Registration Dossier
Registration Dossier
Data platform availability banner - registered substances factsheets
Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.
The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.
Diss Factsheets
Use of this information is subject to copyright laws and may require the permission of the owner of the information, as described in the ECHA Legal Notice.
EC number: 203-564-8 | CAS number: 108-24-7
- 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
Endpoint summary
Administrative data
Key value for chemical safety assessment
Effects on fertility
Description of key information
No data available on acetic anhydride or the read-across substance, acetic acid.
Effect on fertility: via oral route
- Endpoint conclusion:
- no study available
Effect on fertility: via inhalation route
- Endpoint conclusion:
- no study available
Effect on fertility: via dermal route
- Endpoint conclusion:
- no study available
Additional information
Non-human data
No fertility data are available for acetic anhydride. In rat studies, no adverse macroscopic or microscopic findings were observed in the gonads following inhalation of acetic anhydride for 13 weeks (HRC, 1996).
Within an aqueous environment, acetic anhydride is rapidly hydrolysed to acetic acid. Therefore, it is anticipated that acetic anhydride will be rapidly and extensively transformed in vivo to acetic acid and, consequently, it is reasonable to consider systemic exposure to the two substances comparable and systemic toxicity endpoints, such as reproduction and development, would be similar in animals exposed to either substance. However, guideline reproduction studies for acetic acid have also not been reported.
In contrast, local toxicity effects of the two chemicals depend upon the molecular structure of the parent substance and its metabolic/chemical fate within the micro-environment of the site of first contact. The maximum tolerated dose (MTD) for acetic anhydride is associated with local effects (irritation, and in more severe instances resulting in reduced water and food intake and bodyweight depression) and occurs at low concentrations (83.5 mg/m3: highest exposure concentration in rat 90-day inhalation study reported by HRC, 1996). The low MTD may reflect the strongly exothermic aqueous hydrolysis of acetic anhydride which would exacerbate the local effects of the acetic acid produced. Certainly, when considered on a ppm (v/v) basis, acetic anhydride is more potent because, on hydrolysis, it delivers 2 moles of acetic acid per mole of anhydride. A consequence of the low MTD of acetic anhydride is that the extent of systemic exposure to acetic acid will be low when acetic anhydride is administered.
In conclusion, considering systemic exposure to acetate following acetic anhydride exposure, the review of acetic acid for REACH has not uncovered any information to undermine the following statement: “Based on human exposure to orally ingested acetic acid from various foods and the lack of evidence that such exposure is related to fertility problems and developmental deficiencies in humans, neither a new multigeneration study nor any other postnatal evaluation or developmental toxicity study are required” (EU DAR, 2008).
Human data
Although no human data is available for this reproductive endpoint, when considering exposure to acetic anhydride at an atmospheric concentration of 1 ppm (4.18 mg/m3) in the rat 90-day toxicity study, the proposed NOAEC for local irritation effects (4.2 mg/m3) results in an insignificant systemic exposure to acetate at this concentration.For an 8-hour day spent at light work, and assuming 100% absorption of acetic anhydride/acid for a worker, would be 4.2 mg/m3* wRV m3/kg bw * [mw acetic anhydride / acetic acid] = 4.2 * 0.144 * [102.09 / 60.05] = 1.03 mg/kg bw. To put this intake into perspective with the known removal of acetate in humans, it has been shown that about ~0.5 mg/kg bw acetate can be removed each minute via endogenous pathways, such as the citric acid cycle, following administration of acetate in a drink (Smith et al., 2007). Daily administration of 40 mg/kg bw/day may be used as a medicinal product (Johnston & Gaas, 2006), and 25 mg/kg bw /day is estimated as average human (infant) dietary intake (Ishiwata et al., 2002), with peak excursions up to 240 mg/kg bw/day (EU DAR, 2008).
Effects on developmental toxicity
Description of key information
Prenatal developmental toxicity studies (similar to OECD 414) in rat, mouse and rabbit (1974) with acetic acid (5% in cider vinegar) by the oral route. Inhalation range-finding study with acetic anhydride in male rats and pregnant female rats.
Link to relevant study records
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: GLP status not known, near guideline study, published in peer reviewed literature, limitations in design and/or reporting but otherwise adequate for assessment.
