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EC number: 203-794-9 | CAS number: 110-71-4
Repeated dose toxicity: oral
Administrative data
- Endpoint:
- sub-chronic toxicity: oral
- Type of information:
- other: read across based on metabolism
- Adequacy of study:
- key study
- Study period:
- 21 March - 21 October 1988
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Well performed guideline study with minor restrictions in reporting.
Data source
Reference
- Reference Type:
- publication
- Title:
- Unnamed
- Year:
- 1 993
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- 2-methoxyethanol
- EC Number:
- 203-713-7
- EC Name:
- 2-methoxyethanol
- Cas Number:
- 109-86-4
- IUPAC Name:
- 2-methoxyethanol
- Reference substance name:
- 203-86-4
- IUPAC Name:
- 203-86-4
- Details on test material:
- - Name of test material (as cited in study report): 2-Methoxyethanol
- Molecular formula (if other than submission substance): C3H8O2
obtained from Kodak Laboratory Chemicales (NY, USA)
Lot: E16
Puritiy: 98%
Constituent 1
Constituent 2
Test animals
- Species:
- rat
- Strain:
- other: F344/N
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Taconic Farms (Germantown, NY)
- Age at study initiation: 5-7 weeks
- Weight at study initiation: males: 167-172g females: 132-134 g
- Housing: five per polycarbonate cages lined with heat-treated hardwood chips and covered with polyester fiber cage top filters
- Diet (e.g. ad libitum): NIH-07 open Formula Pellets ad libitum
- Water (e.g. ad libitum): drinking water solution of 2-Methoxyethanol at target doses ad libitum
- Acclimation period: 1-2 weeks
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 15.6-25°C
- Humidity (%): 20-70%
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: From: 21.03.1988 To: 21.10.1988
Administration / exposure
- Route of administration:
- oral: drinking water
- Vehicle:
- water
- Details on oral exposure:
- Dose formulations were prepared by mixing the appropriate amount of 2-Methoxyethanol with deionized water to achieve the desired concentrations. Dose formulations were prepared as needed and used within 3 weeks of preparation.
For the 2-week study target doses were established based on published data on the acute and short-term toxicity of 2-Methoyethanol. Drinking water solutions of the test item were formulated at concentrations estimated to deliver the target doses. These concentrations were changed during the second week to account for changes in drinking water consumption and weight gain.
Stability studies showed that doses of 20,000 ppm 2-Methoxyethanol were stable for up to 3 weeks when stored in the dark at 5°C. 2-Methoxyethanol dosed water stored in rhodent drinking bottles was also found to be stable for at least 4 days. Dose fromulations were stored in the dark at 4 +/- 3°C. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Identity and purity analyses were conducted on 2-Methoyethanol at Midwest Research Institute (MRI; MO, USA).
The following analytical methods were used:
- infrared, ultraviolet/visible spectroscopy
- nuclear magnetic resonance spectroscopy
- elemental analysis
- potentiometric titration
- functional group titration
- gas chromatography
Results of all dose formulation analyses were within 10% of theoretical concentrations. - Duration of treatment / exposure:
- Study a: 2 weeks continuously
Study b: 13 weeks continuously - Frequency of treatment:
- continuously; drinking water study
Doses / concentrationsopen allclose all
- Remarks:
- Doses / Concentrations:
200 mg/kg bw/d (study a)
Basis:
actual ingested
- Remarks:
- Doses / Concentrations:
400 mg/kg bw/d (study a)
Basis:
actual ingested
- Remarks:
- Doses / Concentrations:
600 mg/kg bw/d (study a)
Basis:
actual ingested
- Remarks:
- Doses / Concentrations:
1000 mg/kg bw/d (study a)
Basis:
actual ingested
- Remarks:
- Doses / Concentrations:
1200 mg/kg bw/d (study a)
Basis:
actual ingested
- No. of animals per sex per dose:
- Study a: 5
Study b: 10
Doses study b:
750, 1500, 3000, 4500 and 6000 ppm - Control animals:
- yes, concurrent vehicle
- Details on study design:
- Study a:
In the 2-week study groups of 5 rats per sex and dose level were administered 2-Methoxyethanol in drinking water available ad libitum. Doses were chosen due to literature data obtained from acute and subacute studies. Animals were observed twice daily and were weighed at the start, at the end of week 1 and at necropsy. Water consumption by cage was measured two times per week. Complete necropsies and histopathologic examination on those organs showing evidence of lesions were performed on all animals at study termination.
