Registration Dossier
Registration Dossier
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EC number: 224-644-9 | CAS number: 4435-53-4
Repeated dose toxicity: inhalation
Administrative data
- Endpoint:
- sub-chronic toxicity: inhalation
- Remarks:
- As a result of technological difficulties in formulation due to volatility of the test substance, the subchronic toxicity test in rats have to be done via inhalation.
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 2020-2021
- Reliability:
- 1 (reliable without restriction)
- Justification for type of information:
- In the Decision on a Compliance Check (dated December 11, 2018) ECHA requested a subchronic toxicity (90-days) oral route OECD 408 in rats. However, because of technological difficulties in formulation due to volatility of the test substance, the subchronic toxicity test in rats was done via inhalation.
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 021
- Report date:
- 2021
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 413 (90-Day (Subchronic) Inhalation Toxicity Study
- GLP compliance:
- yes (incl. QA statement)
Test material
- Reference substance name:
- 3-methoxybutyl acetate
- EC Number:
- 224-644-9
- EC Name:
- 3-methoxybutyl acetate
- Cas Number:
- 4435-53-4
- Molecular formula:
- C7H14O3
- IUPAC Name:
- 3-methoxybutyl acetate
- Reference substance name:
- butoxyl
- IUPAC Name:
- butoxyl
Constituent 1
Constituent 2
- Specific details on test material used for the study:
- Solvent: 3-methoxy butyl acetate (also known as Butoxyl®)
Lot Number: 120001260103
Storage Conditions: Room temperature
Purity: 99.9%
Correction Factor: 1.0
Expiry Date: 28 October 2020
Test animals
- Species:
- rat
- Strain:
- other: Crl:CD(SD)IGS Rats
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- Age: Approximately 6 to 7 weeks at receipt; approximately 8 to 9 weeks (and no more than 10 weeks) at initiation of dosing. Note: Females will be nulliparous and non-pregnant.
Weight: Males: approximately 250 to 290 grams at first exposure. Females: approximately 180 to 220 grams at first exposure.
Light/Dark Cycle: Twelve-hour light/dark cycle provided via automatic timer.
Temperature: it will be monitored in accordance with Testing Facility’s SOPs to ensure that the desired range of 20 to 26 C is maintained to the maximum extent possible.
Humidity: it will be monitored in accordance with Testing Facility’s SOPs to ensure that the desired range of 30 to 70% is maintained to the maximum extent possible.
Administration / exposure
- Route of administration:
- inhalation: vapour
- Type of inhalation exposure:
- nose only
- Vehicle:
- air
- Details on inhalation exposure:
- Route: Inhalation - nose only vapor exposure.
Control: Air only.
Training for dosing: The animals on study were acclimated to the method of restraint, over a 3 day period immediately preceding the first test item exposure. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- • No 3-Methoxybutyl Acetate was detected in Group 1 samples (0 mg/L)
• Mean achieved concentration for Group 2 was on target (0.6 mg/L)
• Mean achieved concentration for Groups 3 and 4 were 5% (1.90 mg/L ) and 3% (5.83 mg/L) below target, respectively - Duration of treatment / exposure:
- Duration of daily exposure 6 hours (360 minutes) per day, 5 days per week for 13 weeks.
- Frequency of treatment:
- 5 days per week for 13 weeks.
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0.6 mg/L air (nominal)
- Dose / conc.:
- 2 mg/L air (nominal)
- Dose / conc.:
- 6 mg/L air (nominal)
- No. of animals per sex per dose:
- 10 males / 10 famales/ group
- Control animals:
- yes
- Details on study design:
- In the range finding inhalation toxicity study (Covance study 8442-349), rats were exposed to the test item for up to 6 hours per day, for 5 days per week, for 2 weeks at 0.2, 0.6, and 2.0 mg/L. Results to be added by amendment. On the basis of the range finding study, exposure levels will be selected to provide a range of effects.
- Positive control:
- no
Results and discussion
Results of examinations
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- There were no test item-related changes for clinical observations during or following the exposures. (Table 1. Signs - group total distribution of observations)
- Mortality:
- no mortality observed
- Description (incidence):
- All study animals survived to their scheduled necropsy.
- Body weight and weight changes:
- effects observed, non-treatment-related
- Description (incidence and severity):
- There were no adverse test item-related changes for male body weights during the study. However, there was a statistically significant (p≤0.05) lower body weight in the high exposure level males, but not in the mid exposure level males, at the end of the study. In addition, there were statistically significant decreases in body weight gains seen in the mid exposure level males (18% at end of exposures) and in the high exposure level males (22% at end of exposures). While these decreases in male body weight gains were likely treatment-related at the mid exposure level and clearly treatment-related at the high exposure level, they were not considered adverse since the mid exposure level animals had no statistically significant effects on body weight, compared to controls, and the high exposure level animals gained weight throughout the study. Also, the general health of the animals as well as their health as evaluated by terminal clinical pathology and anatomic pathology (see later discussions) was consistently not affected.
