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EC number: 203-728-9 | CAS number: 110-01-0
- 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
Description of key information
Exposure of rats (6 hours/day, 5 days/week, 13 weeks) leads to a NOAEC for the clinical signs of irritation of 51 ppm (184 mg/m3) and a NOAEC for systemic effect higher than 1442 ppm (5201 mg/m3).
Oral route
There is no repeated dose toxicity study by oral route on THT.
Dermal route
There is no reliable repeated dose toxicity study by dermal route on THT.
Inhalation route
Ten male and ten female Sprague-Dawley rats were whole-body exposed to analytical concentrations of 0, 51, 236 and 1442 ppm (184, 852 or 5201 mg/m3) tetrahydrothiophene (purity > 99%), six hours per day, five days per week for 13 weeks (Hardy, 1988). The study was performed according to the good laboratory practice and the OECD Test Guideline 413. The clinical symptoms of irritation (lacrimation, salivation, eyes closed) are a cluster of symptoms seen with increasing concentration. From 236 ppm, there was a more frequent occurrence of irritative symptoms (eyes closed). The significance of the symptoms of "licking the inside mouth and "shake his head" is unclear and questionable. The animals of the 1442 ppm group and the males of 236 ppm group drank more water than the animals in the control group. Ophthalmological examinations were unremarkable. In females of the 236 and 1442 ppm groups, the hematological parameters showed small differences compared to the control animals, but these changes were considered as not toxicologically significant, excepted an increase of white blood cells and lymphocytes at 1442 ppm. There was also a slight, not toxicologically significant increase in pH urine in females at 1442 ppm. Macroscopic examination and the determination of organ weights provided no abnormal findings. A minimal increase in liver weights was observed in females exposed to 1442 ppm but this effect was not considered toxicologically relevant. Histopathological examinations was performed on the lungs of all animals and on some other tissues of the control and 1442 ppm group animals. This included tissues from the nasal cavity (rostral and caudal). No histopathological changes were observed in any of the tissues examined that were considered to be related to treatment with THT. Free blood in sinuses was observed in one male animal of the 1442 ppm group and sinusoidal free blood in one female of the control group. These changes were considered as random. The NOAEC for the clinical signs of local irritation was 51 ppm (184 mg/m3) and the NOAEC for systemic effect was higher than 1442 ppm (5201 mg/m3).
Key value for chemical safety assessment
Repeated dose toxicity: via oral route - systemic effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: inhalation - systemic effects
Link to relevant study records
- Endpoint:
- sub-chronic toxicity: inhalation
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: GLP guideline study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River (UK) Limited, Manston Road, Margate, Kent, England
- Age at study initiation: approximately 6 weeks
- Weight at study initiation: 175-177 for males and 141-144 for females- Fasting period before study:
- Housing: 5 of the smae sax to a cage in suspended polypropylene cages fitted with stainless steel mesh tops and floors
- Diet (e.g. ad libitum): Labsure diet LAD 1, Lavender Mill, Manea, Cambridgeshire, UK
- Water (e.g. ad libitum): tap water
- Acclimation period: at least 10days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17-25
- Humidity (%): 28-80
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12/12 - Route of administration:
- inhalation
- Type of inhalation exposure:
- whole body
- Vehicle:
- other: unchanged (no vehicle)
- Remarks on MMAD:
- MMAD / GSD: The absence of aerosol was demonstrated using an optical particle monitor (Royco Instruments Inc.) at each level of exposure during Weeks 1, 4, 8 and 12 of the study. Droplet numbers in test chambers were similar to those present in the control chamber. No appreciable amount of THT was present as droplets in the atmospheres generated.
- Details on inhalation exposure:
- The vapour of THT was administered to rats by whole-body exposure, 6 hours a day, 5 days a week for 13 weeks. Control rats received air only.
Vapour generation:
The vapour generation system, contained in a separate, sealed exposure chamber metered the liquid from a pressurised reservoir to a glass sinter, contained in a glass vessel through which air was passed. The vapour produced passed out of this vessel and into each chamber via an inlet duct. By varying the feed rate to each vapour generator it was possible to obtain the desired chamber concentrations.
Exposure chambers:
The exposure chambers were constructed of stainless steel and glass and were approximately 0.675 m3 in volume. The vapour from each generator entered the top of the chamber and was exhausted via a perforated plenum located in the base of each chamber. The exhaust from all chamber was drawn through an activated charcoal scrubbing system (Ventsorb R, Chemviron Ltd., Uppermill, Lancs.) by an extractor fan, before being vented to atmosphere. Extract flow was adjusted using gate valves downstream of the chamber to maintain a chamber internal pressure of 10 mm H20) below ambient, as indicated by magnehelic gauges connected to each chamber.
The rats were held during exposure in compartmented stainless steel mesh cages. A wet and dry bulb hygrometer was positioned in the chamber to monitor chamber temperature and relative humidity during exposure. Ports, fitted with removeable bungs, were present in the walls of each chamber to permit removal of chamber air samples for analysis. Routinely a port mid-centre of the chamber side wall was used.
Exposure chamber conditions:
- Measurement of chamber concentration of THT
The concentration of THT within the exposure chambers was determined on at least three occasions during each exposure.
- Air flow
The air flow into each chamber was monitored continuously using tapered-tube rotameters and recorded at 30-minute intervals throughout each exposure.
- Temperature
The air temperature in each chamber was monitored continuously with a mercury bulb thermometer and recorded at approximately hourly intervals throughout each exposure.
- Pressure
The air pressure in each exposure chamber, relative to that in the exposure room, was monitored using a magnehelic gauge and recorded at 30-minute intervals throughout exposure.
- Relative humidity
The humidity in each exposure chamber was monitored continuously with a wet and dry bulb hygrometer and recorded at hourly intervals throughout each exposure. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Samples of chamber air were withdrawn through glass tubes 10 cm in length, nominal bore 2 mm, packed for 2 - 3 cm of their length at one end only with chromosorb 102, 60 - 80 mesh. The vapour was adsorbed on this medium. The samples were thermally desorbed into a gas chromatograph and the amounts of THT collected determined by using external standards.
