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EC number: 225-207-5 | CAS number: 4717-96-8
- 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
Repeated dose toxicity: oral
Administrative data
- Endpoint:
- short-term repeated dose toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 2009-10-22 to 2010-01-14
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 010
- Report date:
- 2010
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
- Version / remarks:
- 2008
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- Tetrahydro-4-methyl-2H-pyran
- EC Number:
- 225-207-5
- EC Name:
- Tetrahydro-4-methyl-2H-pyran
- Cas Number:
- 4717-96-8
- Molecular formula:
- C6H12O
- IUPAC Name:
- 4-methyltetrahydro-2H-pyran
- Test material form:
- liquid
Constituent 1
- Specific details on test material used for the study:
- SOURCE OF TEST MATERIAL
- Chemical name: 4-methyltetrahydropyran (MTHP)
- CAS no.: 4717-96-8
- EC-no.: not assigned
- Source and lot/batch No.of test material: Kuraray / MTHP213536
- Expiration date of the lot/batch: not stated
- Molecular weight: 100.16 g/mol
- Purity: 100%
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Details on species / strain selection:
- refer to "Details on test animals and environmental conditions"
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- Age: 6 weeks at dosing
Weight at dosing: M: 188-214g; F: 151-174g
Source: Charles River Laboratories Japan, Inc.
Acclimation period: 8 days
Diet: Pelleted diet CR-1 (Oriental Yeast Co., Ltd), ad libitum
Water: Municipal water supply, ad libitum
Housing: individually
Environmental conditions
Temperature: 20-24°C
Humidity: 30-70%
Air changes: 10-15 times/hr
Photoperiod: 12 hours light/dark
Administration / exposure
- Route of administration:
- oral: gavage
- Details on route of administration:
- Refer to "Details on study design"
- Vehicle:
- other: 0.1% v/v Tween-80 supplemented with 1%w/v Na CMC
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS:
Test doses were prepared weekly. Refer to "Details on analytical verification of dose or concentrations"
VEHICLE: 0.1% v/v Tween-80 supplemented with 1%w/v Na CMC
- Justification for use and choice of vehicle (if other than water):
- Concentration in vehicle: dose suspension of MTHP in vehicle were preapred at 3, 12 and 50 mg/mL
- Amount of vehicle (if gavage): dose volume 10 mL/kg bg
- Lot/batch no.:
- Vehicle component 1: Carboxymethyl cellulose sodium (Na CMC); lot/batch no.: WKK2269
- Vehicle component 2: Water for injection; lot/batch no.: 9E70
- Vehicle component 3: Tween 80; lot/batch no.: ZBT2C - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Test doses were prepared weekly. Test article was weighed and suspended in 0.1% v/v Tween-80 supplemented with 1%w/v Na CMC. The sponsor confirmed that the test article was stable in the chosen vehicle at concentrations 0.1 and 100 mg/mL when stored at room temperature or refrigerated for 7 days.
The test dose suspensions perpared in weeks 1 and 4 of administration were analysed for concetration and homogeneity. - Duration of treatment / exposure:
- 28 days, with a further 6 animals/sex for the control and high dose group included for recovery purposes, with a 2 week withdrawal at the end of the administration period
- Frequency of treatment:
- daily
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- Remarks:
- 0.1% v/v Tween-80 supplemented with 1%w/v Na CMC
- Dose / conc.:
- 30 mg/kg bw/day (nominal)
- Dose / conc.:
- 120 mg/kg bw/day (nominal)
- Dose / conc.:
- 500 mg/kg bw/day (nominal)
- No. of animals per sex per dose:
- 6/sex/gp
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- After an acclimatisation period of ca. 8 days, rats were screened for ill health, weighed and allocated to treatment four groups of 6 animals/sex according to a randomised block design. A further 6 animals/sex for the control and high dose group were included for recovery purposes, with a 2 week withdrawal at the end of the administration period to examine any potential reversible effects. The test article was administered orally via gavage at concentrations of 0, 30, 120 or 500 mg/kg bw/day, employing a dose volume of 10 mL/kg bw. Six animals/sex/group were sacrificed at day 29.
