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EC number: 215-578-1 | CAS number: 1333-07-9
- 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
Toxicity to reproduction
Administrative data
- Endpoint:
- two-generation reproductive 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:
- 2006 October 19 - 2007 July 02
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: Study performed according to OECD and EU guidelines and according to GLP principles.
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 007
- Report date:
- 2008
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.35 (Two-Generation Reproduction Toxicity Test)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EPA OPPTS 870.3800 (Reproduction and Fertility Effects)
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Reference substance name:
- Toluene-4-sulphonamide
- EC Number:
- 200-741-1
- EC Name:
- Toluene-4-sulphonamide
- Cas Number:
- 70-55-3
- Molecular formula:
- C7H9NO2S
- IUPAC Name:
- 4-methylbenzenesulfonamide
- Reference substance name:
- p-Toluenesulfonamide
- IUPAC Name:
- p-Toluenesulfonamide
- Details on test material:
- - Name of test material (as cited in study report): p-TSA
- Substance type: White crystalline powder
- Physical state: Solid
- Analytical purity: 99.9%
- Impurities (identity and concentrations): 0.1% water
- Purity test date: 2006 July 28
- Lot/batch No.: 0603514009
- Expiration date of the lot/batch: 2008 March 31
- Stability under test conditions: Stable in diet for at least 36 days at room temperature
- Storage condition of test material: At room temperature in the dark in tightly closed containers. Keep dry.
- Other: Hygroscopic. Reacts with acids with formation of heat.
Constituent 1
Constituent 2
Test animals
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: (P) 5-6 wks; (F1) 3 wks
- Housing: Pre-mating: Animals were housed in groups of 4 animals/sex/cage in Macrolon plastic cages.
Mating: Females were caged together with males on a one-to-one-basis in Macrolon plastic cages
Post-mating: Males were housed in groups of 4 animals/sex/cage in Macrolon plastic cages. Females were individually housed in Macrolon plastic cages.
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least 5 days.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17.6-24.2
- Humidity (%): 27-95
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12
Administration / exposure
- Route of administration:
- oral: feed
- Vehicle:
- unchanged (no vehicle)
- Details on exposure:
- DIET PREPARATION
- Rate of preparation of diet (frequency): Diets were prepared for one week during the first week of study and every two weeks from Week 2 of study onwards. For the last weeks of the study, diets were prepared for a maximum of 36 days.
- Mixing appropriate amounts with Standard powder rodent diet - Details on mating procedure:
- - M/F ratio per cage: 1/1
- Length of cohabitation: 2 weeks
- Proof of pregnancy: vaginal plug / sperm in vaginal smear referred to as day 0 of pregnancy
- After 10 days of unsuccessful pairing replacement of first male by another male with proven fertility.
- After successful mating each pregnant female was caged: individually - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Sampling and analysis of diet preparations were performed on four occasions (week 1, 11, 22 and 33) according to the following scheme:
Group 1: accuracy (middle position of container)
Group 2: accuracy and homogeneity (top, middle and bottom position of container)
Group 3: accuracy (middle position of container)
Group 4: accuracy and homogeneity (top, middle and bottom position of container) - Duration of treatment / exposure:
- F0-generation: 10 weeks prior to mating and continuing until euthanasia.
F1-generation (F0-offspring): The F1-generation was potentially exposed to the test substance in utero, through nursing during lactation and directly following weaning. After weaning, pups were treated for a minimum of 10 weeks prior to mating and continuing until euthanasia.
F2-generation (F1-offspring): The F2-generation was potentially exposed to the test substance in utero and through nursing during lactation. - Frequency of treatment:
- Ad libitum
- Details on study schedule:
- - F1 parental animals not mated until 70 days after selected from the F1 litters.
- Selection of parents from F1 generation when pups were 21 days of age.