- Duration of treatment / exposure:
- 13 weeks
- Frequency of treatment:
- 6 h/day; 5 d/week
- Remarks:
- Doses / Concentrations:
50, 275 and 1500 ppm
Basis:
nominal conc. - Remarks:
- Doses / Concentrations:
51, 236 and 1442 ppm (184, 852 and 5201 mg/m3)
Basis:
analytical conc. - No. of animals per sex per dose:
- 10
- Control animals:
- yes, sham-exposed
- Details on study design:
- Post-exposure period: none
- Positive control:
- Not required
- Observations and examinations performed and frequency:
- Clinical signs:
- During exposure
Clinical signs during exposure were recorded either as a group response where all visible animals appeared to be responding similarly, or as an individual response where one particular rat was affected.
- At other times
Animals were examined at least twice each day.
Bodyweight:
Each rat was weighed for allocation to groups and weekly thereafter from Week -1 (pre-exposure) until day of death.
Food consumption:
The quantity of food consumed by each cage of rats was recorded weekly, commencing at Week -1 (pre-exposure) until day of death.
Water consumption:
The amount of water consumed by each cage of rats was recorded daily, commencing at Week 3 until day of death.
Ophthalmoscopy:
The eyes of all rats were examined pre-exposure using a Keeler indirect ophthalmoscope. During Week 12 of exposure the eyes of Group 1 and 4 rats were examined.
Laboratory investigations:
Samples of blood were collected from 5 male and 5 female rats in each group on Week 5 of exposure. Samples of blood and urine were collected from all rats on Week 13 of exposure.
- Haematology Units
Packed cell volume (PCV) %
Haemoglobin (Hb) g/dl
Red cell count (RBC) 10e6/mm3
Mean corpuscular haemoglobin concentrations (MCHC)
calculated: Hb (g/dl) x 100 = PCV (%) %
Mean corpuscular haemoglobin (MCH) - calculated:
Hb (g/d1) x 100 = RBC (106/mm3) pg
Mean corpuscular volume (MCV) - calculated:
PCV (%) x 100 = RBC (10e6/mm3) fl
Reticulocyte counts (Retic) % (of red cells)
Total white cell count (WBC) 10e3/mm3
Differential count (Diff)
Neutrophils (N) 10e3/mm3
Lymphocytes (L) 10e3/mm3
Eosinophils (E) 10e3/mm3
Basophils (B) 10e3/mm3
Monocytes (M) 10e3/mm3
Platelet count (Plts) 10e3/mm3
Thrombotest (TT) s
- Blood biochemistry Units
Glucose mg/dl
Total protein g/dl
Albumin g/dl
Globulin g/dl
Albumin/Globulin ratio
Urea nitrogen mg/dl
Creatinine mg/dl
Alkaline phosphatase mU/ml
Glutamic-pyruvic transaminase (GPT) mU/ml
Glutamic-oxaloacetic transaminase (GOT) mU/ml
Total bilirubin mg/dl
Sodium (Na) mEq/l
Potassium (K) mEq/l
Calcium (Ca mEq/l
Inorganic phosphorus (P) mEq/l
Chloride (Cl) mEq/l
Cholesterol (Chol) mg/dl
- Urinalysis Units
Volume ml
pH
Osmolality (Osmol) mOsm/kg
Protein mg/dl
Qualitative tests:
Glucose, Ketones, Bile pigments, Haemoglobin - Sacrifice and pathology:
- Sacrifice:
Following 13 weeks exposure all rats were sacrificed.
Macroscopic pathology and organ weight analysis:
A detailed macroscopic examination of all animals was performed and the following organs dissected free from each animal and weighed:
Lungs, Testes, Thyroids (with parathyroids), Epididymides, Liver, Prostate, Spleen, Ovaries, Adrenals, Brain, Heart, Pituitary, Kidneys
Microscopic examination:
Light microscope examination was performed on 5 µm-thick sections, stained with haematoxylin and eosin on the following tissues:
Nasal passages* (head for rostral and caudal nasal cavities), Adrenals*, Kidneys*, Oesophagus*, Urinary bladder*, Stomach*, Testes* (with epididymides), Trachea* (including bifurcation), Duodenum*, Jejunum*, Ovaries*, Lungs**, Ileum*, Uterus*, Tracheobronchial lymph nodes*, Caecum*, Brain* (section of medulla/pons, cerebellar cortex, cerebral cortex), Colon*, Salivary glands with attached mandibular lymph nodes*, Rectum*, Heart*, Aorta*, Pituitary*, Thyroids (with parathyroids)*, Lymph nodes* (cervical and mesenteric), Eyes*, Sciatic nerve*, Liver*, Thymus*, Sternum/ribs* (for bone and marrow), Spleen*, Skin*, Pancreas*, Spinal cord*, Gross abnormalities**, Optic nerve*.
* Groups 1 and 4 only
** All rats - Statistics:
- All statistical analyses were carried out separately for males and females.
Data relating to food and water consumption were analysed on a cage basis. For all other parameters, the analyses were carried out using the individual animal as the basic experimental unit.
Food consumption data were analysed using cumulative cage totals, and water consumption data were analysed as the total recorded intake over selected time periods. Bodyweight data were analysed using weight gains.
The following sequence of statistical tests were used for food consumption, water consumption, bodyweight, organ weight and clinical pathology data:
(i) If the data consisted predominantly of one particular value (relative frequency of the mode exceeded 75%), the proportion of animals with values different from the mode was analysed by appropriate methods. Otherwise:
(ii) Bartlett's test was applied to test for heterogeneity of variance between treatments. Where significant (at the 1% level) heterogeneity was found, logarithmic transformation was tried to see if a more stable variance structure could be obtained.
(iii) If no significant heterogéneity was detected (or if a satisfactory transformation was found), a one-way analysis of variance was carried out. If significant heterogeneity of variance was present, and could not be removed by a transformation, the Kruskal-Wallis analysis of ranks was used.
(iv) Except for pre-dose data, analyses of variance were followed by Student's 't' test and Williams' test for a dose-related response, although only Williams' was reported. The Kruskal-Wallis analyses were followed by the non-parametric equivalents of the 't' test and Williams' test (Shirley's test.