There were no statistically significant or biologically relevant changes in body weights or body weight gains in the females at any exposure level. At the end of treatment, females at the high exposure level had lower body weights (16%) than the females in the control group (not statistically significant), but the high exposure level females also had lower body weights (7%) at the start of the study. See tables in: "Any other information on results incl. tables" - Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- There were no adverse test item-related changes for food consumption during the study.
However, significant decreases in food consumption were seen at 1.90 mg/L in the males (up to 10%) and at 5.83 mg/L in both sexes (up to 15% for males and 13% for females) and correlated with the effects on body weights discussed above. See tables in: "Overall remarks, attachments" - Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- no effects observed
- Description (incidence and severity):
- There were no test item-related changes for ocular observations at end of 13 weeks of exposures. See Tables in: "Overall remarks, attachments"
- Haematological findings:
- no effects observed
- Description (incidence and severity):
- There were no 3-Methoxybutyl Acetate-related effects on hematology test results.
All differences in hematology test results, statistically significant or not, between control and 3-Methoxybutyl Acetate-treated animals were consistent with normal variation and considered incidental. Most or all of the following characterized these differences: small magnitude, lack of dose relationship, and/or the absence of correlative findings.
There were no 3-Methoxybutyl Acetate-related effects on coagulation test results.
All differences in coagulation test results, statistically significant or not, between control and 3-Methoxybutyl Acetate-treated animals were consistent with normal variation and considered incidental. Most or all of the following characterized these differences: small magnitude, lack of dose relationship, and/or the absence of correlative findings. - Clinical biochemistry findings:
- no effects observed
- Description (incidence and severity):
- 3-Methoxybutyl Acetate-related effects on clinical chemistry test results included minimal decreases in glucose and minimal increases in phosphorus in males at exposures of 2.0 and 6.0 mg/L and females at exposures of 6.0 mg/L; and minimal to mild decreases in triglycerides in females at exposures of 2.0 and 6.0 mg/L and males at exposures of
6.0 mg/L. All of these changes were considered non-adverse due to their relatively small magnitude.
All other differences in clinical chemistry test results, statistically significant or not, between control and 3-Methoxybutyl Acetate-treated animals were consistent with normal variation and considered incidental. Most or all of the following characterized these differences: small magnitude, lack of dose relationship, and/or the absence of correlative findings.
All other differences in clinical chemistry test results, statistically significant or not, between control and 3-Methoxybutyl Acetate-treated animals were consistent with normal variation and considered incidental. Most or all of the following characterized these differences: small magnitude, lack of dose relationship, and/or the absence of correlative findings. - Endocrine findings:
- not examined
- Urinalysis findings:
- no effects observed
- Behaviour (functional findings):
- no effects observed
- Description (incidence and severity):
- There were no test item-related changes for Functional Observational Battery at end of 13 weeks of exposures.
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Description (incidence and severity):
- No test item-related effects were noted on organ weight parameters.
All differences in organ weight parameters, statistically significant or not, were consistent with normal variation and considered incidental. These differences were characterized by one or more of the following: inconsistency between sexes; presence only in absolute weight or in relative (to body or brain weight) ratios but not both; lack of a dose relationship or correlative findings; and/or the magnitude was considered small. - Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- Macroscopic observations: No test item-related macroscopic findings were observed in animals administered ≥0.6 mg/L of 3-methoxy butyl acetate. All macroscopic findings were considered spontaneous and/or incidental because they occurred at a low incidence, were randomly distributed across groups (including concurrent controls), and/or were as expected for this species/strain and age; therefore, they were considered not test article related.
- Neuropathological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- There were a few statistically significant differences between treated animals and control animals, listed below, however the differences were not consistent with any adverse test item-related changes at end of 13 weeks of exposures.
Horizontal Males There were no statistically significant differences between the 3-Methoxybutyl Acetate treated groups and the vehicle control group. Females The 3-Methoxybutyl Acetate at 6.0 mg/L group had significantly decreased motor activity compared to control during interval 11 (p=0.012, Williams’ test).
Vertical Males
The 3-Methoxybutyl Acetate at 6.0 mg/L group had significantly decreased motor activity compared to control during interval 1 (p=0.017, Williams’ test).
Females
The 3-Methoxybutyl Acetate at 6.0 mg/L group had significantly decreased motor activity compared to control during interval 3 (p=0.034, Williams’ test). - Histopathological findings: non-neoplastic:
- no effects observed
- Description (incidence and severity):
- All differences in organ weight parameters, statistically significant or not, were consistent with normal variation and considered incidental. These differences were characterized by one or more of the following: inconsistency between sexes; presence only in absolute weight or in relative (to body or brain weight) ratios but not both; lack of a dose relationship or correlative findings; and/or the magnitude was considered small.