Doses / concentrationsopen allclose all
- Remarks:
- Doses / Concentrations:
1000 ppm
Basis:
nominal in diet
- Remarks:
- Doses / Concentrations:
3000 ppm
Basis:
nominal in diet
- Remarks:
- Doses / Concentrations:
10000
Basis:
nominal in diet
- No. of animals per sex per dose:
- 24
- Control animals:
- yes, plain diet
- Details on study design:
- - Dose selection rationale: based on results of a 28-day toxicity study in Wistar Han rats at dose levels of 0, 1000, 5000 and 25000 ppm.
Examinations
- Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: At least twice daily.
- Cage side observations: mortality, viability.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: At least once daily.
BODY WEIGHT: Yes
- Time schedule for examinations: Males and females were weighed on the first day of exposure and weekly thereafter. Mated females were weighed on days 0, 4, 7, 11, 14, 17 and 20 of gestation, and during lactation on days 1, 4, 7, 14 and 21.
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
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes
WATER CONSUMPTION : Yes
- Time schedule for examinations: subjective appraisal. - Oestrous cyclicity (parental animals):
- Daily over a period of 3 weeks prior to pairing and throughout cohabitation
- Sperm parameters (parental animals):
- testis weight, epididymis weight, enumeration of homogenisation-resistant spermatids in testes and epididymis, enumeration of cauda epididymal sperm reserve, sperm motility, sperm morphology.
- Litter observations:
- PARAMETERS EXAMINED
number and sex of pups
stillbirths
live births
presence of gross anomalies
weight gain
physical or behavioural abnormalities
The day of vaginal opening or balanopreputial separation for F1-weanlings selected for mating. As a slightly delayed balanopreputial separation and vaginal opening for high dose F1-weanlings was observed, ano-genital distance was measured on day 1 of lactation for all F2-pups.
GROSS EXAMINATION OF DEAD PUPS:
yes, for external and internal abnormalities; possible cause of death was determined for pups born or found dead. - Postmortem examinations (parental animals):
- SACRIFICE
- Male animals: All surviving animals as soon as possible after the last litters in each generation were produced.
- Maternal animals: All surviving animals on day 21 post partum or shortly thereafter. Females showing no evidence of copulation were killed approximately 21 days after the last day of the mating period.
GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations of the cranial, thoracic and abdominal tissues and organs, with special attention being paid to the reproductive organs.
HISTOPATHOLOGY / ORGAN WEIGHTS
The following tissues were prepared for microscopic examination: cervix, coagulation gland, epididymides, ovaries, prostate gland, seminal vesicles, testes, uterus, vagina, all gross lesions.
The following organs were weighed: Adrenal glands, Brain, Epididymides, Kidneys, Liver, Ovaries, Pituitary gland, Prostate, Seminal vesicles, Spleen,
Testes, Thyroid, Uterus
- Postmortem examinations (offspring):
- SACRIFICE
- The F1 offspring not selected as parental animals and all F2 offspring were sacrificed at day 21 post partum or shortly thereafter.
- These animals were subjected to postmortem examinations (macroscopic and microscopic examination) as follows:
Vagina, uterus, ovaries, testis, epididymis, seminal vesicle, prostate, coagulating gland
GROSS NECROPSY
- Gross necropsy consisted of external examination of the cranium, and macroscopic examination of the thoracic and abdominal tissues and organs with emphasis on developmental morphology.
HISTOPATHOLOGY / ORGAN WEIGTHS
The following tissues were prepared for microscopic examination: Vagina, uterus, ovaries, testis, epididymis, seminal vesicle, prostate, coagulating gland
The following tissues were weighed: brain, spleen, thymus - Statistics:
- The following statistical methods were used to analyse the data:
- If the variables could be assumed to follow a normal distribution, the Dunnett-test (Dunnett, 1955) (many-to-one t-test) based on a pooled variance estimate was applied for the comparison of the treated groups and the control groups for each sex.
- The Steel-test (Miller, 1981) (many-to-one rank test) was applied if the data could not be assumed to follow a normal distribution.
- The Fisher Exact-test (Fisher 1950) was applied to frequency data.
