxicity: via oral route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 1 000 mg/kg bw/day
- Study duration:
- subacute
- Species:
- rat
- Quality of whole database:
- Reliable quality (Klimisch2)
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
screening
No
test data were available for current substance, however read across data
were available from Butanedioic acid, 2(or 3)-sulfo-,
4-[2-[(1-oxo(C12-C18(even numbered) and
C18unsaturated)alkyl))amino]ethyl]esters, disodium salts. Justification
for read across within the category of N-containing sulphosuccinates (N2
subcategory) is documented in a separate document attached in Section 13.
Supporting data for absence of developmental toxicity were available from an oral combined repeated dose and reproduction/development screening study according to OECD guideline 422 (Hansen, 2013e). The test item was administered orally by gavage to rats with a formulation containing 41.5% active ingredient at dose levels of 100, 300 and 1000 mg act. ingr./kg bw/day for at least 28 days in male rats and at least 39 days in females. No test item-related premature death was noted in any treatment group. No signs of clinical toxicity were noted for the male and female rats of the low and intermediate dose groups (100 and 300 mg/kg bw/day), whereas slightly increased salivation was noted in one male rat as the only finding at 1000 mg/kg bw/day. A slight reduction in body weight was noted for the male and female rats dosed at 1000 mg/kg bw/day. Other parameters such as neurological observations, haematology and serum chemistry are discussed in the repeated dose toxicity section.
No test item-related influence was noted on the developmental toxicity parameters in any treatment group (100, 300 and 1000 mg/kg bw/day). Microscopic examination revealed no changes in the reproductive organs from the male and female rats of the high dose group (1000 mg/kg bw/day). No test item related influence was noted on the survival rate and the mean and total body weights of the pups. External examination of the pups revealed no visible changes related to the test item. NOAEL for systemic toxicity was 300 mg/kg bw/day, whereas NOAEL for reproductive and developmental toxicity was >= 1000 mg/kg bw.
Teratogenicity
testing
Further
data on prenatal developmental toxicity were available from read across
substance Docusate sodium (CAS No. 577-11-7). Justification for read
across with the category of Di-ester sulphosuccinates is documented in a
separate document attached in Section 13.
-
A key study for prenatal developmental toxicity was performed in rats
dosed from day 6-15 of gestation with read across substance Docusate
sodium dosed at dietary dose levels of 1.0 and 2.0 % in the diet (Roell
et al., 1976). The study was conducted according to OECD 414 guideline,
and was considered to be reliable, adequate and relevant. Subtoxic
dietary levels of 1.0% showed no adverse effects on the various maternal
or fetal parameters. Toxic dietary levels of 2.0% Docusate sodium
produced significant depressions in maternal weight-gains and increased
incidences of resorptions (13.7%) and gross abnormalities either among
litters (25.0%) or fetal populations (20.2%) as compared to controls.
These abnormalities consisted primarily of exencephaly of varying
degrees with, at times, spina bifida, anophthalmia and associated
skeletal defects. The visceral observations confirmed the significance
of the exencephalous characteristics and anophthalmia for the group
given dietary levels of 2.0%. In this group, skeletal observations
revealed a significant incidence of incomplete ossification to absence
of the various cranial bones, a curved or open vertebral column, and a
variety of defects of the vertebrae and ribs. Interpretation of the
results of the present experiment, in which only maternally toxic doses
induce teratogenicity, indicates no real hazard with the recommended
human use of these surfactants. The concentration of 1% in the diet is
considered as maternal and developmental NOAEL. This dose level
corresponded with a test article intake of 1074 mg/kg body weight, as
calculated in the study.
- As supporting information, prenatal developmental toxicity was also
studied in rats by dietary administration of Docusate 'calcium' (DCS) at
dose levels of 0.5, 1.0, 1.5 and 2.0 % in the diet as well as by oral
gavage at 250, 500, 750 and 1000 mg/kg bw (Roell et all., 1976).
Subtoxic dietary levels of 0.5 and 1.0% Docusate calcium ingested on
gestational days 6 through 15 showed no adverse effects on the various
maternal or fetal parameters. Near toxic or toxic dietary levels of 1.5
and 2.0% DCS produced significant incidences of resorptions and gross
abnormalities consisting primarily of exencephaly of varying degrees
with spina bifida, anophthalmia and associated skeletal defects.
However, dietary levels of 2% of DCS fed to pregnant rats for 3 days
(days 6-8, 8-10 or 10-12) did not produce teratogenic response. Also,
DCS given to pregnant rats by oral intubation at maternally subtoxic
doses (250-750 mg/kg) and a slightly toxic dose (1000 mg/kg) did not
lead to malformations, however the incidence of resorptions was
increased at the 2 toxic doses. Likewise doses of 500 and 750 mg/kg
given by gavage from day 6-15 produced an increase in resorptions at the
highest dose without a teratogenic effect. Since only maternally toxic
doses fed on gestational day 6-15 produced embryotoxic and teratogenic
effects, it is concluded that no real hazard exists.
Conclusion
An
oral gavage reproductive screening study with read across substance
Butanedioic acid, 2(or 3)-sulfo-, 4-[2-[(1-oxo(C12-C18(even numbered)
andC18unsaturated)alkyl) amino ]ethyl]esters, disodium salts showed
NOAEL of 300 mg/kg bw for paternal/maternal systemic toxicity, whereas
1000 mg/kg bw was NOAEL for reproductive and developmental toxicity.
Prenatal developmental toxicity was tested by dietary administration of read across substance Docusate sodium in rats from day 6 to 15 of gestation. 1% in the diet was a maternal and developmental NOAEL corresponding to 1074 mg/kg bw, whereas at 2% in the diet visceral and skeletal anomalies were observed, which were considreed secondary to maternal toxicity. This was confirmed in a similar study with Docusate calcium given at subtoxic and toxic dose levels, where the same could be observed.
Based on the absence of developmental findings in the screening study and teratogenicity study with structurally similar substances, no further testing is needed wiht registered substance.
Justification for selection of Effect on developmental toxicity: via oral route:
Supporting study
Justification for classification or non-classification
Based on these results and according to the EC Directive (No.93/21/EEC) and CLP (No. 1272/2008 of 16 December 2008), the test item does not have to be classified and has no obligatory labelling requirement for repeated dose toxicity.
Additional information
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.