Dose level selection was based on a range-finder experiment where 3 animals/sex were administered the test article orally via gavage at concentrations of 0, 15, 60, 250, 1000 mg/kg bw/d for 14 days. At doses of 1000 mg/kg bw/d decreased group-mean body weight and anesthetic effects in males and emaciation immediately before death and anesthetic effects in females were observed. Therefore, 500 mg/kg bw/d was deemed to be the maximum tolerated dose (MTD). - Positive control:
- n/a
Examinations
- Observations and examinations performed and frequency:
- Examined for clinical signs including external appearance, nutritional condition, posture, behaviour and excretment before dosing, immediately after and approximately 2 h post dosing. On the day of functional examinations (week 4 of dosing and once during the recovery period) observation frequency was reduced to twice daily (before and immediately post dosing). Recovery animals were examined once daily during the recovery period
- Sacrifice and pathology:
- - Gross pathology: All external features and orifices were examined visually. The cranial roof was removed to allow observation of the brain, pituitary gland and cranial nerves. After ventral mid-line incision, the neck and associated tissues and the thoracic, abdominal and pelvic cavities and their viscera were exposed and examined in situ.
- Histopathology: the following tissues were examined from all control and high dose group animals, with the liver examined from all low and mid dose groups:
adrenals, brain (cerebrum, cerebellum), epididymides, eyeballs, femur (+ bone marrow), gastrointestinal tract (stomach, duodenum, jejunum, ileum (+Peyer's patch), caecum, colon, rectum), heart, kidneys, liver, lungs (+bronchus), lymph nodes (submandibular, mesenteric), mammary glands (inguinal region), ovaries, pituitary, prostate, sciatic nerve, seminal vesicles (+coagulating gland), skeletal muscle (femoral), skin (inguinal region), spinal cord (together with vertebra in the thoracic region), spleen, sternum (+bone marrow), testes, thymus, thyroid (+parathyroid), trachea, uterus (+cervix), urinary bladder, vagina
The following tissues were collected, preserved and not examined: aorta (thoracic), Harderian glands, oesphagus, optic nerves, pancreas, salivary glands (submandibular, sublingual) - Other examinations:
- Refer to "Any other information on materials and methods incl. tables"
- Statistics:
- Bartlett's test (to determine homogeneity of variance between groups). If variances were homogenous, data were analysed by the Dunnett test, whereas heterogenous data were analysed by the Dunnett-type mean tank test between the control group and each dose level.
For the recovery groups, homogeneity of variance was tested for each group by the F-test. For homogenous data, the difference in the mean values between the control and treatment groups were analysed by the Student's t-test. Heterogenous data were analysed by the Aspin-Welch t-test
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- In the high dose group (500 mg/kg bw/d), decreased motor activity was observed early on in males from day 1 (M: 2/12) ; females from on day 2 and 3 (F: 2/12). By day 2 and day 4 for males and females, respectively all animals showed no abnormalities.
- Mortality:
- no mortality observed
- Description (incidence):
- No test article related effects on mortality were observed
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- No test article related effect on body weight or body weight gain were observed over the entire treatment period including the recovery period.
- Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- No test article related effects on food consumption were observed.
- Food efficiency:
- not examined
- Description (incidence and severity):
- n/a
- Water consumption and compound intake (if drinking water study):
- effects observed, treatment-related
- Description (incidence and severity):
- High water intake in high dose females. Refer to "Urinalysis findings" for further details
- Ophthalmological findings:
- not examined
- Description (incidence and severity):
- Not conducted.
- Haematological findings:
- no effects observed
- Description (incidence and severity):
- No test article related effects on haematological parameters were observed.
In the recovery group, high dose group males showed a statistically significant lower value in mean haemoglobin concentration and females showed a statistically significant lower value in white blood cell count. High dose males showed a statistically significant increase in monocytes when expressed as a percentage; whilst females showed a statistically significant reduction in large unstained cells (expressed both as a percentage and actual number).
The haematological changes in the recovery group were considered to be incidental and not treatment related as the changes observed were minimal, were not consistent between both sexes and were not evident at the end of treatment (refer to "Any other information on results incl. tables" Table CA 7.5.1/01-1). - Clinical biochemistry findings:
- no effects observed
- Description (incidence and severity):
- No test article related effects on serum chemistry parameters were observed
- Urinalysis findings:
- effects observed, treatment-related
- Description (incidence and severity):
- A high water intake and low urine osmolality were observed in females in the 500 mg/kg bw/d gp in the wk 4 administration. No such effects were observed in the recovery group. It therefore can be concluded that reversibility of the changes after withdrawal of administration was observed (refer to "Any other information on results incl. tables" Table CA 7.5.1/01-2)
- Behaviour (functional findings):
- effects observed, non-treatment-related
- Description (incidence and severity):
- In the detailed clinical observsations, functional examinations and grip strength there were no treatement related effects observed.
- Immunological findings:
- not examined
- Description (incidence and severity):
- n/a
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- A statistically significant increase in relative liver and kidney weights were observed in high dose males only at the end of treatment. These changes were not observed after withdrawal of treatment. Histopathological changes were observed in the liver only.