All tests were two-sided and in all cases p < 0.05 were accepted as the lowest level of significance. - Reproductive indices:
- Percentage mating: Number of females mated x 100 / Number of females paired
Fertility index: Number of pregnant females x 100 / Number of females paired
Conception rate: Number of pregnant females x 100 / Number of females mated
Gestation index: Number of females bearing live pups x 100 / Number of pregnant females
Duration of gestation: Number of days between confirmation of mating and the beginning of parturition - Offspring viability indices:
- Percentage live males at First Litter Check: Number of live male pups at First Litter Check x 100 / Number of live pups at First Litter Check
Percentage live females at First Litter Check: Number of live female pups at First Litter Check x 100 / Number of live pups at First Litter Check
Percentage of postnatal loss days 0-4 post partum: Number of dead pups on day 4 post partum x 100 / Number of live pups at First Litter Check
Percentage of breeding loss day 5 until weaning: Number of dead pups between days 5 and 21 post partum x 100 / Number of live pups on day 4 post partum
Percentage live males at weaning: Number of live male pups on day 21 post partum x 100 / Number of live pups on day 21 post partum
Percentage live females at weaning: Number of live female pups on day 21 post partum x 100 / Number of live pups on day 21 post partum
Viability index: Number of live pups on day 4 post partum x 100 / Number of pups born alive
Weaning index: Number of live pups on day 21 post partum x 100 / Number of live pups on day 4 post partum
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- no effects observed
- Body weight and weight changes:
- effects observed, treatment-related
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Histopathological findings: non-neoplastic:
- no effects observed
- Other effects:
- no effects observed
Reproductive function / performance (P0)
- Reproductive function: oestrous cycle:
- no effects observed
- Reproductive function: sperm measures:
- no effects observed
- Reproductive performance:
- no effects observed
Details on results (P0)
ORGAN WEIGHTS (PARENTAL ANIMALS)
Males P generation:
At 3000 ppm:
Decreased body weights and body weight gain. Terminal body weights at necropsy (92% of control) were decreased which resulted in relative organ weight changes for the brain and kidneys (105% and 110% of control, respectively).
At 10000 ppm:
Decreased body weights and body weight gain. Terminal body weights at necropsy (91% of control) were decreased which resulted in relative organ weight changes for the brain, liver, kidneys and seminal vesicles (108%, 108%, 118% and 116% of control, respectively).
Females P generation:
At 3000 ppm:
Decreased body weights and body weight gain. Terminal body weights at necropsy (94% of control) were decreased which resulted in relative organ weight changes for the brain (107% of control).
At 10000 ppm:
Decreased body weights and body weight gain. Terminal body weights at necropsy (91% of control) were decreased which resulted in relative organ weight changes for the brain, kidneys, adrenals and spleen (109%, 121%, 112% and 110% of control, respectively).
Males F1 generation:
At 3000 ppm:
Decreased body weights and body weight gain. Terminal body weights at necropsy (93% of control) were decreased which resulted in absolute organ weight changes for the spleen (90% of control) and relative organ weight changes for the brain (108% of control).
At 10000 ppm:
Decreased body weights and body weight gain. Terminal body weights at necropsy (87% of control) were decreased which resulted in absolute organ weight changes for the brain, liver, and spleen (95%, 89% and 89% of control, respectively), and relative organ weight changes for the brain, kidneys, seminal vesicles, testes and prostate (108%, 111%, 124%, 109% and 118% of control, respectively).
Females F1 generation:
At 3000 ppm:
Decreased body weights, body weight gain and terminal body weights at necropsy (93% of control).
At 10000 ppm:
Decreased body weights and body weight gain. Decreased food consumption during the last week of pregnancy. Terminal body weights at necropsy (85% of control) were decreased which resulted in absolute organ weight changes for the brain (93% of control) and relative organ weight changes for the brain, kidneys, adrenals, spleen and pituitary gland (110%, 118%, 112%, 113% and 120% of control, respectively).