Study b:
In the 2-week study groups of 10 rats per sex and dose level were administered 2-Methoxyethanol in drinking water available ad libitum. Dosages are based on the results of the 2-week study. Animals were observed for mortality and clinical signs. Urinalysis, haematology, clinical biochemistry and examination of sperm morphology/vaginal cytology were performed. Animals were weighed weekly. Water consumption by cage was measured two times per week. Complete necropsies and histopathologic examination were performed on all animals at study termination. - Positive control:
- None
Examinations
- Observations and examinations performed and frequency:
- Study a:
- clinical signs: twice daily
- water consumption: twice weekly
- body weight: weekly
Study b:
- clinical signs: twice daily
- water consumption: twice weekly
- body weight: weekly
- haematology: days 5 and 21, week 13
- clinical biochemistry: days 5 and 21, week 13
- sperm morphology: at necropsy
- vaginal cytology: determination of estrus cycle - Sacrifice and pathology:
- Study a:
- complete necropsy of all animals
- microscopical examination of organs showing gross lesions
Study b:
- complete necropsy of all animals
- microscopical examination of all tissues of control animals and animals in the highest dose group with at least 60% survivors and all animals in the higher dose groups - Other examinations:
- no data
- Statistics:
- Analysis of continuous variables:
parametric multiple comparisons procedures of Williams or Dunnett, nonparametric multiple comparisons methods of Shirley or Dunn, Jonckheer's test, ourlier test of Dixon and Massey
Analysis of vaginal cytology data:
multivariate analysis of Variance (Morrison)
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, treatment-related
- Mortality:
- mortality observed, treatment-related
- Body weight and weight changes:
- effects observed, treatment-related
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- 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:
- effects observed, treatment-related
- Urinalysis findings:
- effects observed, treatment-related
- Behaviour (functional findings):
- no effects observed
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Gross pathological findings:
- effects observed, treatment-related
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Histopathological findings: neoplastic:
- no effects observed
- Details on results:
- Study a:
No rats died or were killed before the end of the study. The final mean body weights and mean body weights gains of males and females receiving target doses of 600, 1000 or 1200 mg/kg bw/d were notably lower than those of the control group. Dose-related decreases in mean water consumption were noted for male and female rats. Dehydration, abnormal posture, and thin appearance were noted for males treated with the two highest concentrations (1000 and 1200 mg/kg bw/d) and all females in the three highest dose groups (600, 1000 and 1200 mg/kg bw/d) were dehydrated. Abnormal posture and thin appearance were observed in all females in the two highest dose groups (1000 and 1200 mg/kg bw/d), and all females receving the highest dose (1200 mg/kg bw/d) were emaciated by the end of the study. Most changes in absolute and relative organ weights were related to low body weights, excluding changes in thymus and testis weights. Absolute and relative thymus weights decreased in a dose-related fashion for males and females as did absolute and relative testis weights for males. Chemical-related gross lesions were present only in rats in the 1000 and 1200 mg/kg bw/d dose groups. Gross lesions were observed in the forestomach and mesentric lymph nodes of male and female rats receiving 1200 mg/kg bw/d and in females receving 1000 mg/kg bw/d. Microscopic changes in the forestomach that corresponded to the gross lesions included hemorrhage and edema of the mucosa and focal necrosis and ulceration of the squamous epithelium. Mild hyperplasia of the fore stomach squamous mucosa was also present and was generally associated with the focal areas of necrosis or ulceration. Sinusoidal congestion, hemorrhage, and erythrophagocytosis were present in the mesentric lymph nodes, which appeared enlarged or reddened at necropsy. In addition the chemical-related gross lesions, the testis and epididymis from all doses and control rats were examined microscopically. Degeneration was clearly present in the testis of male rats in all but the lowest dose group (200 mg/kg bw/d). This degeneration consisted of moderate to marked loss of germinal epithelium and the presence of multinucleated spermatid giant cells and cell debris in the lumen of seminiferous tubules. In male rats in the three highest dose groups (600, 1000 and 1200 mg/kg bw/d), the lumen of the epididymis contained necrotic cells and cell debris and only a few spermatozoa. Degeneration was of mild severity at the targeted 400 mg/kg bw/d dose level and in one of five rats administered the lowest dose (200 mg/kg bw/d), there was minimal degeneration of the testes.