No test item-related macroscopic findings were observed in animals administered
≥0.6 mg/L of 3-methoxy butyl acetate.
No test item-related microscopic findings were observed in animals administered
6.0 mg/L of 3-methoxy butyl acetate.
Bronchoalveolar Lavage (BAL) Fluid Results: 3-Methoxybutyl Acetate-related effects on BAL test results included minimal increases in macrophage percentages and decreases in neutrophil percentages in males at all exposure levels. These changes were considered non-adverse due to their relatively small magnitude.
All other differences in BAL test results, statistically significant or not, between control and 3-Methoxybutyl Acetate-treated animals were consistent with normal variation and considered incidental. Most or all of the following characterized these differences: small magnitude, lack of dose relationship, and/or the absence of correlative findings.
Macroscopic observations: No test item-related macroscopic findings were observed in animals administered ≥0.6 mg/L of 3-methoxy butyl acetate. All macroscopic findings were considered spontaneous and/or incidental because they occurred at a low incidence, were randomly distributed across groups (including concurrent controls), and/or were as expected for this species/strain and age; therefore, they were considered not test article related.
Microscopic examination: No test item-related microscopic findings were observed in animals administered 6.0 mg/L of 3-methoxy butyl acetate. All microscopic findings were considered spontaneous and/or incidental because they occurred at a low incidence, were randomly distributed across groups (including concurrent controls), and/or similarity to background pathology of this strain of rats (McInnes, 2012); therefore, they were considered not test article-related. - Histopathological findings: neoplastic:
- no effects observed
- Description (incidence and severity):
- Macroscopic observations: No test item-related macroscopic findings were observed in animals administered ≥0.6 mg/L of 3-methoxy butyl acetate. All macroscopic findings were considered spontaneous and/or incidental because they occurred at a low incidence, were randomly distributed across groups (including concurrent controls), and/or were as expected for this species/strain and age; therefore, they were considered not test article related.
Microscopic examination: No test item-related microscopic findings were observed in animals administered 6.0 mg/L of 3-methoxy butyl acetate. All microscopic findings were considered spontaneous and/or incidental because they occurred at a low incidence, were randomly distributed across groups (including concurrent controls), and/or similarity to background pathology of this strain of rats (McInnes, 2012); therefore, they were considered not test article-related. - Other effects:
- no effects observed
- Description (incidence and severity):
- No test item-related macroscopic findings were observed in animals administered
≥0.6 mg/L of 3-methoxy butyl acetate.
No test item-related microscopic findings were observed in animals administered 6.0 mg/L of 3-methoxy butyl acetate. - Details on results:
- No test item-related macroscopic findings were observed in animals administered
≥0.6 mg/L of 3-methoxy butyl acetate.
No test item-related microscopic findings were observed in animals administered 6.0 mg/L of 3-methoxy butyl acetate.
Effect levels
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- >= 6 mg/L air
- Based on:
- test mat.
- Basis for effect level:
- body weight and weight gain
- Remarks on result:
- other: No-Observed-Adverse-Effect-Level (NOAEL) for male rats exposed to 3-methoxybutyl acetate is 2 mg/L and the Lowest-Observed-Adverse-Effect-Level (LOAEL) is 6 mg/L. The highest dose tested of 6 mg/L is the NOAEL for female rats.
Target system / organ toxicity
- Key result
- Critical effects observed:
- no
- Organ:
- other: no adverse effects
Any other information on results incl. tables