High dose males in the recovery group exhibited statistically significant decreases in absolute brain and seminal vesicle weights. These were not reflected when organ weights were corrected for body weights. The marginal reduction in absolute weights of these organs were considered incidental and not treatment related as they were: i) minimal; ii) only evident in the recovery period; iii) not replicated in females (where relevant); iv) no associated histopathology (refer to "Any other information on results incl. tables" Table CA 7.5.1/01-3) - Gross pathological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- End of administration period:
- Dark red foci in the lungs (2M control, 1M mid and 2M high dose gp)
- Dysplasia of the spleen (1M in the mid dose gp)
- Diverticulum in the ileum (1F control gp)
Recovery period:
- Dark red focus in the eyeballs (1F control gp)
- Small testes (1M high dose gp)
The gross pathological changes were sporadically, and deemed to not be treatment related based on incidence, lack of dose response and no associated histopathology - Neuropathological findings:
- no effects observed
- Description (incidence and severity):
- No central or peripheral nervous system histopathological changes observed.
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- Refer to Table CA 5.7.1/01-4.
Hypertrophy of centrilobular hepatocytes (graded as minimal) was observed in 5/6 and 2/6 high dose males and females, respectively, with no effect observed in the respective concurrent control groups. Hypertrophy of centrilobular hepatocytes were not observed in the recovery group. Liver effects that were observed in treated animals in the recovery group (hepatocyte vacuolation in the periportal region) occurred with the same frequency in both concurrent control groups and test article treated animals, and therefore was not considered treatment related.
Tubular regeneration (graded minimal) was observed in high dose males (3/6), however this observation was also observed in 5/6 male control animals, and therefore was not considered treatment related. Tubular regeneration was not observed in either control or test article treated females. The kidney was not examined in recovery animals.
Other histopathological changes were considered not treatment related based on incidence and lack of dose response. - Histopathological findings: neoplastic:
- not examined
- Description (incidence and severity):
- n/a
- Other effects:
- effects observed, treatment-related
- Description (incidence and severity):
- Motor activity:
Some inter-group variation was noted during the motor activity investigations (refer to Table CA 5.7.1/01-5). Main differences included:
- Low values were recorded at 40 – 50 and 50 – 60 minutes after the start of measurement and the total value from 0 – 60 minutes after the start of measurement in males in the high dose group in week 4 of administration. These low values were not replicated in the recovery group, and whilst there is evidence of treatment related effects, no associated peripheral or central nervous system histopathology was evident.
- High values in the measurement was recorded at 10 – 20 minutes after the start of measurement in males and a low value in the measurement recorded at 0 – 10 minutes after the start of measurement in females in the low dose group. These changes were judged to be incidental as they were minimal changes and there were no similar changes in the high dose group.
- High dose group females showed high values in the measurement values at 40 – 50 minutes and 50 – 60 minutes and in the total value from 0 – 60 minutes. These changes were however deemed to be incidental as they were slight and also observed in the control group.
Effect levels
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- ca. 120 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- clinical signs
- histopathology: non-neoplastic
- organ weights and organ / body weight ratios
- urinalysis
Target system / organ toxicity
- Key result
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 500 mg/kg bw/day (nominal)
- System:
- hepatobiliary
- Organ:
- liver
- Treatment related:
- yes
- Dose response relationship:
- yes
- Relevant for humans:
- yes
Any other information on results incl. tables
Table
CA 7.5.1/01-1:
