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EC number: 431-090-3 | CAS number: 190085-41-7
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Toxicity to reproduction
Administrative data
- Endpoint:
- three-generation reproductive toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- no data available
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- guideline study without detailed documentation
- Justification for type of information:
- To address some of the toxicological endpoints as part of the REACH registration of 2-Hydroxybenzoic acid, 2-Butyloctyl ester (CAS 190085-41-7) (target substance), it is proposed to read across to methyl salicylate (CAS 119-36-8) (source substance) to fulfill the data requirements of the OECD 416 study.
Both the above mentioned substance share similar chemical structures. As mentioned, both substances have identical functionality, they are both esters of salicylic acid. The only difference in the two substances is in the alcohol portion of the ester group.
Read across has been deemed as suitable.
Cross-reference
- Reason / purpose for cross-reference:
- reference to same study
Data source
Referenceopen allclose all
- Reference Type:
- review article or handbook
- Title:
- Evaluation of safety for food additives: An illustration involving the influence of methyl salicylate on rat reproduction
- Author:
- Gross MA, Fitzhugh OG
- Year:
- 1 970
- Bibliographic source:
- Biometrics 26:181-184
- Reference Type:
- publication
- Title:
- Effect of methyl salicylate on rat reproduction
- Author:
- Collins TFX, Hansen WH, Keeler HV
- Year:
- 1 971
- Bibliographic source:
- Toxicol. Appl. Pharmacol. 18:755-765
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)
- Deviations:
- yes
- Remarks:
- several deficiencies in relation to OECD Guideline 416 in terms of parameters studied
- GLP compliance:
- no
- Limit test:
- no
Test material
- Reference substance name:
- Methyl salicylate
- EC Number:
- 204-317-7
- EC Name:
- Methyl salicylate
- Cas Number:
- 119-36-8
- IUPAC Name:
- methyl salicylate
- Details on test material:
- - Name of test material: methyl salicylate
- Molecular formula: C8H8O3
- Molecular weight: 152
- Substance type: oily liquid
- Physical state: no data
- Analytical purity: no data
- Impurities (identity and concentrations): no data
- Purity test date: no data
- Lot/batch No.: no data
- Stability under test conditions: no data
- Storage condition of test material: no data
- Source: Dodge and Olcott, Inc., New York
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Osborne-Mendel
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: no data
- Age at study initiation: (P) x wks; (F1) x wks
- Weight at study initiation: no data
- Fasting period before study: no data
- Housing: no data
- Diet: ad libitum (Purina Laboratory Chow)
- Water: ad libitum
- Acclimation period: no data
ENVIRONMENTAL CONDITIONS
- Temperature (°C): no data
- Humidity (%): no data
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): no data
IN-LIFE DATES: no data
Administration / exposure
- Route of administration:
- oral: feed
- Vehicle:
- unchanged (no vehicle)
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
DIET PREPARATION
- Rate of preparation of diet (frequency): the diet was prepared every 14 days in a manner identical to that of Webb and Hansen (1963) and according to the results of Jones et al (1962).
- Mixing appropriate amounts with (Type of food): no data
- Storage temperature of food: no data
VEHICLE: none - Analytical verification of doses or concentrations:
- no
- Details on analytical verification of doses or concentrations:
- no information available
- Duration of treatment / exposure:
- 100 days prior to the first mating until study termination
- Frequency of treatment:
- continuos in the feed
- Details on study schedule:
- no information available
Doses / concentrations
- Remarks:
- Doses / Concentrations:
0, 500, 1500, 3000 and 5000 ppm
Basis:
nominal in diet
(equivalent to 25, 75, 150, 250 mg/kg bw as Methyl Salicylate, or 22.5, 67.5, 135, 225 mg/kg bw as Salicylic Acid)
- No. of animals per sex per dose:
- 10
- Control animals:
- yes, concurrent no treatment
- Details on study design:
- no information available
- Positive control:
- none employed
Examinations
- Oestrous cyclicity (parental animals):
- not examined
- Sperm parameters (parental animals):
- not examined
- Litter observations:
- STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: yes
- If yes, maximum of 10 pups/litter ; excess pups were killed and discarded.