Study b:
Please refer to "Remarks on results"
Effect levels
open allclose all
- Dose descriptor:
- NOAEL
- Effect level:
- 200 mg/kg bw/day (actual dose received)
- Sex:
- male
- Basis for effect level:
- other: based on testes degeneration (2 weeks drinking water study)
- Dose descriptor:
- NOEL
- Effect level:
- 400 mg/kg bw/day (actual dose received)
- Sex:
- female
- Basis for effect level:
- other: based on dehydration, thin appearance and abnormal posture (2 weeks drinking water study)
- Dose descriptor:
- NOAEL
- Effect level:
- < 750 ppm
- Sex:
- male
- Basis for effect level:
- other: based on testicular degeneration in males and decreased thymus weight in males and females (13 weeks drinking water study)
Target system / organ toxicity
- Critical effects observed:
- not specified
Any other information on results incl. tables
Results of Study b:
Eight males and five females in the 4500 ppm group and all males and females in the 6000 ppm grooup did or were killed prior to scheduled termination.The final mean body weights for males and females receiving 1500 to 4500 ppm were notably lower than values for the control group. Body weight analyses were not performed for males or females in the 6000 ppm group due to 100% mortality. Decreaes in mean water consumtion were noted for males and females in the 3000 and 6000 ppm group as well as for females in the 1500 ppm group. For male and female rats, clinical signs of toxicity considered to be chemical related included tremors, emaciation, abnormal posture, pallor, tachypnea, hypoactivity and comatose state.
At week 1 in the hematologic evaluations, mild anemia, moderate leukopenia, and moderate thrombocytopenia were present in male rats in the higher dose groups. These animals had decreases in hematocrit (HCT) and hemoglobin (HGB) concentrations and in erythrocyte (RBC), platelet, and total leukocyte counts. The anemia was normocytic (no change in mean cell volume), normochromic ( no chenge in mean cell hemoglobin concentration), and poorly regenerative (indicated by a decrease in reticulocyte count). Leukopenia was produced by decreases in neutrophils and lymphocytes. There were moderate decreases in bone marrow cellularity counts in the rats in the higher dose groups. At weeks 3 and 13, the anemia was moderate, progressive, normocytic, and normochromic, with inadequate regeneration (lymphopenia and neutropenia) and thrombocytopenia were present at each time point, and bone marrow cellularity counts were decreased in male rats in the higher dose groups at week 13.
Changes in clinical chemistry variables at the various time points for male rats included decreases in creatinine, total protein, albumin, and alkaline phosphatase (AP) (all consistent with decreased food intake) and mild increases in concentrations of bile acids at weeks 1 and 13.
At week1, female rats had a mild normochromic, poorly regenerative anemia. At weeks 3 and 13, the anemia remained mild but, unlike that in male rats, was slightly microcytic (weeks 1 and 13). Reticulocyte counts were unchanged in the presence of anemia at weeks 1 and 13. Moderate thrombocytopenia and leukopenia (lymphopenia and neutropenia) occured at all time points in numerous dose groups. Bone marro cellularity was decreased by treatment at weeks 1 and 3 but was unchanged at week 13.
Clinical chemistry effects in female rats included decreases in AP activity and total protein and albumin concentrations in numerous dose groups at all time points. These findings are consistent with the decreased feed consumption of these animals. Additionally, there were mild increases in concnetraions of bile acids in multiple dose groups at weeks 1 and 3.