Where appropriate, analysis of covariance was used in place of analysis of variance in the above sequence. For organ weight data, the final bodyweight was used as a covariate in an attempt to allow for differences in bodyweight which might influence the organ weights. - Clinical signs:
- effects observed, treatment-related
- Mortality:
- mortality observed, treatment-related
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- effects observed, treatment-related
- Ophthalmological findings:
- no effects observed
- Haematological findings:
- effects observed, treatment-related
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- no effects observed
- Behaviour (functional findings):
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- not examined
- Details on results:
- CHAMBER ATMOSPHERE CONDITIONS
Chamber temperature:
Chamber temperatures during exposure were similar for all groups.
Chamber relative humidity:
Chamber relative humidities were similar for all groups.
CLINICAL OBSERVATIONS
Clinical signs:
During exposure; no abnormalities were seen for rats in Group 1 (Air Control).
Signs noted in exposed groups considered related to exposure to THT were as follows:
Groups 2: licking of the inside of the mouth, salivation on week 4 and lachrymation on week 7
Group 3: licking of the inside of the mouth, salivation on weeks 3, 4 and 5 and lachrymation on weeks 4 and 6
Group 4: licking of the inside of the mouth, salivation, lachrymation, adoption of a hunched posture, rubbing the chin on the grid mesh floor of the exposure cage and a marked reduced response to a sharp tap on the exposure chamber side wall.
At all other times; no abnormalities were seen.
Bodyweight:
Over the course of the 13-week study period there was a minimal reduction in bodyweight gain by female rats exposed to THT which attained statistical significance compared with control values. However, the reduced gain was not dose-related and therefore considered not of toxicological significance.
No treatment-related differences were seen for male rats exposed to THT.
Food consumption:
No treatment-related differences were seen.
Water consumption:
Measurement was initiated at the commencement of Week 3 of exposure after a difference in the amount of water consumed by High dose THT groups was noted visually.
Increased amounts of water were consumed by male and female rats in Group 4 (High dose THT) and by male rats in Group 3 (Inter. dose THT). These values were statistically significant compared with control values. Water consumption by female rats in Group 3 (Inter. dose THT) was also increased but did not achieve statistically significant separation compared with control data.
Ophthalmoscopy:
No treatment-related defects were seen.
LABORATORY INVESTIGATIONS
Haematology:
No differences were seen for male rats during Weeks 5 and 13 of the study.
Differences from control values achieving a degree of statistical significance were noted for female rats in Groups 3 (Inter. dose THT) and 4 (High dose THT) at Week 5, including:
reduced mean corpuscular haemoglobin concentration (MCHC)
(Group 4); increased mean corpuscular volume (MCV) (Groups 3 and 4); increased mean corpuscular haemoglobin (MCH) (Group 4); increased total white cell and lymphocyte counts (Group 4).
At Week 13 a similar effect was noted but confined to female rats in Group 4 only, including:
increased mean corpuscular volume; increased mean corpuscular haemoglobin; increased total white cell and lymphocyte counts.
The changes in red blood cell parameters MCHC, MCV and MCH were minimal and considered not be of toxicological significance.
The increases in total white cells and lymphocytes were inconsistent but the possibility of a treatment-related effect cannot be excluded.
Blood biochemistry:
Differences between treated and control groups achieving a degree of statistical significance during Weeks 5 and 13 of the study, were noted for; proteins, urea, creatinine, alkaline phosphatase, glutamic-pyruvic transaminase, glutamic-oxaloacetic transaminase, electrolytes and cholesterol.
The differences were not dose-related, inconsistent between the sexes and minimal in scale, and were therefore considered not to be of toxicological significance.
Urinalysis:
There was a slight increase in the urinary pH of female rats from Group 4 (6.2) compared with control values (6.0). This difference was very small and considered unlikely to be of toxicological significance.
No other intergroup differences were seen achieving statistically significant separation.
TERMINAL STUDIES
Macroscopic pathology
No effects were seen that were considered related to exposure to THT.
Organ weights:
A minimal increase in the liver weights of female rats from Group 4 (High dose THT) achieved statistically significant separation from control values. However, this change was considered not of toxicological significance.
No other differences were seen that were considered related to exposure to THT.
Microscopic pathology:
Inhalation of THT by rats under the conditions of this study did not produce any observable treatment-related histopathological changes.
- Treatment-related changes
No histopathological changes were observed in any of the tissues examined that were considered to be related to treatment with THT.
- Incidental changes
The small number of minor histopathological changes observed in occasional tissues were within the background range normally observed in rats of this strain and age and were considered to be of no toxicological significance. - Key result
- Dose descriptor:
- NOAEC
- Remarks:
- systemic toxicity
- Effect level:
- >= 1 442 ppm (analytical)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: (5201 mg/m3)
- Remarks on result:
- not determinable due to absence of adverse toxic effects
- Key result
- Dose descriptor:
- NOAEC
- Remarks:
- local irritation
- Effect level:
- 51 ppm (analytical)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- clinical signs
- other: (184 mg/m3)
- Key result
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 236 ppm (analytical)
- System:
- eye
- Organ:
- lacrimal gland
- Treatment related:
- yes
- Dose response relationship:
- yes
- Relevant for humans:
- yes
- Conclusions:
- Clinical signs indicative of mild local irritation were seen at 236 and 1442 ppm. These signs were not apparent between exposures and not related to any macro-or microscopic abnormalities.
Lacrimation and salivation occurred also once at the lowest concentration of 51 ppm However, this seems not significant due to the low frequency.
The amount of water consumed by male and female rats exposed at 1442 ppm and by male rats exposed at 236 ppm was significantly higher than control values but whithout any effects on blood chemistry, urinalysis and the histophatology of kidneys.
There were no other toxicologically significant effects at levels of exposure up to 1442 ppm.
The no effect level for clinical signs of irritation is 51 ppm.