Body weight - group mean values (g) MALES Continue | |||||||||||||
Group/Sex |
| Day |
| Day | Day | Day | Day | Day | Day | Day | Day | Day | Day |
(mg/L) |
| Ra8 | Ra14 | 1 | 4 | 8 | 11 | 15 | 18 | 22 | 25 | 29 | 32 |
Statistics | test | Av | Av | Wi | Wi | Wi | Wi | Wi | Wi | Wi | Wi | Wi | Wi |
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Group 1/M | Mean | 206 | 256 | 264 | 278 | 298 | 310 | 334 | 345 | 367 | 372 | 393 | 403 |
Air Control | SD | 14.5 | 18.3 | 18.7 | 21.6 | 23.6 | 24.8 | 28.6 | 32.1 | 36.4 | 40.5 | 45.1 | 47.6 |
| N | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 |
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Group 2/M | Mean | 201 | 253 | 259 | 272 | 295 | 305 | 325 | 337 | 355 | 361 | 377 | 385 |
(0.6) | SD | 12.4 | 18.7 | 19.9 | 21.6 | 26.2 | 27.4 | 32.4 | 36.0 | 38.5 | 38.3 | 39.8 | 41.7 |
| N | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 |
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Group 3/M | Mean | 202 | 252 | 259 | 271 | 294 | 302 | 323 | 332 | 350 | 353 | 370 | 375 |
(2.0) | SD | 6.2 | 10.4 | 9.6 | 10.4 | 13.6 | 14.9 | 17.5 | 22.4 | 23.3 | 24.8 | 25.1 | 25.9 |
| N | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 |
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Group 4/M | Mean | 204 | 256 | 260 | 271 | 293 | 303 | 323 | 331 | 350 | 353 | 371 | 376 |
(6.0) | SD | 10.7 | 14.8 | 14.5 | 15.7 | 18.1 | 19.0 | 22.2 | 24.6 | 29.0 | 30.1 | 32.6 | 34.1 |
| N | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 |
*Statistically significant (p<0.05); ** Statistically significant (p<0.01) | |||||||||||||
Body weight - group mean values (g) MALES | |||||||||||||
Group/Sex |
| Day | Day | Day | Day | Day | Day | Day | Day | Day | Day |
| Change |
(mg/L) |
| 36 | 39 | 43 | 46 | 50 | 57 | 64 | 71 | 78 | 85 |
| 1-4 |
Statistics | test | Wi | Wi | Wi | Wi | Wi | Wi | Wi | Wi | Wi | Wi |
| Wi |
Group 1/M | Mean | 418 | 413 | 435 | 433 | 452 | 468 | 482 | 492 | 503 | 513 |
| 14 |
Air Control | SD | 49.7 | 51.9 | 55.7 | 56.5 | 57.9 | 61.7 | 64.4 | 65.5 | 67.7 | 68.3 |
| 5.9 |
| N | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 |
| 10 |
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Group 2/M | Mean | 398 | 394 | 413 | 410 | 429 | 443 | 453 | 461 | 466 | 480 |
| 13 |
(0.6) | SD | 43.1 | 42.6 | 46.6 | 45.4 | 48.0 | 50.9 | 52.5 | 51.4 | 52.4 | 53.1 |
| 3.9 |
| N | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 |
| 10 |
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Group 3/M | Mean | 383 | 380 | 399 | 396 | 412 | 426 | 438 | 451 | 456 | 464 |
| 12 |
(2.0) | SD | 32.1 | 29.3 | 30.9 | 32.3 | 35.4 | 41.4 | 41.7 | 41.0 | 42.6 | 43.2 |
| 3.0 |
| N | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 |
| 10 |
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Group 4/M | Mean | 387 | 382 | 399 | 395 | 412 | 422 | 430* | 436* | 442* | 455* |
| 11 |
(6.0) | SD | 34.9 | 34.0 | 35.7 | 35.0 | 35.6 | 38.9 | 39.1 | 37.1 | 39.5 | 42.6 |
| 5.1 |
| N | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 |
| 10 |
*Statistically significant (p<0.05); ** Statistically significant (p<0.01) | |||||||||||||
Body weight - group mean values (g) MALES Continue | |||||||||||||
Group/Sex |
| Change | Change | Change | Change | Change | Change | Change | Change | Change | Change | Change | Change |
(mg/L) |
| 1-8 | 1-11 | 1-15 | 1-18 | 1-22 | 1-25 | 1-29 | 1-32 | 1-36 | 1-39 | 1-43 | 1-46 |
Statistics | test | Wi | Wi | Wi | Wi | Wi | Wi | Wi | Wi | Wi | Wi | Wi | Wi |
Group 1/M | Mean | 34 | 46 | 70 | 81 | 103 | 108 | 129 | 139 | 154 | 149 | 171 | 169 |
Air Control | SD | 6.2 | 14.7 | 15.1 | 20.0 | 24.0 | 28.7 | 34.6 | 37.7 | 40.2 | 42.9 | 46.8 | 47.7 |
| N | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 |
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Group 2/M | Mean | 37 | 47 | 66 | 78 | 96 | 102 | 119 | 126 | 140 | 135 | 155 | 151 |
(0.6) | SD | 8.3 | 11.0 | 15.6 | 19.5 | 23.1 | 22.5 | 23.9 | 25.6 | 27.9 | 27.0 | 31.3 | 29.9 |