Effect levels (P0)
open allclose all
- Dose descriptor:
- NOAEL
- Remarks:
- parental
- Effect level:
- 1 000 ppm (nominal)
- Sex:
- male/female
- Basis for effect level:
- other: Corresponds to 52-78 mg/kg bw/day for males and 75-161 mg/kg bw/day for females.
- Remarks on result:
- other: Generation: P and F1 (migrated information)
- Dose descriptor:
- NOAEL
- Remarks:
- developmental
- Effect level:
- 3 000 ppm (nominal)
- Sex:
- male/female
- Basis for effect level:
- other: Corresponds to 165-237 mg/kg bw/day for males and 232-499 mg/kg bw/day for females.
- Remarks on result:
- other: Generation: F1 and F2 (migrated information)
- Dose descriptor:
- NOAEL
- Remarks:
- reproduction and breeding
- Effect level:
- 10 000 ppm (nominal)
- Sex:
- male/female
- Basis for effect level:
- other: Corresponds to 566-832 mg/kg bw/day for males and 733-1631 mg/kg bw/day for females.
- Remarks on result:
- other: Generation: P and F1 (migrated information)
- Dose descriptor:
- LOAEL
- Remarks:
- parental
- Effect level:
- 3 000 ppm (nominal)
- Sex:
- male/female
- Basis for effect level:
- other: Based on decreased body weights and body weight gain, and due to this organ weight changes.
- Remarks on result:
- other: Generation: P and F1 (migrated information)
- Dose descriptor:
- LOAEL
- Remarks:
- developmental
- Effect level:
- 10 000 ppm (nominal)
- Sex:
- male/female
- Basis for effect level:
- other: Based on decreased body weights and body weight gain, and due to this organ weight changes.
- Remarks on result:
- other: Generation: F1 and F2 (migrated information)
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
- Sexual maturation:
- no effects observed
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Gross pathological findings:
- no effects observed
- Histopathological findings:
- no effects observed
Details on results (F1)
ORGAN WEIGHTS (OFFSPRING)
Male pups F1 generation:
At 10000 ppm:
Lower body weights for pups (terminal body weight at necropsy was 85% of control) which resulted in absolute organ weight changes for the brain, spleen and thymus (95%, 78% and 74% of control, respectively), relative organ weight changes for the brain (111% of control), and a delay in balanopreputial separation (108% of control).
Female pups F1 generation:
At 10000 ppm:
Lower body weights for pups (terminal body weight at necropsy was 84% of control) which resulted in absolute organ weight changes for the brain, spleen and thymus (94%, 78% and 73% of control, respectively), relative organ weight changes for the brain (112% of control), and a delay in vaginal opening (114% of control).
Male pups F2 generation:
At 10000 ppm:
Lower body weights for pups (terminal body weight at necropsy was 81% of control) which resulted in absolute organ weight changes for the brain, spleen and thymus (95%, 75% and 70% of control, respectively) and relative organ weight changes for the brain (117% of control).
Female pups F2 generation:
At 10000 ppm:
Lower body weights for pups (terminal body weight at necropsy was 82% of control) which resulted in absolute organ weight changes for the spleen and thymus (76% and 73% of control, respectively) and relative organ weight changes for the brain and thymus (118% and 90% of control, respectively).