The no effect level for sytemic toxicity is higher than 1442 ppm. - Executive summary:
Ten male and ten female Sprague-Dawley rats were whole-body exposed to analytical concentrations of 0, 51, 236 and 1442 ppm (184, 852 or 5201 mg/m3) tetrahydrothiophene (purity > 99%), six hours per day, five days per week for 13 weeks (Hardy, 1988). The study was performed according to the good laboratory practice and the OECD Test Guideline 413. The clinical symptoms of irritation (lacrimation, salivation, eyes closed) are a cluster of symptoms seen with increasing concentration. From 236 ppm, there was a more frequent occurrence of irritative symptoms (eyes closed). The significance of the symptoms of "licking the inside mouth and "shake his head" is unclear and questionable. The animals of the 1442 ppm group and the males of 236 ppm group drank more water than the animals in the control group. Ophthalmological examinations were unremarkable. In females of the 236 and 1442 ppm groups, the hematological parameters showed small differences compared to the control animals, but these changes were considered as not toxicologically significant, excepted an increase of white blood cells and lymphocytes at 1442 ppm. There was also a slight, not toxicologically significant increase in pH urine in females at 1442 ppm. Macroscopic examination and the determination of organ weights provided no abnormal findings. A minimal increase in liver weights was observed in females exposed to 1442 ppm but this effect was not considered toxicologically relevant. Histopathological examinations was performed on the lungs of all animals and on some other tissues of the control and 1442 ppm group animals. This included tissues from the nasal cavity (rostral and caudal). No histopathological changes were observed in any of the tissues examined that were considered to be related to treatment with THT. Free blood in sinuses was observed in one male animal of the 1442 ppm group and sinusoidal free blood in one female of the control group. These changes were considered as random. The NOAEC for the local irritation was 51 ppm (184 mg/m3) based on the clinical signs observed during exposure and the NOAEC for systemic effect was higher than 1442 ppm (5201 mg/m3).
Reference
Bodyweights - group means (g)
Group.and dosage |
||||||||
Week |
- |
|||||||
Male |
Female |
|||||||
Air Control |
Low dose THT |
Int.dose THT |
High dose THT |
Air Control |
Low dose THT |
Int.dose THT |
High dose THT |
|
Pre-dose |
||||||||
-1 |
201 |
202 |
199 |
203 |
157 |
156 |
159 |
157 |
Dosing 0 |
263 |
261 |
254 |
258 |
181 |
176 |
179 |
184 |
1 |
304 |
304 |
290 |
294 |
200 |
191 |
194 |
196 |
2 |
340 |
341 |
323 |
329 |
217 |
204 |
209 |
214 |
3 |
370 |
371 |
353 |
360 |
232 |
216* |
223* |
226* |
4 |
400 |
397 |
377 |
392 |
247 |
225* |
234* |
237* |
5 |
417 |
415 |
393 |
410 |
251 |
232* |
237* |
243* |
6 |
447 |
439 |
414 |
436 |
262 |
239* |
249* |
251* |
7 |
465 |
459 |
435 |
456 |
267 |
246* |
253* |
255* |
8 |
483 |
477 |
451 |
472 |
275 |
253* |
259* |
261* |
9 |
502 |
491 |
467 |
488 |
280 |
258* |
265* |
267* |
10 |
518 |
506 |
481 |
507 |
286 |
264* |
271* |
273* |
11 |
531 |
519 |
498 |
523 |
291 |
270 |
280 |
278 |
12 |
541 |
527 |
511 |
536 |
296 |
271* |
277* |
281* |
13 |
544 |
529 |
509 |
536 |
292 |
269* |
275* |
279* |
Gain -1 to 13 |
324 |
327 |
310 |
334 |
135 |
113* |
115* |
123* |
* P<0.05 compared with control values using Williams' test
Water consumption - group mean cumulative values (g)
Group and dosage |
||||||||
Week |
Male |
Female |
||||||
Air Control |
Low dose THT |
Int. dose THT |
High dose THT |
Air Control |
Low dose THT |
Int. dose THT |
High dose THT |
|
Dosing 3 |
202 |
207 |
228 |
281** |
169 |
178 |
166 |
222* |
4 |
403 |
409 |
458 |
569** |
334 |
356 |
340 |
438* |
5 |
617 |
620 |
689 |
860** |
491 |
543 |
507 |
666* |
6 |
836 |
827 |
922 |
1146** |
655 |
719 |
684 |
900* |
7 |
1047 |
1030 |
1153 |
1436** |
816 |
901 |
850 |
1130** |
8 |
1252 |
1228 |
1388 |
1728** |
976 |
1079 |
1017 |
1355* |
9 |
1460 |
1433 |
1629 |
2015** |
1127 |
1262 |
1195 |
1584* |
10 |
1664 |
1638 |
1879 |
2320** |
1285 |
1453 |
1377 |
1811* |
11 |
1867 |
1839 |
2127 |
2617** |
1441 |
1636 |
1580 |
2027* |
12 |
2062 |
2036 |
2374* |
2908** |
1587 |
1804 |
1759 |
2246* |
13 |
2251 |
2230 |
2598* |
3166** |
1728 |
1983 |
1924 |
2437* |
* P<0.05 compared with control data using Williams' test
** P<0.01 compared with control data using Williams' test
(Haematology – Female) Week 5
Group |
PCV % |
Hb g/dl |
RBC Xl06/ mm3 |
MCHC % |
MCV fl |
MCH pg |
Retic % |
WBC + Diff x103/mm3 |
Plts x103/ mm3 |
TT s |
||||||
Total |
N |
L |
E |
B |
M |
|||||||||||
Air Control |
48 |
17.2 |
7.9 |
35.6 |
62 |
21.9 |
9.5 |
1.30 |
8.08 |
0.11 |
0.00 |
0.03 |
1077 |
25 |
||
Low dose THT |
48 |
16.8 |
7.6 |
35.4 |
62 |
22.0 |
11.5 |
1.47 |
10.01 |
0.04 |
0.00 |
0.00 |
1013 |
24 |
||
Int.dose THT |
50 |
17.5 |
7.8 |
35.3 |
64** |
22.4 |
10.6 |
0.62 |
9.95 |
0.07 |
0.00 |
0.00 |
1055 |
23 |
||
High dose THT |
50 |
17.6 |
7.7 |
35.1* |
65** |
22.9** |
15.2* |
1.47 |
13.58* |
0.14 |
0.00 |
0.05 |
1005 |
23 |
(Haematology - female) Week 13
Group |
PCV % |
Hb g/dl |
RBC x106/ mm3 |
MCHC % |
MCV fl |
MCH pg |
Retic % |
WBC + Diff x103/mm3 |
Plts x103/ mm3 |
TT s |
||||||
Total |
N |
L |
E |
B |
M |
|||||||||||
Air Control |
#48 |
#14.8 |
#7.3 |
30.8 |
66 |
20.3 |
7.9 |
1.12 |
6.70 |
0.05 |
0.00 |
0.01 |
839 |
20 |
||
Low dose THT |
48 |
14.9 |
7.2 |
31.0 |
67 |
20.6 |
9.4 |
1.12 |
8.15 |
0.09 |
0.00 |
0.00 |
820 |
21 |
||
Int.dose THT |
49 |
14.8 |
7.2 |
30.4 |
68 |
20.7 |
9.4 |
0.96 |
8.29 |
0.09 |
0.00 |
0.01 |
924 |
20 |
||
High dose THT |
49 |
15.1 |
7.2 |
30.7 |
68* |
21.0** |
12.7** |
1.28 |
11.31** |
0.05 |
0.00 |
0.07 |
847 |
20 |
* P<0.05 compared with control data using Williams' test; ** P<0.01
# Distribution-free analysis applied to data F Frequency analysis applied to data
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEC
- 5 201 mg/m³
- Study duration:
- subchronic