| N | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 |
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Group 3/M | Mean | 35 | 43 | 64 | 73 | 91 | 94 | 111 | 116 | 124 | 121 | 140 | 137 |
(2.0) | SD | 6.0 | 9.1 | 11.6 | 15.7 | 16.8 | 18.7 | 18.9 | 20.5 | 28.1 | 25.6 | 26.3 | 27.3 |
| N | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 |
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Group 4/M | Mean | 34 | 43 | 63 | 71 | 90 | 93 | 111 | 116 | 127 | 122 | 139 | 135* |
(6.0) | SD | 8.8 | 9.2 | 11.6 | 14.6 | 18.5 | 19.7 | 21.9 | 23.4 | 24.4 | 24.5 | 25.1 | 24.3 |
| N | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 |
*Statistically significant (p<0.05); ** Statistically significant (p<0.01) | |||||||||||||
Body weight - group mean values (g) MALES | |||||||
Group/Sex |
| Change | Change | Change | Change | Change | Change |
(mg/L) |
| 1-50 | 1-57 | 1-64 | 1-71 | 1-78 | 1-85 |
Statistics | test | Wi | Wi | Wi | Wi | Wi | Wi |
Group 1/M | Mean | 188 | 204 | 217 | 227 | 238 | 249 |
Air Control | SD | 48.8 | 51.5 | 54.7 | 55.1 | 57.5 | 58.1 |
| N | 10 | 10 | 10 | 10 | 10 | 10 |
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Group 2/M | Mean | 170 | 184 | 195 | 202 | 208 | 222 |
(0.6) | SD | 32.7 | 35.5 | 37.3 | 35.8 | 37.0 | 37.8 |
| N | 10 | 10 | 10 | 10 | 10 | 10 |
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Group 3/M | Mean | 153* | 167* | 179* | 192 | 197* | 205* |
(2.0) | SD | 30.2 | 36.1 | 37.0 | 36.0 | 37.3 | 37.3 |
| N | 10 | 10 | 10 | 10 | 10 | 10 |
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Group 4/M | Mean | 152* | 162* | 170* | 176** | 182** | 195** |
(6.0) | SD | 25.2 | 28.7 | 29.0 | 25.7 | 28.6 | 32.7 |
| N | 10 | 10 | 10 | 10 | 10 | 10 |
*Statistically significant (p<0.05); ** Statistically significant (p<0.01) | |||||||
Body weight - group mean values (g) FEMALES Continue | |||||||||||||
Group/Sex |
| Day |
| Day |
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(mg/L) |
| Ra8 | Ra14 | 1 | 4 | 8 | 11 | 15 | 18 | 22 | 25 | 29 | 32 |
Statistics | test | Av | Av | Wi | Wi | Wi | Wi | Wi | Wi | Wi | Wi | Wi | Wi |
Group 1/F | Mean | 194 | 217 | 216 | 221 | 230 | 230 | 236 | 235 | 242 | 241 | 251 | 253 |
Air Control | SD | 20.3 | 21.1 | 19.8 | 20.5 | 21.2 | 21.0 | 20.9 | 20.8 | 20.1 | 18.6 | 19.5 | 20.4 |
| N | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 |
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Group 2/F | Mean | 197 | 218 | 217 | 225 | 228 | 232 | 238 | 240 | 245 | 247 | 256 | 260 |
(0.6) | SD | 19.5 | 21.2 | 23.5 | 25.7 | 25.3 | 26.1 | 24.9 | 27.1 | 29.8 | 29.3 | 28.7 | 31.3 |
| N | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 |
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Group 3/F | Mean | 196 | 217 | 219 | 223 | 234 | 234 | 241 | 246 | 252 | 251 | 260 | 259 |
(2.0) | SD | 19.2 | 25.6 | 22.3 | 22.0 | 24.7 | 29.8 | 33.3 | 31.5 | 32.6 | 30.5 | 32.3 | 35.8 |
| N | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 |
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Group 4/F | Mean | 184 | 202 | 203 | 208 | 213 | 215 | 220 | 221 | 231 | 226 | 235 | 234 |
(6.0) | SD | 13.2 | 16.5 | 13.5 | 13.8 | 13.9 | 14.4 | 15.3 | 17.5 | 19.6 | 16.8 | 16.9 | 19.3 |
| N | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 |
Body weight - group mean values (g) FEMALES | |||||||||||||
Group/Sex |
| Day |
|
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| Change |
(mg/L) |
| 36 | 39 | 43 | 46 | 50 | 57 | 64 | 71 | 78 | 85 |
| 1-4 |
Statistics | test | Wi | Wi | Wi | Wi | Wi | Wi | Wi | Wi | Wi | Wi |
| Wi |
Group 1/F | Mean | 258 | 248 | 262 | 254 | 266 | 270 | 276 | 277 | 277 | 280 |
| 5 |
Air Control | SD | 20.3 | 21.0 | 21.5 | 19.3 | 20.7 | 22.4 | 23.3 | 22.5 | 24.7 | 24.3 |
| 4.4 |
| N | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 |
| 10 |
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Group 2/F | Mean | 263 | 259 | 268 | 264 | 275 | 278 | 282 | 288 | 289 | 288 |
| 7 |