PARAMETERS EXAMINED
The following parameters were examined in [F1 / F2 / F3] offspring:
number of pups, stillbirths, live births, presence of gross anomalies
GROSS EXAMINATION OF DEAD PUPS: no - Postmortem examinations (parental animals):
- not examined
- Statistics:
- The Chi-square test was used to determine significant differences between each dose and the control for each mating in each generation.
- Reproductive indices:
- The fertility index (number of litters/number of females mated).
- Offspring viability indices:
- viability index (number of liveborn/total number born)
survival index (number alive at day 4/ number born alive)
weaning index (adjusted number of day 21 survivors/number alive at day 4)
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- no effects observed
- Body weight and weight changes:
- not examined
- Food consumption and compound intake (if feeding study):
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Histopathological findings: neoplastic:
- not examined
- Other effects:
- not examined
Reproductive function / performance (P0)
- Reproductive function: oestrous cycle:
- not examined
- Reproductive function: sperm measures:
- not examined
- Reproductive performance:
- no effects observed
Details on results (P0)
- Average litter size/female: significant decreases were seen in the second generation in the second mating at 3000 ppm and in both matings at 5000 ppm. Although decreases were seen at 1500 ppm, they were not statistically significant because of the large variation in progeny between females within a group.
Effect levels (P0)
open allclose all
- Dose descriptor:
- NOAEL
- Effect level:
- 75 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: Reduced neonate viability
- Remarks on result:
- other: Generation: development
- Dose descriptor:
- NOAEL
- Effect level:
- 3 000 ppm
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: Reduced neonate viability
- Remarks on result:
- other: Generation: development
- Dose descriptor:
- NOAEL
- Effect level:
- 1 500 ppm
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No significant effects at the highest dose tested
- Remarks on result:
- other: Generation: reproduction
- Dose descriptor:
- NOAEL
- Effect level:
- 1 500 ppm
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No significant effects at the highest dose tested
Results: F1 generation
General toxicity (F1)
- Clinical signs:
- not examined
- Mortality / viability:
- mortality observed, treatment-related
- Body weight and weight changes:
- effects observed, treatment-related
- Sexual maturation:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- no effects observed
- Histopathological findings:
- no effects observed
Details on results (F1)
- The average number of liveborn young per mated female: Statistically significant differences were observed in both matings of the second generation at 3000 ppm and at 5000 ppm.
- Viability index: "possible loss of young through stillbirths" in 2 matings/5000 ppm.
- Average no. of surviving progeny/female, day 4: significant decreases occurred in both matings of the second generation at 3000 ppm and 5000 ppm
- Survival index, day 4: an adverse effect was observed in the second generation at the 3000 and 5000 ppm and in the first mating of the third generation at the same dose levels.
- Average no. progeny weaned/female, day 21: significant decreases were observed in the second generation at 3000 ppm in the first mating and at 5000 ppm in the first and second matings.
- Weaning index: "appreciable decrease" in 2nd generation/2nd litter/5000 ppm.
BODY WEIGHT:
- Average weanling weight,( day 21/sex): decreases in weight appeared consistently at the 3000 and 5000 ppm levels(in all generations).
GROSS PATHOLOGY (OFFSPRING)
no grossly visible abnormalities.
HISTOPATHOLOGY (OFFSPRING)
Histopathological examinations of the livers and kidneys of 3rd weanlings at the 0, 3000 and 5000 ppm dose levels showed no indication of toxic effects.
Effect levels (F1)
open allclose all
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- 3 000 ppm
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- body weight and weight gain
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- 1 500 ppm (nominal)
- Based on:
- test mat.
- Sex:
- not specified
- Basis for effect level:
- body weight and weight gain
Overall reproductive toxicity
- Reproductive effects observed:
- not specified
Any other information on results incl. tables
Supplemental study: the results obtained after addition of calcium carbonate to methyl salicylate did not differ from those obtained after administration of methyl salicylate alone.