Overall reproductive toxicity
- Reproductive effects observed:
- not specified
Any other information on results incl. tables
Table 1. Mean test article intake when corrected for mean value of recovery
Nominal dose |
1000 ppm |
3000 ppm |
10000 ppm |
Mean value of recovery |
930 ppm |
2820 ppm |
9600 ppm |
MALES F0 |
|||
Pre mating |
75 |
236 |
787 |
Post mating |
52 |
165 |
568 |
FEMALES F0 |
|||
Premating |
85 |
264 |
862 |
Postcoitum |
75 |
238 |
739 |
Lactation |
161 |
499 |
1631 |
MALES F1 |
|||
Premating |
78 |
237 |
832 |
Post mating |
53 |
165 |
566 |
FEMALES F1 |
|||
Premating |
86 |
264 |
887 |
Postcoitum |
75 |
232 |
733 |
Lactation |
160 |
487 |
1582 |
Table 2. Reproductive toxicity
Dose (ppm) |
0 |
1000 |
3000 |
10000 |
dr |
||||||||||||||||||||||
m |
f |
m |
f |
m |
f |
m |
f |
||||||||||||||||||||
F0 animals |
|||||||||||||||||||||||||||
Mortality |
no treatment-related findings |
||||||||||||||||||||||||||
Clinical signs |
no treatment-related findings |
||||||||||||||||||||||||||
Body weight gain |
dc |
dc |
dc |
dc |
mf |
||||||||||||||||||||||
Food consumption |
no treatment-related findings |
||||||||||||||||||||||||||
Mating/fertility/gestation |
no treatment-related findings |
||||||||||||||||||||||||||
Oestrus cycle |
no treatment-related findings |
||||||||||||||||||||||||||
Sperm evaluation |
no treatment-related findings |
||||||||||||||||||||||||||
Organ weight |
|||||||||||||||||||||||||||
- terminal body weight |
dc (94%) |
dc (92%) |
dc (91%) |
dc (91%) |
|||||||||||||||||||||||
- brain |
icr (107%) |
icr (105%) |
icr (109%) |
icr (108%) |
|||||||||||||||||||||||
- liver |
icr (108%) |
||||||||||||||||||||||||||
- kidneys |
icr (110%) |
icr (121%) |
icr (118%) |
f |
|||||||||||||||||||||||
- adrenals |
icr (112%) |
||||||||||||||||||||||||||
- spleen |
icr (110%) |
||||||||||||||||||||||||||
- seminal vesicles |
icr (116%) |
||||||||||||||||||||||||||
Pathology |
|||||||||||||||||||||||||||
Macroscopy |
no treatment-related findings |
||||||||||||||||||||||||||
Microscopy |
no treatment-related findings |
||||||||||||||||||||||||||
F1 pups |
|||||||||||||||||||||||||||
Litter size |
no treatment-related findings |
||||||||||||||||||||||||||
Post implantation loss |
no treatment-related findings |
||||||||||||||||||||||||||
Live birth index |
no treatment-related findings |
||||||||||||||||||||||||||
Viability index |
no treatment-related findings |
||||||||||||||||||||||||||
Lactation index |
no treatment-related findings |
||||||||||||||||||||||||||
Sex ratio |
no treatment-related findings |
||||||||||||||||||||||||||
Clinical signs |
no treatment-related findings |
||||||||||||||||||||||||||
Body weight |
dc |
dc |
|||||||||||||||||||||||||
Sexual maturation |
ic |
ic |
|||||||||||||||||||||||||
Pup development |
no treatment-related findings |
||||||||||||||||||||||||||
Organ weight |
|||||||||||||||||||||||||||
- terminal body weight |
dc (84%) |
dc (85%) |
|||||||||||||||||||||||||
- brain |
dca (94%) icr (112%) |
dca (95%) icr (111%) |
|||||||||||||||||||||||||
- spleen |
dca (78%) |
dca (78%) |
|||||||||||||||||||||||||
- thymus |
dca (73%) |
dca (74%) |
|||||||||||||||||||||||||
Pathology |
|||||||||||||||||||||||||||
Macroscopy |
no treatment-related findings |
||||||||||||||||||||||||||
Microscopy |
no treatment-related findings |
||||||||||||||||||||||||||
F1 animals |
|||||||||||||||||||||||||||
Mortality |
no treatment-related findings |
||||||||||||||||||||||||||
Clinical signs |
no treatment-related findings |
||||||||||||||||||||||||||
Body weight gain |
dc |
dc |
dc |
dc |
mf |
||||||||||||||||||||||
Food consumption |
dc |
||||||||||||||||||||||||||
Mating/fertility/gestation |