(0.6) | SD | 31.8 | 31.0 | 29.6 | 32.3 | 35.4 | 31.1 | 32.0 | 32.6 | 33.6 | 30.0 |
| 6.1 |
| N | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 |
| 10 |
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Group 3/F | Mean | 264 | 260 | 273 | 270 | 278 | 281 | 286 | 290 | 291 | 293 |
| 4 |
(2.0) | SD | 34.3 | 35.9 | 41.3 | 38.5 | 38.2 | 43.3 | 43.3 | 44.9 | 46.8 | 45.8 |
| 3.3 |
| N | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 |
| 10 |
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Group 4/F | Mean | 240 | 234 | 243 | 236 | 246 | 250 | 252 | 258 | 256 | 258 |
| 5 |
(6.0) | SD | 18.0 | 20.4 | 18.9 | 20.5 | 20.2 | 19.3 | 18.1 | 20.2 | 21.6 | 20.9 |
| 5.2 |
| N | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 |
| 10 |
Body weight - group mean values (g) FEMALES | |||||||||||||
Group/Sex |
| Change | Change | Change | Change | Change | Change | Change | Change | Change | Change | Change | Change |
(mg/L) |
| 1-8 | 1-11 | 1-15 | 1-18 | 1-22 | 1-25 | 1-29 | 1-32 | 1-36 | 1-39 | 1-43 | 1-46 |
Statistics | test | Wi | Wi | Wi | Wi | Wi | Wi | Wi | Wi | Wi | Wi | lWi | Wi |
Group 1/F | Mean | 14 | 14 | 20 | 19 | 26 | 25 | 35 | 37 | 42 | 32 | 46 | 38 |
Air Control | SD | 6.2 | 5.6 | 8.1 | 7.0 | 6.4 | 8.7 | 8.6 | 10.0 | 9.6 | 10.5 | 10.8 | 9.4 |
| N | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 |
|
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Group 2/F | Mean | 11 | 14 | 20 | 23 | 28 | 30 | 39 | 42 | 46 | 42 | 50 | 47 |
(0.6) | SD | 6.2 | 7.0 | 8.9 | 6.9 | 9.2 | 8.9 | 8.9 | 11.2 | 12.3 | 12.0 | 9.2 | 14.0 |
| N | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 |
|
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Group 3/F | Mean | 15 | 15 | 22 | 27 | 33 | 32 | 41 | 40 | 45 | 41 | 54 | 51 |
(2.0) | SD | 4.3 | 9.8 | 14.7 | 13.3 | 15.0 | 12.8 | 15.5 | 18.9 | 18.2 | 18.3 | 24.1 | 20.8 |
| N | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 |
|
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|
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Group 4/F | Mean | 10 | 12 | 17 | 18 | 28 | 23 | 31 | 31 | 37 | 31 | 40 | 33 |
(6.0) | SD | 5.3 | 4.0 | 5.2 | 8.4 | 13.8 | 7.4 | 7.0 | 8.3 | 8.6 | 10.2 | 9.3 | 10.6 |
| N | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 |
Body weight - group mean values (g) FEMALES Continue | |||||||
Group/Sex |
| Change | Change | Change | Change | Change | Change |
(mg/L) |
| 1-50 | 1-57 | 1-64 | 1-71 | 1-78 | 1-85 |
Statistics | test | Wi | lWi | Wi | Wi | Wi | lWi |
Group 1/F | Mean | 50 | 55 | 60 | 61 | 61 | 64 |
Air Control) | SD | 8.6 | 11.6 | 12.9 | 12.3 | 14.6 | 13.7 |
| N | 10 | 10 | 10 | 10 | 10 | 10 |
|
|
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|
|
Group 2/F | Mean | 58 | 61 | 65 | 71 | 72 | 71 |
(0.6) | SD | 17.3 | 12.3 | 12.5 | 13.8 | 16.1 | 9.2 |
| N | 10 | 10 | 10 | 10 | 10 | 10 |
|
|
|
|
|
|
|
|
Group 3/F | Mean | 59 | 62 | 67 | 71 | 72 | 74 |
(2.0) | SD | 21.5 | 27.5 | 27.3 | 29.1 | 30.2 | 29.9 |
| N | 10 | 10 | 10 | 10 | 10 | 10 |
|
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Group 4/F | Mean | 43 | 47 | 49 | 55 | 53 | 54 |
(6.0) | SD | 10.9 | 10.5 | 10.8 | 15.0 | 12.8 | 12.2 |
| N | 10 | 10 | 10 | 10 | 10 | 10 |
Body weight change - group mean values (g) MALES Continue | |||||||||||||
Group/Sex |
| Day |
| Day |
|
|
|
|
|
|
|
|
|
(mg/L) |
| Ra8-Ra14 | Ra14-1 | 1-4 | 4-8 | 8-11 | 11-15 | 15-18 | 18-22 | 22-25 | 25-29 | 29-32 | 32-36 |
Statistics | test | Av | Wi | Wi | Wi | Sh | Wi | Wi | Wi | Wi | Wi | Wi | Sh |
Group 1/M | Mean | 50 | 8 | 14 | 20 | 12 | 24 | 11 | 22 | 5 | 21 | 10 | 15 |
Air Control | SD | 5.7 | 3.8 | 5.9 | 8.3 | 16.0 | 7.2 | 5.7 | 6.2 | 5.4 | 8.5 | 3.5 | 4.1 |
| N | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 |
|
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Group 2/M | Mean | 51 | 6 | 13 | 24 | 10 | 20 | 12 | 19 | 6 | 16 | 7 | 14 |
(0.6) | SD | 7.8 | 3.1 | 3.9 | 5.3 | 3.9 | 5.9 | 4.8 | 4.8 | 2.6 | 3.3 | 4.3 | 4.1 |
| N | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 |