- Species:
- rat
- Quality of whole database:
- Key study
Repeated dose toxicity: inhalation - local effects
Link to relevant study records
- Endpoint:
- sub-chronic toxicity: inhalation
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: GLP guideline study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River (UK) Limited, Manston Road, Margate, Kent, England
- Age at study initiation: approximately 6 weeks
- Weight at study initiation: 175-177 for males and 141-144 for females- Fasting period before study:
- Housing: 5 of the smae sax to a cage in suspended polypropylene cages fitted with stainless steel mesh tops and floors
- Diet (e.g. ad libitum): Labsure diet LAD 1, Lavender Mill, Manea, Cambridgeshire, UK
- Water (e.g. ad libitum): tap water
- Acclimation period: at least 10days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17-25
- Humidity (%): 28-80
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12/12 - Route of administration:
- inhalation
- Type of inhalation exposure:
- whole body
- Vehicle:
- other: unchanged (no vehicle)
- Remarks on MMAD:
- MMAD / GSD: The absence of aerosol was demonstrated using an optical particle monitor (Royco Instruments Inc.) at each level of exposure during Weeks 1, 4, 8 and 12 of the study. Droplet numbers in test chambers were similar to those present in the control chamber. No appreciable amount of THT was present as droplets in the atmospheres generated.
- Details on inhalation exposure:
- The vapour of THT was administered to rats by whole-body exposure, 6 hours a day, 5 days a week for 13 weeks. Control rats received air only.
Vapour generation:
The vapour generation system, contained in a separate, sealed exposure chamber metered the liquid from a pressurised reservoir to a glass sinter, contained in a glass vessel through which air was passed. The vapour produced passed out of this vessel and into each chamber via an inlet duct. By varying the feed rate to each vapour generator it was possible to obtain the desired chamber concentrations.
Exposure chambers:
The exposure chambers were constructed of stainless steel and glass and were approximately 0.675 m3 in volume. The vapour from each generator entered the top of the chamber and was exhausted via a perforated plenum located in the base of each chamber. The exhaust from all chamber was drawn through an activated charcoal scrubbing system (Ventsorb R, Chemviron Ltd., Uppermill, Lancs.) by an extractor fan, before being vented to atmosphere. Extract flow was adjusted using gate valves downstream of the chamber to maintain a chamber internal pressure of 10 mm H20) below ambient, as indicated by magnehelic gauges connected to each chamber.
The rats were held during exposure in compartmented stainless steel mesh cages. A wet and dry bulb hygrometer was positioned in the chamber to monitor chamber temperature and relative humidity during exposure. Ports, fitted with removeable bungs, were present in the walls of each chamber to permit removal of chamber air samples for analysis. Routinely a port mid-centre of the chamber side wall was used.
Exposure chamber conditions:
- Measurement of chamber concentration of THT
The concentration of THT within the exposure chambers was determined on at least three occasions during each exposure.
- Air flow
The air flow into each chamber was monitored continuously using tapered-tube rotameters and recorded at 30-minute intervals throughout each exposure.
- Temperature
The air temperature in each chamber was monitored continuously with a mercury bulb thermometer and recorded at approximately hourly intervals throughout each exposure.
- Pressure
The air pressure in each exposure chamber, relative to that in the exposure room, was monitored using a magnehelic gauge and recorded at 30-minute intervals throughout exposure.
- Relative humidity
The humidity in each exposure chamber was monitored continuously with a wet and dry bulb hygrometer and recorded at hourly intervals throughout each exposure. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Samples of chamber air were withdrawn through glass tubes 10 cm in length, nominal bore 2 mm, packed for 2 - 3 cm of their length at one end only with chromosorb 102, 60 - 80 mesh. The vapour was adsorbed on this medium. The samples were thermally desorbed into a gas chromatograph and the amounts of THT collected determined by using external standards.
- Duration of treatment / exposure:
- 13 weeks
- Frequency of treatment:
- 6 h/day; 5 d/week
- Remarks:
- Doses / Concentrations:
50, 275 and 1500 ppm
Basis:
nominal conc. - Remarks:
- Doses / Concentrations:
51, 236 and 1442 ppm (184, 852 and 5201 mg/m3)
Basis:
analytical conc. - No. of animals per sex per dose:
- 10
- Control animals:
- yes, sham-exposed
- Details on study design:
- Post-exposure period: none
- Positive control:
- Not required
- Observations and examinations performed and frequency:
- Clinical signs:
- During exposure
Clinical signs during exposure were recorded either as a group response where all visible animals appeared to be responding similarly, or as an individual response where one particular rat was affected.
- At other times
Animals were examined at least twice each day.
Bodyweight:
Each rat was weighed for allocation to groups and weekly thereafter from Week -1 (pre-exposure) until day of death.
Food consumption:
The quantity of food consumed by each cage of rats was recorded weekly, commencing at Week -1 (pre-exposure) until day of death.
Water consumption:
The amount of water consumed by each cage of rats was recorded daily, commencing at Week 3 until day of death.
Ophthalmoscopy:
The eyes of all rats were examined pre-exposure using a Keeler indirect ophthalmoscope. During Week 12 of exposure the eyes of Group 1 and 4 rats were examined.
Laboratory investigations:
Samples of blood were collected from 5 male and 5 female rats in each group on Week 5 of exposure. Samples of blood and urine were collected from all rats on Week 13 of exposure.