Overview of 28-day repeat dose toxicity in rats treated orally (via gavage)
with MTHP: selected serum haematology parameters (group mean values)
Parameters |
Sample Time |
/m (mg/kg bw/d) |
F (mg/kg bw/d) |
|||||||
0 |
30 |
120 |
500 |
0 |
30 |
120 |
500 |
|||
Haematology |
||||||||||
- MCHC (g/dL) |
ET |
34.8 |
34.8 |
34.8 |
34.8 |
36.0 |
35.7 |
35.4 |
35.9 |
|
- WBC (x102/uL) |
ET |
96.7 |
95.0 |
120.4 |
93.4 |
105.4 |
87.3 |
84.4 |
85.1 |
|
Selected differential leukocyte counts expressed as a % |
||||||||||
Monocytes (%) |
ET |
1.8 |
1.8 |
2.0 |
1.7 |
1.5 |
1.2 |
1.5 |
1.4 |
|
LUC (%) |
ET |
1.5 |
1.0 |
1.0 |
1.0 |
1.2 |
0.9 |
0.9 |
1.0 |
|
Selected differential leukocyte counts expressed as a conc. (x102/uL) |
||||||||||
Monocytes (x102/uL) |
ET |
1.8 |
1.7 |
2.5 |
1.6 |
1.7 |
1.0 |
1.3 |
1.2 |
|
LUC (x102/uL) |
ET |
1.5 |
0.9 |
1.2 |
1.0 |
1.3 |
0.8 |
0.8 |
0.8 |
|
*p=0.05 ER: end of recovery (wk 6, i.e. 2 wks post dosing) |
MCHC: Mean cell haemoglobin concentration WBC: white blood cells LUC: large unstained cells |
|||||||||
Table
CA 7.5.1/01-2:
Overview of 28-day repeat dose toxicity in rats treated orally (via gavage)
with MTHP: selected urinalysis parameters (group mean values)
Parameters |
Sample Time |
M (mg/kg bw/d) |
F (mg/kg bw/d) |
|||||||
0 |
30 |
120 |
500 |
0 |
30 |
120 |
500 |
|||
Water intake |
ET |
34 |
35 |
36 |
39 |
28 |
28 |
29 |
34* |
|
Urine vol. (mL/24h) |
ET |
11.0 |
8.8 |
10.4 |
13.8 |
7.6 |
7.7 |
7.0 |
9.7 |
|
Osmolality (mOsm/kg) |
ET |
1983 |
2150 |
2074 |
1697 |
2191 |
1975 |
2052 |
1727* |
|
|
|
|||||||||
Table
CA 7.5.1/01-3:
Overview of 28-day repeat dose toxicity in rats treated orally (via gavage)
with MTHP: selected organ weights (group mean values)
Parameters |
M (mg/kg bw/d) |
F (mg/kg bw/d) |
|||||||
0 |
30 |
120 |
500 |
0 |
30 |
120 |
500 |
||
End of administration (wk 4) |
|||||||||
Ter. body wt (g) |
369 |
368 |
353 |
338 |
225 |
221 |
223 |
226 |
|
Organ weights (rel: g%; abs: g) |
|||||||||
- Liver: abs |
10.93 |
11.20 |
10.13 |
11.34 |
6.57 |
6.37 |
6.42 |
6.98 |
|
- Kid: abs |
2.75 |
2.75 |
2.70 |
2.80 |
1.76 |
1.66 |
1.73 |
1.84 |
|
- Brain: abs |
1.98 |
1.98 |
1.96 |
1.93 |
1.86 |
1.84 |
1.86 |
1.80 |
|
- S.V: abs |
2.08 |
2.21 |
2.22 |
1.97 |
- |
- |
- |
- |
|
End of recovery (wk 6, i.e. 2 wks post dosing) |
|||||||||
Ter. body wt (g) |
438 |
- |
- |
421 |
246 |
- |
- |
238 |
|
- Liver: abs |
11.70 |
- |
- |
11.92 |
6.61 |
- |
- |
6.57 |
|
- Kid: abs |
2.95 |
- |
- |
2.91 |
1.74 |
- |
- |
1.75 |
|
- Brain: abs |
2.11 |
- |
- |
2.02** |
1.87 |
- |
- |
1.88 |
|
- S.V: abs |
2.84 |
- |
- |
2.48* |
- |
- |
- |
- |
|
*p=0.05; **p=0.01 |
rel: relative |
||||||||
Table
CA 7.5.1/01-4:
Overview of 28-day repeat dose toxicity in rats treated orally (via gavage)
with MTHP: Non-neoplastic histopathological findings
Parameters |
M (mg/kg bw/d) |
F (mg/kg bw/d) |
|||||||
0 |
30 |
120 |
500 |
0 |
30 |
120 |
500 |
||
Liver(incidence / total no. examined [minimal) |
|||||||||
-Cen. hep. hyper. |
0/6 |
0/6 |
0/6 |
5/6 |
0/6 |
0/6 |
0/6 |
2/6 |
|
Kidney(incidence / total no. examined [minimal) |
|||||||||
-Reg, tubul. |
5/6 |
0/6 |
0/6 |
3/6 |
0/6 |
0/6 |
0/6 |
0/6 |
|
Cen. hep. hyper.: Centrilobular hepatocyte hypertrophy |
Reg. tubul.: regeneration, tubular |
||||||||
Table
CA 5.7.1/02-5:
Overview of 28-day repeat dose toxicity in rats treated orally (via gavage)
with MTHP: locomotor activity – mean beam break scores
Dose level (mg/kg bw/d) |
Time (minutes) |
|||||||
0-10 |
10-20 |
20-30 |
30-40 |
40-50 |
50-60 |
Total |
||
Males: end of administration (wk 4) |
||||||||
0 |
426 |
357 |
349 |
330 |
330 |
318 |
2110 |
|
30 |
432 |
403** |
348 |
383 |
406 |
392 |
2364 |
|
120 |
432 |
386 |
347 |
353 |
328 |
301 |
2147 |
|
500 |
421 |
385 |
332 |
281 |
183** |
61** |
1864** |
|
Females: end of administration (wk 4) |
||||||||
0 |
418 |
364 |
270 |
277 |
211 |
222 |
1761 |
|
30 |
378* |
313 |
247 |
236 |
241 |
295 |
1709 |
|
120 |
396 |
342 |
324 |
302 |
312 |
298 |
1972 |
|
500 |
439 |
371 |
320 |
327 |
335* |
288* |
2080* |
|
Males: end of recovery (wk 6, i.e. 2 wks post dosing) |
||||||||
0 |
422 |
356 |
321 |
313 |
319 |
285 |
2016 |
|
500 |
410 |
365 |
326 |
340 |
305 |
277 |
2022 |
|
Females: end of recovery (wk 6, i.e. 2 wks post dosing) |
||||||||
0 |
385 |
307 |
234 |
276 |
272 |
190 |
1664 |
|
500 |
403 |
323 |
298 |
290 |
262 |
240 |
1815 |
|