For males and females, treatment-related parameters consisted of decreases in urine volume and increases in specific gravitiy. With the exception of changes in thymus and testis weights, changes in absolute and relative organ weights could be attributed to low final mean body weights. Dose-related decreases were noted for the absolute and relative testis weights of male rats and the absolute thymus weightss of male and female rats.
Almost all observed gross lesions were considered to be secondary to the marked reduction in bosy weight gain and the overall smaller size of rats administered the higher exposure concentrations. The only gross lesion attributed directly to the toxicity of 2 -Methoxyethanol was a reduction in testis size in males at concentraions of 1500 ppm and greater.
Histopathological changes in the testis consitisted of a minimal to marked degeneration of germinal epithelium in the seminiferous tubules; in more severely affected rats, the atrophic seminiferous tubules contained only Sertoli cels and a few spermatogonia. The presence of cell debris and a decrease in sperm within the lumen of the epididymis were associated with these changes. Degeneration was present at all dose levels but was only minimal in 7 of 10 rats in the 750 ppm group.
Additionally, a chemical-related fibrosis of the splenic capsule was present in male and female rats and was most prominent in animals in the 1500 to 4500 ppm groups. This fibrosis was characterised by focal areas in which there was thickening of the splenic capsule by fibrous connective tissue and a minimal mixed inflammatory cell infiltrate; inflammation and fibrosis of the serosal surfaces of other abdominal organs did not occur.
Other micoscopical changes were associated with the marked reduction in body weight gain or stress-related physiological changes typically seen in animals that die during study or are killed moribund. Specifically, these changes included atrophy of the clitoral/preputial glands, uterus, ovary, salivary glands, and prostate. Atrophic changes included not only an overall reduction in the size of the organs but a depletion of secretory product in the lumen of glands, decreased height of the secretory epithelium, and an increased number of degenerative and apototic cells. Lymphoid depletion (atrophy) in lymph nodes, thymus and spleen, bone marrow depletion, absence of metaphyseal bone growth, focal erosion/ulcerations of the glandular stomach, and focal proliferation of bacterial or fungal organisms were also seen in animals that died or were killed moribund during the study; these lesions were considered to be secondary to the marked generalized toxicity and reduction in body weight gain seen in the 4500 and 6000 ppm groups.
Sperm morphology evaluations were performed on male rats treated with 0, 750, 1500 or 3000 ppm, and vaginal cytology evaluations were performed on female rats treated with 0, 1500, 3000 or 4500 ppm. Tesicular and epididymal weight were significantly lower than control values for males receiving 1500 or 3000 ppm. Also, spermatozoal measurements were significantly decreased for males in the two highest dose groups (1500 or 3000 ppm). There were no significant differences from control in estrous cycle length for females treated with 2 -Methoxyethanol. However, there was evidence to suggest that animals in the 1500 and 3000 ppm groups differed from the control animals in the relative frequency of time spent in estrous stages. The lack of significance at the 4500 ppm dose level may have been due to increased variability and/or the small sample size.
Applicant's summary and conclusion
- Conclusions:
- The daily intake of 200 to 1200 mg/kg bw/d 2-Methoxyethanol over a 2 week period via drinking water led to the degenration of the testis in male rats at 400 mg/kg bw/d and clinical signs (dehydration, thin apearance, abnormal posture) in female rats at 600 mg/kg bw/d. Therefore, the NOEL (2 weeks, males) is considered to be 200 mg/kg bw/d and the NOEL (2 weeks, females) 400 mg/kg bw/d.
The daily intake of 750 to 6000 ppm 2-Methoxyethanol over a 13 weeks period via drinking resulted in testicular degenration in male rats and reduced thymus weights in all rats at all dosages. The NOAEL is considered to be lower than 750 ppm. - Executive summary:
There is a strong evidence in literature that Ethyleneglycoldimethylether is metabolised to 2-Methoxyethanol. Therefore, a read across to the 2 and 13-week drinking water study study with 2 -Methoxyethanol in mice was conducted.