- Haematology Units
Packed cell volume (PCV) %
Haemoglobin (Hb) g/dl
Red cell count (RBC) 10e6/mm3
Mean corpuscular haemoglobin concentrations (MCHC)
calculated: Hb (g/dl) x 100 = PCV (%) %
Mean corpuscular haemoglobin (MCH) - calculated:
Hb (g/d1) x 100 = RBC (106/mm3) pg
Mean corpuscular volume (MCV) - calculated:
PCV (%) x 100 = RBC (10e6/mm3) fl
Reticulocyte counts (Retic) % (of red cells)
Total white cell count (WBC) 10e3/mm3
Differential count (Diff)
Neutrophils (N) 10e3/mm3
Lymphocytes (L) 10e3/mm3
Eosinophils (E) 10e3/mm3
Basophils (B) 10e3/mm3
Monocytes (M) 10e3/mm3
Platelet count (Plts) 10e3/mm3
Thrombotest (TT) s
- Blood biochemistry Units
Glucose mg/dl
Total protein g/dl
Albumin g/dl
Globulin g/dl
Albumin/Globulin ratio
Urea nitrogen mg/dl
Creatinine mg/dl
Alkaline phosphatase mU/ml
Glutamic-pyruvic transaminase (GPT) mU/ml
Glutamic-oxaloacetic transaminase (GOT) mU/ml
Total bilirubin mg/dl
Sodium (Na) mEq/l
Potassium (K) mEq/l
Calcium (Ca mEq/l
Inorganic phosphorus (P) mEq/l
Chloride (Cl) mEq/l
Cholesterol (Chol) mg/dl
- Urinalysis Units
Volume ml
pH
Osmolality (Osmol) mOsm/kg
Protein mg/dl
Qualitative tests:
Glucose, Ketones, Bile pigments, Haemoglobin - Sacrifice and pathology:
- Sacrifice:
Following 13 weeks exposure all rats were sacrificed.
Macroscopic pathology and organ weight analysis:
A detailed macroscopic examination of all animals was performed and the following organs dissected free from each animal and weighed:
Lungs, Testes, Thyroids (with parathyroids), Epididymides, Liver, Prostate, Spleen, Ovaries, Adrenals, Brain, Heart, Pituitary, Kidneys
Microscopic examination:
Light microscope examination was performed on 5 µm-thick sections, stained with haematoxylin and eosin on the following tissues:
Nasal passages* (head for rostral and caudal nasal cavities), Adrenals*, Kidneys*, Oesophagus*, Urinary bladder*, Stomach*, Testes* (with epididymides), Trachea* (including bifurcation), Duodenum*, Jejunum*, Ovaries*, Lungs**, Ileum*, Uterus*, Tracheobronchial lymph nodes*, Caecum*, Brain* (section of medulla/pons, cerebellar cortex, cerebral cortex), Colon*, Salivary glands with attached mandibular lymph nodes*, Rectum*, Heart*, Aorta*, Pituitary*, Thyroids (with parathyroids)*, Lymph nodes* (cervical and mesenteric), Eyes*, Sciatic nerve*, Liver*, Thymus*, Sternum/ribs* (for bone and marrow), Spleen*, Skin*, Pancreas*, Spinal cord*, Gross abnormalities**, Optic nerve*.
* Groups 1 and 4 only
** All rats - Statistics:
- All statistical analyses were carried out separately for males and females.
Data relating to food and water consumption were analysed on a cage basis. For all other parameters, the analyses were carried out using the individual animal as the basic experimental unit.
Food consumption data were analysed using cumulative cage totals, and water consumption data were analysed as the total recorded intake over selected time periods. Bodyweight data were analysed using weight gains.
The following sequence of statistical tests were used for food consumption, water consumption, bodyweight, organ weight and clinical pathology data:
(i) If the data consisted predominantly of one particular value (relative frequency of the mode exceeded 75%), the proportion of animals with values different from the mode was analysed by appropriate methods. Otherwise:
(ii) Bartlett's test was applied to test for heterogeneity of variance between treatments. Where significant (at the 1% level) heterogeneity was found, logarithmic transformation was tried to see if a more stable variance structure could be obtained.
(iii) If no significant heterogéneity was detected (or if a satisfactory transformation was found), a one-way analysis of variance was carried out. If significant heterogeneity of variance was present, and could not be removed by a transformation, the Kruskal-Wallis analysis of ranks was used.
(iv) Except for pre-dose data, analyses of variance were followed by Student's 't' test and Williams' test for a dose-related response, although only Williams' was reported. The Kruskal-Wallis analyses were followed by the non-parametric equivalents of the 't' test and Williams' test (Shirley's test.
Where appropriate, analysis of covariance was used in place of analysis of variance in the above sequence. For organ weight data, the final bodyweight was used as a covariate in an attempt to allow for differences in bodyweight which might influence the organ weights. - Clinical signs:
- effects observed, treatment-related
- Mortality:
- mortality observed, treatment-related
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- effects observed, treatment-related
- Ophthalmological findings:
- no effects observed
- Haematological findings:
- effects observed, treatment-related
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- no effects observed
- Behaviour (functional findings):
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- not examined
- Details on results:
- CHAMBER ATMOSPHERE CONDITIONS
Chamber temperature:
Chamber temperatures during exposure were similar for all groups.
Chamber relative humidity:
Chamber relative humidities were similar for all groups.
CLINICAL OBSERVATIONS
Clinical signs:
During exposure; no abnormalities were seen for rats in Group 1 (Air Control).
Signs noted in exposed groups considered related to exposure to THT were as follows:
Groups 2: licking of the inside of the mouth, salivation on week 4 and lachrymation on week 7
Group 3: licking of the inside of the mouth, salivation on weeks 3, 4 and 5 and lachrymation on weeks 4 and 6
Group 4: licking of the inside of the mouth, salivation, lachrymation, adoption of a hunched posture, rubbing the chin on the grid mesh floor of the exposure cage and a marked reduced response to a sharp tap on the exposure chamber side wall.
At all other times; no abnormalities were seen.
Bodyweight:
Over the course of the 13-week study period there was a minimal reduction in bodyweight gain by female rats exposed to THT which attained statistical significance compared with control values. However, the reduced gain was not dose-related and therefore considered not of toxicological significance.