no treatment-related findings |
||||||||||||||||||||||||||
Oestrus cycle |
no treatment-related findings |
||||||||||||||||||||||||||
Sperm evaluation |
no treatment-related findings |
||||||||||||||||||||||||||
Organ weight |
|||||||||||||||||||||||||||
- terminal body weight |
dc (93%) |
dc (93%) |
dc (87%) |
dc (85%) |
mf |
||||||||||||||||||||||
- brain |
icr (108%) |
dca (95%) icr (108%) |
dca (93%) icr (110%) |
||||||||||||||||||||||||
- pituitary |
icr (120%) |
||||||||||||||||||||||||||
- liver |
dca (89%) |
||||||||||||||||||||||||||
- kidneys |
icr (111%) |
icr (118%) |
|||||||||||||||||||||||||
- adrenals |
icr (112%) |
||||||||||||||||||||||||||
- spleen |
dca (90%) |
dca (89%) |
icr (113%) |
||||||||||||||||||||||||
- testes |
icr (109%) |
||||||||||||||||||||||||||
- prostate |
icr (118%) |
||||||||||||||||||||||||||
- seminal vesicles |
icr (124%) |
||||||||||||||||||||||||||
Pathology |
|||||||||||||||||||||||||||
Macroscopy |
no treatment-related findings |
||||||||||||||||||||||||||
Microscopy |
no treatment-related findings |
||||||||||||||||||||||||||
F2 pups |
|||||||||||||||||||||||||||
Litter size |
no treatment-related findings |
||||||||||||||||||||||||||
Post implantation loss |
no treatment-related findings |
||||||||||||||||||||||||||
Live birth index |
no treatment-related findings |
||||||||||||||||||||||||||
Viability index |
no treatment-related findings |
||||||||||||||||||||||||||
Lactation index |
no treatment-related findings |
||||||||||||||||||||||||||
Sex ratio |
no treatment-related findings |
||||||||||||||||||||||||||
Clinical signs |
no treatment-related findings |
||||||||||||||||||||||||||
Body weight |
dc |
dc |
|||||||||||||||||||||||||
Pup development |
no treatment-related findings |
||||||||||||||||||||||||||
Auditory and visual response |
not performed |
||||||||||||||||||||||||||
Organ weight |
|||||||||||||||||||||||||||
- terminal body weight |
dc (81%) |
dc (82%) |
|||||||||||||||||||||||||
- brain |
dca (95%) icr (117%) |
icr (118%) |
|||||||||||||||||||||||||
- spleen |
dca (75%) |
dca (76%) |
|||||||||||||||||||||||||
- thymus |
dca (70%) |
dca (73%) dcr (90%) |
|||||||||||||||||||||||||
Pathology |
no treatment-related findings |
||||||||||||||||||||||||||
dc/ic statistically significantly decreased/increased compared to the controls
a/r absolute/relative organ weight
(%) relative to control
dr dose-related
Applicant's summary and conclusion
- Conclusions:
- Parental toxicity was observed for both generations at the mid and high dose groups (3000 and 10000 ppm).
Developmental toxicity was observed for both generations at the high dose group (10000 ppm).
Reproduction and breeding parameters were unaffected for both generations for treatment up to 10000 ppm.
Based on these findings, the definitive parental No Observed Adverse Effect Level (NOAEL) was established as being 1000 ppm.
The definitive development NOAEL was established as being 3000 ppm.
The definitive reproduction and breeding NOAEL was established as being at least 10000 ppm.
When corrected for mean test article intake the NOAEL of 1000 ppm corresponds to 52-78 mg/kg bw/day for males and 75-161 mg/kg bw/day for females, the NOAEL of 3000 ppm corresponds to 165-237 mg/kg bw/day for males and 232-499 mg/kg bw/day for females, and the NOAEL of 10000 ppm corresponds to 566-832 mg/kg bw/day for males and 733-1631 mg/kg bw/day for females. - Executive summary:
A two-generation reproduction toxicity study of p-TSA in rats by dietary administration.
The study was based on the following guidelines:
- OECD 416, Two-Generation Reproduction Toxicity Study, January 2001.
- OPPTS 870.3800, Reproduction and Fertility Effects, August 1998.