The animals were treated with 0, 200, 400, 600, 1000 or 1200 mg/kg bw/d 2 -Methoxyethanol for 2 weeks or with 0, 750, 1500, 3000, 4500 or 6000 ppm 2 -Methoxyethanol for 13 weeks via drinking water.
2 weeks study:
No rats died or were killed before the end of the study. The final mean body weights and mean body weights gains of males and females receiving target doses of 600, 1000 or 1200 mg/kg bw/d were notably lower than those of the control group. Dose-related decreases in mean water consumption were noted for male and female rats. Dehydration, abnormal posture, and thin appearance were noted for males treated with the two highest concentrations (1000 and 1200 mg/kg bw/d) and all females in the three highest dose groups (600, 1000 and 1200 mg/kg bw/d) were dehydrated. Abnormal posture and thin appearance were observed in all females in the two highest dose groups (1000 and 1200 mg/kg bw/d), and all females receving the highest dose (1200 mg/kg bw/d) were emaciated by the end of the study. Most changes in absolute and relative organ weights were related to low body weights, excluding changes in thymus and testis weights. Absolute and relative thymus weights decreased in a dose-related fashion for males and females as did absolute and relative testis weights for males. Chemical-related gross lesions were present only in rats in the 1000 and 1200 mg/kg bw/d dose groups. Gross lesions were observed in the forestomach and mesentric lymph nodes of male and female rats receiving 1200 mg/kg bw/d and in females receving 1000 mg/kg bw/d. Microscopic changes in the forestomach that corresponded to the gross lesions included hemorrhage and edema of the mucosa and focal necrosis and ulceration of the squamous epithelium. Mild hyperplasia of the fore stomach squamous mucosa was also present and was generally associated with the focal areas of necrosis or ulceration. Sinusoidal congestion, hemorrhage, and erythrophagocytosis were present in the mesentric lymph nodes, which appeared enlarged or reddened at necropsy. In addition the chemical-related gross lesions, the testis and epididymis from all doses and control rats were examined microscopically. Degeneration was clearly present in the testis of male rats in all but the lowest dose group (200 mg/kg bw/d). This degeneration consisted of moderate to marked loss of germinal epithelium and the presence of multinucleated spermatid giant cells and cell debris in the lumen of seminiferous tubules. In male rats in the three highest dose groups (600, 1000 and 1200 mg/kg bw/d), the lumen of the epididymis contained necrotic cells and cell debris and only a few spermatozoa. Degeneration was of mild severity at the targeted 400 mg/kg bw/d dose level and in one of five rats administered the lowest dose (200 mg/kg bw/d), there was minimal degeneration of the testes.
13 weeks study:
Eight males and five females in the 4500 ppm group and all males and females in the 6000 ppm grooup did or were killed prior to scheduled termination.The final mean body weights for males and females receiving 1500 to 4500 ppm were notably lower than values for the control group. Body weight analyses were not performed for males or females in the 6000 ppm group due to 100% mortality. Decreaes in mean water consumtion were noted for males and females in the 3000 and 6000 ppm group as well as for females in the 1500 ppm group. For male and female rats, clinical signs of toxicity considered to be chemical related included tremors, emaciation, abnormal posture, pallor, tachypnea, hypoactivity and comatose state.
At week 1 in the hematologic evaluations, mild anemia, moderate leukopenia, and moderate thrombocytopenia were present in male rats in the higher dose groups. These animals had decreases in hematocrit (HCT) and hemoglobin (HGB) concentrations and in erythrocyte (RBC), platelet, and total leukocyte counts. The anemia was normocytic (no change in mean cell volume), normochromic ( no chenge in mean cell hemoglobin concentration), and poorly regenerative (indicated by a decrease in reticulocyte count). Leukopenia was produced by decreases in neutrophils and lymphocytes. There were moderate decreases in bone marrow cellularity counts in the rats in the higher dose groups. At weeks 3 and 13, the anemia was moderate, progressive, normocytic, and normochromic, with inadequate regeneration (lymphopenia and neutropenia) and thrombocytopenia were present at each time point, and bone marrow cellularity counts were decreased in male rats in the higher dose groups at week 13.