No treatment-related differences were seen for male rats exposed to THT.
Food consumption:
No treatment-related differences were seen.
Water consumption:
Measurement was initiated at the commencement of Week 3 of exposure after a difference in the amount of water consumed by High dose THT groups was noted visually.
Increased amounts of water were consumed by male and female rats in Group 4 (High dose THT) and by male rats in Group 3 (Inter. dose THT). These values were statistically significant compared with control values. Water consumption by female rats in Group 3 (Inter. dose THT) was also increased but did not achieve statistically significant separation compared with control data.
Ophthalmoscopy:
No treatment-related defects were seen.
LABORATORY INVESTIGATIONS
Haematology:
No differences were seen for male rats during Weeks 5 and 13 of the study.
Differences from control values achieving a degree of statistical significance were noted for female rats in Groups 3 (Inter. dose THT) and 4 (High dose THT) at Week 5, including:
reduced mean corpuscular haemoglobin concentration (MCHC)
(Group 4); increased mean corpuscular volume (MCV) (Groups 3 and 4); increased mean corpuscular haemoglobin (MCH) (Group 4); increased total white cell and lymphocyte counts (Group 4).
At Week 13 a similar effect was noted but confined to female rats in Group 4 only, including:
increased mean corpuscular volume; increased mean corpuscular haemoglobin; increased total white cell and lymphocyte counts.
The changes in red blood cell parameters MCHC, MCV and MCH were minimal and considered not be of toxicological significance.
The increases in total white cells and lymphocytes were inconsistent but the possibility of a treatment-related effect cannot be excluded.
Blood biochemistry:
Differences between treated and control groups achieving a degree of statistical significance during Weeks 5 and 13 of the study, were noted for; proteins, urea, creatinine, alkaline phosphatase, glutamic-pyruvic transaminase, glutamic-oxaloacetic transaminase, electrolytes and cholesterol.
The differences were not dose-related, inconsistent between the sexes and minimal in scale, and were therefore considered not to be of toxicological significance.
Urinalysis:
There was a slight increase in the urinary pH of female rats from Group 4 (6.2) compared with control values (6.0). This difference was very small and considered unlikely to be of toxicological significance.
No other intergroup differences were seen achieving statistically significant separation.
TERMINAL STUDIES
Macroscopic pathology
No effects were seen that were considered related to exposure to THT.
Organ weights:
A minimal increase in the liver weights of female rats from Group 4 (High dose THT) achieved statistically significant separation from control values. However, this change was considered not of toxicological significance.
No other differences were seen that were considered related to exposure to THT.
Microscopic pathology:
Inhalation of THT by rats under the conditions of this study did not produce any observable treatment-related histopathological changes.
- Treatment-related changes
No histopathological changes were observed in any of the tissues examined that were considered to be related to treatment with THT.
- Incidental changes
The small number of minor histopathological changes observed in occasional tissues were within the background range normally observed in rats of this strain and age and were considered to be of no toxicological significance. - Key result
- Dose descriptor:
- NOAEC
- Remarks:
- systemic toxicity
- Effect level:
- >= 1 442 ppm (analytical)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: (5201 mg/m3)
- Remarks on result:
- not determinable due to absence of adverse toxic effects
- Key result
- Dose descriptor:
- NOAEC
- Remarks:
- local irritation
- Effect level:
- 51 ppm (analytical)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- clinical signs
- other: (184 mg/m3)
- Key result
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 236 ppm (analytical)
- System:
- eye
- Organ:
- lacrimal gland
- Treatment related:
- yes
- Dose response relationship:
- yes
- Relevant for humans:
- yes
- Conclusions:
- Clinical signs indicative of mild local irritation were seen at 236 and 1442 ppm. These signs were not apparent between exposures and not related to any macro-or microscopic abnormalities.
Lacrimation and salivation occurred also once at the lowest concentration of 51 ppm However, this seems not significant due to the low frequency.
The amount of water consumed by male and female rats exposed at 1442 ppm and by male rats exposed at 236 ppm was significantly higher than control values but whithout any effects on blood chemistry, urinalysis and the histophatology of kidneys.
There were no other toxicologically significant effects at levels of exposure up to 1442 ppm.
The no effect level for clinical signs of irritation is 51 ppm.
The no effect level for sytemic toxicity is higher than 1442 ppm. - Executive summary:
Ten male and ten female Sprague-Dawley rats were whole-body exposed to analytical concentrations of 0, 51, 236 and 1442 ppm (184, 852 or 5201 mg/m3) tetrahydrothiophene (purity > 99%), six hours per day, five days per week for 13 weeks (Hardy, 1988). The study was performed according to the good laboratory practice and the OECD Test Guideline 413. The clinical symptoms of irritation (lacrimation, salivation, eyes closed) are a cluster of symptoms seen with increasing concentration. From 236 ppm, there was a more frequent occurrence of irritative symptoms (eyes closed). The significance of the symptoms of "licking the inside mouth and "shake his head" is unclear and questionable. The animals of the 1442 ppm group and the males of 236 ppm group drank more water than the animals in the control group. Ophthalmological examinations were unremarkable. In females of the 236 and 1442 ppm groups, the hematological parameters showed small differences compared to the control animals, but these changes were considered as not toxicologically significant, excepted an increase of white blood cells and lymphocytes at 1442 ppm. There was also a slight, not toxicologically significant increase in pH urine in females at 1442 ppm. Macroscopic examination and the determination of organ weights provided no abnormal findings. A minimal increase in liver weights was observed in females exposed to 1442 ppm but this effect was not considered toxicologically relevant. Histopathological examinations was performed on the lungs of all animals and on some other tissues of the control and 1442 ppm group animals. This included tissues from the nasal cavity (rostral and caudal). No histopathological changes were observed in any of the tissues examined that were considered to be related to treatment with THT. Free blood in sinuses was observed in one male animal of the 1442 ppm group and sinusoidal free blood in one female of the control group. These changes were considered as random. The NOAEC for the local irritation was 51 ppm (184 mg/m3) based on the clinical signs observed during exposure and the NOAEC for systemic effect was higher than 1442 ppm (5201 mg/m3).