|
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Group 3/M | Mean | 49 | 8 | 12 | 23 | 9 | 21 | 9 | 18 | 3 | 17 | 4 | 8 |
(2.0) | SD | 4.5 | 2.8 | 3.0 | 4.1 | 4.1 | 3.9 | 6.8 | 3.8 | 3.8 | 3.9 | 8.5 | 12.2 |
| N | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 |
|
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Group 4/M | Mean | 51 | 4** | 11 | 22 | 10 | 20 | 8 | 18 | 4 | 18 | 5 | 11* |
(6.0) | SD | 6.2 | 2.5 | 5.1 | 4.9 | 2.8 | 3.9 | 4.0 | 4.9 | 3.7 | 4.3 | 3.3 | 3.8 |
| N | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 |
*Statistically significant (p<0.05); ** Statistically significant (p<0.01) | |||||||||||||
Body weight change - group mean values (g) MALES | ||||||||||
Group/Sex |
| Day |
|
|
|
|
|
|
|
|
(mg/L) |
| 36-39 | 39-43 | 43-46 | 46-50 | 50-57 | 57-64 | 64-71 | 71-78 | 78-85 |
Statistics | test | Wi | Wi | Wi | Sh | Wi | Wi | Wi | Wi | Wi |
Group 1/M | Mean | -5 | 22 | -2 | 20 | 16 | 14 | 10 | 11 | 10 |
Air Control | SD | 3.7 | 4.8 | 3.6 | 4.1 | 7.0 | 6.0 | 7.3 | 6.5 | 6.4 |
| N | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 |
|
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Group 2/M | Mean | -5 | 20 | -3 | 19 | 14 | 11 | 8 | 5* | 14 |
(0.6) | SD | 4.1 | 6.7 | 3.5 | 5.0 | 4.6 | 3.6 | 4.2 | 2.1 | 4.0 |
| N | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 |
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Group 3/M | Mean | -3 | 19 | -3 | 16 | 14 | 12 | 12 | 5* | 8 |
(0.6) | SD | 6.4 | 7.5 | 6.3 | 7.6 | 10.6 | 4.6 | 4.5 | 5.9 | 4.5 |
| N | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 |
|
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Group 4/M | Mean | -4 | 17 | -4 | 17 | 10 | 8** | 6 | 7* | 13 |
(6.0) | SD | 4.2 | 3.9 | 3.6 | 2.0 | 5.9 | 4.5 | 7.3 | 5.8 | 9.6 |
| N | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 |
*Statistically significant (p<0.05); ** Statistically significant (p<0.01) | ||||||||||
Body weight change - group mean values (g) FEMALES Continue | |||||||||||||
Group/Sex |
| Day |
| Day |
|
|
|
|
|
|
|
|
|
(mg/L) |
| Ra8-Ra14 | Ra14-1 | 1-4 | 4-8 | 8-11 | 11-15 | 15-18 | 18-22 | 22-25 | 25-29 | 29-32 | 32-36 |
Statistics | test | Av | Wi | Wi | Du | Wi | Wi | Wi | Sh | Wi | Wi | Wi | Wi |
Group 1/F | Mean | 23 | -1 | 5 | 9 | 0 | 6 | -1 | 7 | -1 | 10 | 2 | 5 |
Air Control | SD | 7.8 | 4.7 | 4.4 | 4.0 | 4.3 | 3.7 | 5.0 | 4.1 | 3.8 | 3.2 | 6.0 | 3.6 |
| N | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 |
|
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Group 2/F | Mean | 21 | -1 | 7 | 4** | 3 | 6 | 2 | 5 | 2 | 9 | 4 | 4 |
(0.2) | SD | 5.7 | 4.9 | 6.1 | 3.2 | 3.9 | 5.1 | 4.7 | 3.8 | 5.9 | 3.7 | 4.5 | 2.9 |
| N | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 |
|
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Group 3/F | Mean | 20 | 2 | 4 | 10 | 0 | 7 | 5 | 6 | -1 | 9 | -2 | 6 |
(0.6) | SD | 9.3 | 5.3 | 3.3 | 4.7 | 7.4 | 7.2 | 7.1 | 3.5 | 4.7 | 3.7 | 5.9 | 2.9 |
| N | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 |
|
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Group 4/F | Mean | 18 | 1 | 5 | 6 | 2 | 5 | 1 | 10 | -5 | 8 | 0 | 6 |
(6.0) | SD | 8.6 | 6.4 | 5.2 | 1.7 | 3.3 | 2.3 | 4.5 | 10.1 | 9.0 | 3.3 | 4.3 | 3.6 |
| N | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 |
Body weight change - group mean values (g) FEMALES | ||||||||||
Group/Sex |
| Day |
|
|
|
|
|
|
|
|
(mg/L) |
| 36-39 | 39-43 | 43-46 | 46-50 | 50-57 | 57-64 | 64-71 | 71-78 | 78-85 |
Statistics | test | Wi | Wi | Wi | Wi | Wi | Wi | Wi | Wi | Wi |
Group 1/F | Mean | -10 | 14 | -8 | 12 | 4 | 5 | 1 | 0 | 2 |
Air Control | SD | 3.7 | 5.4 | 5.2 | 4.1 | 6.4 | 5.6 | 4.5 | 5.6 | 5.3 |
| N | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 |
|
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|
Group 2/F | Mean | -4** | 8 | -3 | 11 | 3 | 4 | 6 | 1 | -1 |
(0.2) | SD | 3.6 | 3.5 | 5.8 | 4.5 | 7.2 | 3.7 | 6.8 | 5.5 | 9.1 |
| N | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 |
|