Table 1 : fertility indexes of rats fed methyl salicylate for 3 generations
dietary level (ppm) | |||||||||||
|
| 0 | 500 | 1500 | 3000 | 5000 | |||||
generation | mating | FI (a) | % (b) | FI | % | FI | % | FI | % | FI | % |
1 | 1 | 20/20 | 100 | 20/20 | 100 | 20/20 | 100 | 20/20 | 100 | 20/20 | 100 |
| 2 | 19/19 | 100 | 20/20 | 100 | 18/19 | 95 | 19/19 | 100 | 20/20 | 100 |
2 | 1 | 20/20 | 100 | 19/20 | 95 | 20/20 | 100 | 19/20 | 95 | 17/20 | 85 |
| 2 | 19/19 | 100 | 19/20 | 95 | 19/19 | 100 | 19/20 | 95 | 10/13 | 77 |
3 | 1 | 20/20 | 100 | 18/20 | 90 | 18/19 | 95 | 19/20 | 95 | 17/19 | 89 |
| 2 | 18/20 | 90 | 16/18 | 89 | 17/19 | 89 | 15/17 | 88 | 16/19 | 84 |
(a) Fertility Index (number of litters/ number of females mated)
(b) Percent females pregnant
Table 2: average litter size of rats fed methyl salicylate for 3 generations
dietary level (ppm) | |||||||||||
|
| 0 | 500 | 1500 | 3000 | 5000 | |||||
generation | mating | No. (a) | Av. (b) | No. | Av. | No. | Av. | No. | Av. | No. | Av. |
1 | 1 | 208/20 | 10.4 | 211/19 | 11.1 | 207/20 | 10.4 | 235/20 | 11.8 | 188/18 | 10.4 |
| 2 | 213/19 | 11.2 | 232/20 | 11.6 | 228/19 | 12.0 | 238/19 | 12.5 | 198/19 | 10.4 |
2 | 1 | 216/20 | 10.8 | 205/20 | 10.2 | 206/20 | 10.3 | 169/20 | 8.4 | 124/20 | 6.2 (c) |
| 2 | 226/19 | 11.9 | 204/20 | 10.2 | 189/18 | 10.5 | 187/20 | 9.4 (d) | 86/13 | 6.6 (c) |
3 | 1 | 192/20 | 9.6 | 188/19 | 9.9 | 172/19 | 9.1 | 170/20 | 8.5 | 179/19 | 9.4 |
| 2 | 197/20 | 9.8 | 191/18 | 10.6 | 163/19 | 8.6 | 132/17 | 7.38 | 172/19 | 9.1 |
(a) Total number progeny/number females mated
(b) Average litter size per female mated
(c) significant at P<0.01
(d) significant at P<0.05
Table 3: viability data for rats fed methyl salicylate for 3 generations
dietary level (ppm) | ||||||||||||||||
|
| 0 | 500 | 1500 | 3000 | 5000 | ||||||||||
gen. | mating | No. (a) | Av. (b) | VI (c, d) | No. | Av. | VI (c, d) | No. | Av. | VI (c, d) | No. | Av. | VI (c, d) | No. | Av. | VI (c, d) |
1
| 1 | 208/20 | 10.4 | 1,00 | 211/19 | 11.1 | 1,00 | 195/20 | 9,8 | 0,94 | 229/20 | 11,4 | 0,97 | 167/18 | 9,3 | 0,88 |
2 | 213/19 | 11.2 | 1,00 | 231/20 | 11.6 | 1,00 | 226/19 | 11,9 | 0,99 | 237/19 | 12,5 | 1,00 | 189/19 | 9,9 | 0,95 | |
2
| 1 | 215/20 | 10.8 | 1,00 | 203/20 | 10.2 | 0,99 | 203/20 | 10,2 | 0,99 | 164/20 | 8,2 (e) | 0,97 | 106/19 | 5,6 (f) | 0,85 |
2 | 225/19 | 11.8 | 1,00 | 203/20 | 10.2 | 1,00 | 189/18 | 10,5 | 1,00 | 182/20 | 9,1 (e) | 0,97 | 82/13 | 6,3 (f) | 0,95 | |
3
| 1 | 188/20 | 9,4 | 0,98 | 184/19 | 9,7 | 0,98 | 160/19 | 8,4 | 0,93 | 164/20 | 8,2 | 0,96 | 174/19 | 9,2 | 0,97 |
2 | 196/20 | 9.8 | 1,00 | 186/18 | 10,3 | 0,97 | 155/19 | 8,2 | 0,95 | 118/17 | 6,9 | 0,89 | 166/19 | 8,7 | 0,97 |
(a) Total number liveborn/number females mated
(b) Average number liveborn per female mated
(c) Viability index (no. liveborn/total no. born)
(d) Not analyzed for statistical significance
(e) significant at P<0.05
(f) significant at P<0.01