Changes in clinical chemistry variables at the various time points for male rats included decreases in creatinine, total protein, albumin, and alkaline phosphatase (AP) (all consistent with decreased food intake) and mild increases in concentrations of bile acids at weeks 1 and 13.
At week1, female rats had a mild normochromic, poorly regenerative anemia. At weeks 3 and 13, the anemia remained mild but, unlike that in male rats, was slightly microcytic (weeks 1 and 13). Reticulocyte counts were unchanged in the presence of anemia at weeks 1 and 13. Moderate thrombocytopenia and leukopenia (lymphopenia and neutropenia) occured at all time points in numerous dose groups. Bone marro cellularity was decreased by treatment at weeks 1 and 3 but was unchanged at week 13.
Clinical chemistry effects in female rats included decreases in AP activity and total protein and albumin concentrations in numerous dose groups at all time points. These findings are consistent with the decreased feed consumption of these animals. Additionally, there were mild increases in concnetraions of bile acids in multiple dose groups at weeks 1 and 3.
For males and females, treatment-related parameters consisted of decreases in urine volume and increases in specific gravitiy. With the exception of changes in thymus and testis weights, changes in absolute and relative organ weights could be attributed to low final mean body weights. Dose-related decreases were noted for the absolute and relative testis weights of male rats and the absolute thymus weightss of male and female rats.
Almost all observed gross lesions were considered to be secondary to the marked reduction in bosy weight gain and the overall smaller size of rats administered the higher exposure concentrations. The only gross lesion attributed directly to the toxicity of 2 -Methoxyethanol was a reduction in testis size in males at concentraions of 1500 ppm and greater.
Histopathological changes in the testis consitisted of a minimal to marked degeneration of germinal epithelium in the seminiferous tubules; in more severely affected rats, the atrophic seminiferous tubules contained only Sertoli cels and a few spermatogonia. The presence of cell debris and a decrease in sperm within the lumen of the epididymis were associated with these changes. Degeneration was present at all dose levels but was only minimal in 7 of 10 rats in the 750 ppm group.
Additionally, a chemical-related fibrosis of the splenic capsule was present in male and female rats and was most prominent in animals in the 1500 to 4500 ppm groups. This fibrosis was characterised by focal areas in which there was thickening of the splenic capsule by fibrous connective tissue and a minimal mixed inflammatory cell infiltrate; inflammation and fibrosis of the serosal surfaces of other abdominal organs did not occur.
Other micoscopical changes were associated with the marked reduction in body weight gain or stress-related physiological changes typically seen in animals that die during study or are killed moribund. Specifically, these changes included atrophy of the clitoral/preputial glands, uterus, ovary, salivary glands, and prostate. Atrophic changes included not only an overall reduction in the size of the organs but a depletion of secretory product in the lumen of glands, decreased height of the secretory epithelium, and an increased number of degenerative and apototic cells. Lymphoid depletion (atrophy) in lymph nodes, thymus and spleen, bone marrow depletion, absence of metaphyseal bone growth, focal erosion/ulcerations of the glandular stomach, and focal proliferation of bacterial or fungal organisms were also seen in animals that died or were killed moribund during the study; these lesions were considered to be secondary to the marked generalized toxicity and reduction in body weight gain seen in the 4500 and 6000 ppm groups.
Sperm morphology evaluations were performed on male rats treated with 0, 750, 1500 or 3000 ppm, and vaginal cytology evaluations were performed on female rats treated with 0, 1500, 3000 or 4500 ppm. Tesicular and epididymal weight were significantly lower than control values for males receiving 1500 or 3000 ppm. Also, spermatozoal measurements were significantly decreased for males in the two highest dose groups (1500 or 3000 ppm). There were no significant differences from control in estrous cycle length for females treated with 2 -Methoxyethanol. However, there was evidence to suggest that animals in the 1500 and 3000 ppm groups differed from the control animals in the relative frequency of time spent in estrous stages. The lack of significance at the 4500 ppm dose level may have been due to increased variability and/or the small sample size.
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