*p=0.05; *p=0.01 |
|
|||||||
Applicant's summary and conclusion
- Conclusions:
- Under the conditions of this study, NOAEL for MTHP was 120 mg/kg bw/day following dosing for 28-daysviaoral gavage for males and females based on increased relative liver weights (exceeding 110% of control), with associated histopathology (minimal hypertrophy of centrilobular hepatocyte). High dose males also showed increased relative kidney weight, without any associated histopathology and reduced motor activity (without associated histopathology), with high dose group females showinga significant increase in water intake, with significantly reduced urine osmolality. These effects were all reversible following withdrawal of administration.
- Executive summary:
In a 28-day sub-acute study, MTHP was administered orally via gavage to male and female rats at dose levels of 0, 30, 120 or 500 mg/kg bw/day, employing a dose volume of 10 mL/kg. Group sizes were 6 animals/sex, with a further 6 animals/sex/ group for control and high dose groups in order to assess recovery following withdrawal of treatment.
In addition to standard parameters measured (body weight, food consumption, blood haematology, clinical chemistry, urinalysis), a neurobehavioral test battery consisting of motor activity, functional observational battery (FOB) and detailed clinical observations were conducted on all rats onstudy week 4 of administration and in week 2 of recovery. At termination, all control and high dose animals were subjected to animals were subjected to histopathological examination including brain, spinal cord and sciatic nerve. The liver was examined from all low and mid dose groups.
There were no test article-related clinical findings noted at any exposure level.Overall (week 0-4) bodyweight gain was low vs.controls (11%) for high dose males. These differences from control were most apparent from ca. day 4 of treatment, but did not achieve statistical significance. These effects were not carried through to the recovery group.
No test article-related effects were noted on FOB parameters, including home cage, handling, open field, sensory, neuromuscular, and physiological observations, in the all test article treated dose groups during the study. Low motor activities were recorded for high dose males at 40-50 and 50-60 minutes after the start of measurement and the total value from 0-60 minutes after the start of measure in the week 4 administration. No associated histopathology was evident in the central or peripheral nervous system and there were no changes in week 2 of recovery.
A slight, but statistically significant increase in water intake, with significantly reduced urine osmolality was observed in high dose group females.
Hypertrophy of centrilobular hepatocytes (graded as minimal) was observed in 5/6 and 2/6 high dose males and females, respectively, with no effect observed in the respective concurrent control groups. Hypertrophy of centrilobular hepatocytes were not observed in the recovery group. Liver effects that were observed in treated animals in the recovery group (hepatocyte vacuolation in the periportal region) occurred with the same frequency in both concurrent control groups and test article treated animals, and therefore was not considered treatment related.
Tubular regeneration (graded minimal) was observed in high dose males (3/6), however this observation was also observed in 5/6 male control animals, and therefore was not considered treatment related. Tubular regeneration was not observed in either control or test article treated females. The kidney was not examined in recovery animals.
Under the conditions of this study, NOAEL for MTHP was 120 mg/kg bw/day following dosing for 28-days via oral gavage for males and females based on increased relative liver weights (exceeding 110% of control), with associated histopathology (minimal hypertrophy of centrilobular hepatocyte). High dose males also showed increased relative kidney weight, without any associated histopathology and reduced motor activity (without associated histopathology), with high dose group females showinga significant increase in water intake, with significantly reduced urine osmolality. These effects were all reversible following withdrawal of administration.
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