Table 4: survival data of rats fed methyl salicylate for 3 generations
dietary level (ppm) | ||||||||||||||||
|
| 0 | 500 | 1500 | 3000 | 5000 | ||||||||||
gen. | mating | No. (a) | Av. (b) | SI (c, d) | No. | Av. | SI | No. | Av. | SI | No. | Av. | SI | No. | Av. | SI |
1 | 1 | 157/17 | 9,2 | 0,90 | 116/14 | 8,3 | 0,82 | 172/19 | 9,1 | 0,96 | 152/15 | 10,1 | 0,92 | 129/15 | 8,6 | 0,94 |
2 | 202/19 | 10,6 | 0,95 | 196/20 | 9,8 | 0,85 | 205/19 | 10,8 | 0,91 | 218/19 | 11,5 | 0,92 | 168/19 | 8,8 | 0,89 | |
2 | 1 | 188/20 | 9,4 | 0,87 | 179/20 | 9 | 0,88 | 190/20 | 9,5 | 0,94 | 123/20 | 6,2 (e) | 0,75 | 82/19 | 4,3 (f) | 0,77 |
2 | 211/19 | 11,1 | 0,94 | 188/20 | 9,4 | 0,93 | 186/18 | 10,3 | 0,98 | 165/20 | 8,2 (e) | 0,91 | 61/13 | 4,7 (f) | 0,74 | |
3 | 1 | 174/20 | 8,7 | 0,93 | 177/19 | 9,3 | 0,96 | 147/19 | 7,7 | 0,92 | 139/20 | 7 | 0,85 | 147/19 | 7,7 | 0,84 |
2 | 174/20 | 8,7 | 0,89 | 179/18 | 9,9 | 0,96 | 150/19 | 7,9 | 0,97 | 113/17 | 6,6 | 0,96 | 153/19 | 8,1 | 0,92 |
(a) Total number day 4 survivors / no. females mated
(b) Average number day 4 survivors per female mated
(c) Survival index (no. day 4 survivors/total no. liveborn)
(d) Not analyzed for statistical significance
(e) significant at P<0.05
(f) significant at P<0.01
See "Overall remarks, attachments" for Table 5.
Applicant's summary and conclusion
- Conclusions:
- Under the conditions of this study, methyl salicylate did not significantly reduce male or female fertility. Methyl salicylate did induce developmental toxicity: adverse effects on offspring viability were observed but with no evidence of increased incidence of malformations at any dose tested.
The NOAELs were identified:
NOAEL (parental): 250 mg/kg bw/day
NOAEL (reproduction): 250 mg/kg bw/day
LOAEL (development): 150 mg/kg bw/day
NOAEL (development): 75 mg/kg bw/day - Executive summary:
In this 3 -generation study, rats were fed methyl salicylate at doses of 500, 1500, 3000 or 5000 ppm in the diet (equivalent to 25, 75, 150 or 250 mg/kg body weight as methyl salicylate, or 22.5, 67.5, 135, 225 mg/kg bw as salicylic acid) 100 days before the first mating and then throughout the experiment. No clinical signs of toxicity were reported at any dose level. No statistically significant decrease was reported in fertility indexes at any dose level at the F1 generation, however it was considered that there were "appreciable" decreases at 250 mg/kg in the F2 and F3 generations. Significant decreases were reported in average litter size, average number of live-born progeny, average numbers of survivors to PND4 and average number of weaning in the 150 and 250 mg/kg bw/day in the F2 generation. No external malformations were reported in pups of any litter and necropsy of the third generation weanlings showed no significant findings. The effects in a calcium carbonate supplement groups did not differ significantly from those of the groups fed methyl salicylate alone.
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