- EC, Commission directive 2004/73/EC, B.35:"Two-generation reproduction toxicity study", April 2004.
After acclimatisation, male and female Wistar rats of the Fe-generation were exposed by dietary inclusion to graduated doses of the test substance. The dose levels for the F0-generation and for the F1-generation were 1000, 3000 and 10000 ppm.
At regular intervals, prepared diets were analysed for accuracy of preparation and homogeneity.
F0-males and F0-females were exposed to the test substance 10 weeks prior to mating and exposure ended at termination. F0-females were allowed to produce and rear a litter until day 21 of lactation. On day 4 of lactation litters were reduced in size to eight pups by random culling of F1-pups. After weaning, one F1-male and one F1-female of each litter were selected for cross mating with a pup of another litter of the same dose group to produce a F2-generation. Mating commenced at least 10 weeks after weaning. F1-offspring selected for mating were dosed from weaning until they were killed after weaning of the F2-offspring on day 21 of lactation. On day 4 of lactation a selection of F2-pups was culled. Pups of the F2-offspring were killed shortly after weaning.
All animals were subjected to daily clinical observation. Body weight and food consumption were measured over the treatment period. The regularity and duration of the estrous cycle was examined. At necropsy, macroscopic observations and organ weights were recorded. Sperm morphology, motility and count were assessed. A histopathological examination was performed on all reproduction organs and tissues. Reproduction parameters, breeding data and pup development were assessed. Blood samples were collection from F1 females (10/group) for possible measurement of thyroid hormones. These samples were discarded without analyses.
RESULTS
Chemical analysis revealed that the diets were prepared properly and were considered to be homogeneous.
The following changes were considered to be related to treatment:
F0-GENERATION
at 1000 ppm (group 2):
• No treatment-related findings.
at 3000 ppm (group 3):
• Decreased body weights and body weight gain.
Terminal body weights at necropsy were decreased which resulted in relative organ weight changes for the brain and kidneys.at 10000 ppm (group 4):
• Decreased body weights and body weight gain.
Terminal body weights at necropsy were decreased which resulted in relative organ weight changes for the brain, liver, kidneys, seminal vesicles, adrenals, and spleen.
Lower body weights for male and female pups which resulted in organ weight changes for the brain, spleen and thymus and a delay in vaginal opening and balanopreputial separation.F1-GENERATION
at1000ppm (group2):
• No treatment-related findings.
at3000ppm (group3):
• Decreased body weights and body weight gain.
Terminal body weights at necropsy were decreased which resulted in organ weight changes for the brain and spleen.at10000ppm (group4):
• Decreased body weights and body weight gain.
Decreased food consumption for females during the last week of pregnancy.
Terminal body weights at necropsy were decreased which resulted in organ weight changes for the brain, liver, kidneys, seminal vesicles, adrenals, spleen, testes, prostate, and pituitary gland. Lower body weights for male and female pups which resulted in organ weight changes for the brain, spleen and thymus.CONCLUSION
Treatment with p-TSA by dietary inclusion in male and female Wistar rats at dose levels of1000, 3000 and 10000 ppm revealed Fo-and F1-parental toxicity at3000and10000ppm and developmental toxicity (related to decreased body weights of dams) at 10000ppm.
Reproduction and breeding parameters were unaffected for both generations for treatment up to 10000 ppm.
Based on these findings, the definitive parental No Observed Adverse Effect Level (NOAEL) was established as being 1000 ppm.
The definitive development NOAEL was established as being 3000 ppm.
The definitive reproduction and breeding NOAEL was established as being at least 10000 ppm.
When corrected for mean test article intake the NOAEL of 1000 ppm corresponds to 52 -78 mg/kg bw/day for males and 75-161mg/kg bw/day for females, the NOAEL of 3000 ppm corresponds to 165-237 mg/kg bw/day for males and 232 -499 mg/kg bw/day for females, and the NOAEL of 10000 ppm corresponds to 566 -832 mg/kg bw/day for males and 733 -1631 mg/kg bw/day for females.
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