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|
|
Group 3/F | Mean | -4** | 13 | -3 | 8 | 3 | 5 | 4 | 1 | 2 |
(0.6) | SD | 6.0 | 6.8 | 5.8 | 2.9 | 9.3 | 4.7 | 4.3 | 4.5 | 4.7 |
| N | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 |
|
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Group 4/F | Mean | -6** | 9 | -8 | 10 | 4 | 2 | 6 | -2 | 2 |
(6.0) | SD | 3.9 | 3.8 | 6.1 | 5.0 | 3.3 | 4.0 | 6.7 | 9.0 | 3.6 |
| N | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 |
Applicant's summary and conclusion
- Conclusions:
- No test item-related adverse effects on mortality, clinical observations (including FOD/MA), food consumption, ophthalmology, hematology, clinical chemistry, bronchiolar lavage, macroscopic pathology, or microscopic pathology were detected. No statistically significant and biologically relevant effects on body weights, body weight gain, or food consumption were noted in the male low- and mid-dose groups or any female group. However, statistically significant decreased body weights (p ≤0.05) were noted in the high-dose males during the last four weeks of treatment and were accompanied by statistically significant decreases in body weight gain and food consumption. Although the males in the high-dose group gained weight throughout the study, and there were no other signs of toxicity, the statistically significant decreases in body weight and body weight gain were considered adverse.
In summary, the No-Observed-Adverse-Effect-Level (NOAEL) for male rats exposed to 3-methoxybutyl acetate is 2 mg/L and the Lowest-Observed-Adverse-Effect-Level (LOAEL) is 6 mg/L. The highest dose tested of 6 mg/L is the NOAEL for female rats. - Executive summary:
Sprague-Dawley CD® rats (10/sex/group) were exposed via nose-only vapor inhalation to 0 (Air control), 0.6, 2.0 or 6.0 mg/L of 3-Methoxybutyl Acetate for 6 hours/day, 5 days/week, for 13 consecutive weeks. At the end of the treatment period, 10 animals/sex/group were euthanized and necropsied. Parameters evaluated during the study were: viability, clinical observations, ophthalmology, body weights, food consumption, locomotor activity and functional observational battery (Week 12), clinical pathology (prior to terminal necropsy), bronchoalveolar lavage (at terminal necropsy) organ weights, macroscopic observations, and microscopic pathology.
Mean 3-Methoxybutyl Acetate atmosphere vapor concentrations are summarized below:
Group
Atmosphere Concentration (mg/L)
Target
Mean Achieved
1
0
0
2
0.6
0.60
3
2.0
1.90
4
6.0
5.83
No 3-Methoxybutyl Acetate was detected in Group 1 samples. Mean achieved concentration for Group 2 was on target. Mean achieved concentration for Groups 3 and 4 were 5% and 3% below target, respectively.
No test item-related adverse effects on mortality, clinical observations (including FOD/MA), food consumption, ophthalmology, hematology, clinical chemistry, bronchiolar lavage, macroscopic pathology, or microscopic pathology were detected. No statistically significant and biologically relevant effects on body weights, body weight gain, or food consumption were noted in the male low- and mid-dose groups or any female group. However, statistically significant decreased body weights (p ≤0.05) were noted in the high-dose males during the last four weeks of treatment and were accompanied by statistically significant decreases in body weight gain and food consumption. Although the males in the high-dose group gained weight throughout the study, and there were no other signs of toxicity, the statistically significant decreases in body weight and body weight gain were considered adverse.
In summary, the No-Observed-Adverse-Effect-Level (NOAEL) for male rats exposed to 3-methoxybutyl acetate is 2 mg/L and the Lowest-Observed-Adverse-Effect-Level (LOAEL) is 6 mg/L. The highest dose tested of 6 mg/L is the NOAEL for female rats.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
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