Reference
Bodyweights - group means (g)
Group.and dosage |
||||||||
Week |
- |
|||||||
Male |
Female |
|||||||
Air Control |
Low dose THT |
Int.dose THT |
High dose THT |
Air Control |
Low dose THT |
Int.dose THT |
High dose THT |
|
Pre-dose |
||||||||
-1 |
201 |
202 |
199 |
203 |
157 |
156 |
159 |
157 |
Dosing 0 |
263 |
261 |
254 |
258 |
181 |
176 |
179 |
184 |
1 |
304 |
304 |
290 |
294 |
200 |
191 |
194 |
196 |
2 |
340 |
341 |
323 |
329 |
217 |
204 |
209 |
214 |
3 |
370 |
371 |
353 |
360 |
232 |
216* |
223* |
226* |
4 |
400 |
397 |
377 |
392 |
247 |
225* |
234* |
237* |
5 |
417 |
415 |
393 |
410 |
251 |
232* |
237* |
243* |
6 |
447 |
439 |
414 |
436 |
262 |
239* |
249* |
251* |
7 |
465 |
459 |
435 |
456 |
267 |
246* |
253* |
255* |
8 |
483 |
477 |
451 |
472 |
275 |
253* |
259* |
261* |
9 |
502 |
491 |
467 |
488 |
280 |
258* |
265* |
267* |
10 |
518 |
506 |
481 |
507 |
286 |
264* |
271* |
273* |
11 |
531 |
519 |
498 |
523 |
291 |
270 |
280 |
278 |
12 |
541 |
527 |
511 |
536 |
296 |
271* |
277* |
281* |
13 |
544 |
529 |
509 |
536 |
292 |
269* |
275* |
279* |
Gain -1 to 13 |
324 |
327 |
310 |
334 |
135 |
113* |
115* |
123* |
* P<0.05 compared with control values using Williams' test
Water consumption - group mean cumulative values (g)
Group and dosage |
||||||||
Week |
Male |
Female |
||||||
Air Control |
Low dose THT |
Int. dose THT |
High dose THT |
Air Control |
Low dose THT |
Int. dose THT |
High dose THT |
|
Dosing 3 |
202 |
207 |
228 |
281** |
169 |
178 |
166 |
222* |
4 |
403 |
409 |
458 |
569** |
334 |
356 |
340 |
438* |
5 |
617 |
620 |
689 |
860** |
491 |
543 |
507 |
666* |
6 |
836 |
827 |
922 |
1146** |
655 |
719 |
684 |
900* |
7 |
1047 |
1030 |
1153 |
1436** |
816 |
901 |
850 |
1130** |
8 |
1252 |
1228 |
1388 |
1728** |
976 |
1079 |
1017 |
1355* |
9 |
1460 |
1433 |
1629 |
2015** |
1127 |
1262 |
1195 |
1584* |
10 |
1664 |
1638 |
1879 |
2320** |
1285 |
1453 |
1377 |
1811* |
11 |
1867 |
1839 |
2127 |
2617** |
1441 |
1636 |
1580 |
2027* |
12 |
2062 |
2036 |
2374* |
2908** |
1587 |
1804 |
1759 |
2246* |
13 |
2251 |
2230 |
2598* |
3166** |
1728 |
1983 |
1924 |
2437* |
* P<0.05 compared with control data using Williams' test
** P<0.01 compared with control data using Williams' test
(Haematology – Female) Week 5
Group |
PCV % |
Hb g/dl |
RBC Xl06/ mm3 |
MCHC % |
MCV fl |
MCH pg |
Retic % |
WBC + Diff x103/mm3 |
Plts x103/ mm3 |
TT s |
||||||
Total |
N |
L |
E |
B |
M |
|||||||||||
Air Control |
48 |
17.2 |
7.9 |
35.6 |
62 |
21.9 |
9.5 |
1.30 |
8.08 |
0.11 |
0.00 |
0.03 |
1077 |
25 |
||
Low dose THT |
48 |
16.8 |
7.6 |
35.4 |
62 |
22.0 |
11.5 |
1.47 |
10.01 |
0.04 |
0.00 |
0.00 |
1013 |
24 |
||
Int.dose THT |
50 |
17.5 |
7.8 |
35.3 |
64** |
22.4 |
10.6 |
0.62 |
9.95 |
0.07 |
0.00 |
0.00 |
1055 |
23 |
||
High dose THT |
50 |
17.6 |
7.7 |
35.1* |
65** |
22.9** |
15.2* |
1.47 |
13.58* |
0.14 |
0.00 |
0.05 |
1005 |
23 |
(Haematology - female) Week 13
Group |
PCV % |
Hb g/dl |
RBC x106/ mm3 |
MCHC % |
MCV fl |
MCH pg |
Retic % |
WBC + Diff x103/mm3 |
Plts x103/ mm3 |
TT s |
||||||
Total |
N |
L |
E |
B |
M |
|||||||||||
Air Control |
#48 |
#14.8 |
#7.3 |
30.8 |
66 |
20.3 |
7.9 |
1.12 |
6.70 |
0.05 |
0.00 |
0.01 |
839 |
20 |
||
Low dose THT |
48 |
14.9 |
7.2 |
31.0 |
67 |
20.6 |
9.4 |
1.12 |
8.15 |
0.09 |
0.00 |
0.00 |
820 |
21 |
||
Int.dose THT |
49 |
14.8 |
7.2 |
30.4 |
68 |
20.7 |
9.4 |
0.96 |
8.29 |
0.09 |
0.00 |
0.01 |
924 |
20 |
||
High dose THT |
49 |
15.1 |
7.2 |
30.7 |
68* |
21.0** |
12.7** |
1.28 |
11.31** |
0.05 |
0.00 |
0.07 |
847 |
20 |
* P<0.05 compared with control data using Williams' test; ** P<0.01
# Distribution-free analysis applied to data F Frequency analysis applied to data
Endpoint conclusion
- Endpoint conclusion:
- adverse effect observed
- Dose descriptor:
- NOAEC
- 184 mg/m³
- Study duration:
- subchronic
- Species:
- rat
- Quality of whole database:
- Key study
Repeated dose toxicity: dermal - systemic effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: dermal - local effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Additional information
Justification for classification or non-classification
According to the available data and the criteria of Regulation (EC) No 1272-2008, no classification is warranted for repeated dose toxicity.
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