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- EU Method B.31 (Prenatal Developmental Toxicity Study)
- GLP compliance:
- not specified
- Limit test:
- no
- Species:
- rabbit
- Strain:
- Dutch
- Details on test animals or test system and environmental conditions:
- Virgin, adult, Dutch-belted female rabbits were individually housed in mesh bottom cages in temperature and humidity-controlled quarters with free access to food and fresh tap water.
- Route of administration:
- oral: gavage
- Vehicle:
- water
- Details on exposure:
- The females were dosed with the indicated dosages by oral intubations. The controls were sham treated with the vehicle at a level equivalent to the group receiving the highest test dose. The test material was prepared and doses calculated according to the following table:
Dosage Dose Concentration
(mg/kg) (ml/kg) (mg/ml)
250 1 250
251 - 500 2 125 - 250
501 - 750 3 133 - 250
751 - 1000 4 187 - 250
1001 - 1250 5 200 - 250
1251 - 1500 6 208 - 250
1501 - 1600 6.4 235 - 250 - Analytical verification of doses or concentrations:
- not specified
- Details on mating procedure:
- On Day 0, each doe was given an injection of 0.4 ml of human chorionic gonadotropin (400 IU) via the marginal ear vein. Three hours later, each doe was inseminated artificially with 0.3 ml of diluted semen from a proven donor buck using approximately 20 x 106 motile sperm.
- Duration of treatment / exposure:
- Days 6 - 18 of gestation
- Frequency of treatment:
- Daily
- Duration of test:
- Days 0-29 of gestation
- Dose / conc.:
- 2.5 mg/kg bw/day (nominal)
- Dose / conc.:
- 16 mg/kg bw/day (nominal)
- Dose / conc.:
- 74.3 mg/kg bw/day (nominal)
- Dose / conc.:
- 345 mg/kg bw/day (nominal)
- Dose / conc.:
- 1 600 mg/kg bw/day (nominal)
- No. of animals per sex per dose:
- Approximately 12 pregnant females.
- Control animals:
- yes, sham-exposed
- Details on study design:
- An additional group of mated females was dosed with 2.5mg/kg 6-aminonicotinamide on day 9 and served as a positive control
- Maternal examinations:
- Body weights were recorded on Days 0, 6, 12, 18, and 29 of gestation.
All animals were observed daily for appearance and behaviour with particular attention to food consumption and weight, in order to rule out any abnormalities which may have occurred as a result of anorexic effects in the pregnant female animal - Ovaries and uterine content:
- On Day 29 all does were subjected to Caesarean section under surgical anaesthesia, and the numbers of corpora lutea, implantation sites, resorption sites and live and dead foetuses were recorded. The urogenital tract of each animal was examined in detail for normality.
- Fetal examinations:
- The body weights of the live pups were recorded. all foetuses underwent a detailed gross examination for the presence of external congenital abnormalities. The live foetuses of each litter were then placed in an incubator for 24 hours for the evaluation of neonatal survival. All surviving pups were sacrificed, and all pups examined for visceral abnormalities (by dissection). All foetuses were then cleared in potassium hydroxide, stained with alizarin red S dye and examined for skeletal defects.
- Clinical signs:
- no effects observed
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Reduced bodyweight observed in dams treated with 1600 mg/kg/day.
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- no effects observed
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- not examined
- Histopathological findings: neoplastic:
- not examined
- Other effects:
- not examined
- Number of abortions:
- effects observed, treatment-related
- Description (incidence and severity):
- Abortions observed in all treated groups at incidences of: 0, 2, 1, 1, 2 for the 0, 16, 74.3, 345 and 1600 mg/kg/day treatment groups.
- Pre- and post-implantation loss:
- no effects observed
- Total litter losses by resorption:
- effects observed, treatment-related
- Description (incidence and severity):
- Reduction in the number of live litters from females treated with 345 and 1600 mg/kg/day.
- Early or late resorptions:
- no effects observed
- Dead fetuses:
- no effects observed
- Changes in pregnancy duration:
- no effects observed
- Changes in number of pregnant:
- no effects observed
- Details on maternal toxic effects:
- Details on maternal toxic effects:
The administration of up to 1600 mg/kg (body weight) of the test material to pregnant rabbits for 13 consecutive days had no clearly discernible effect on nidation or on maternal survival. Report of reduced body weight in dams at 1600 mg/kg bw/day. Some deaths or abortions occurred in all treated groups and some litter losses were reported at 345 and 1600 mg/kg/day. Maternal effects considered consequence of the bactericidal properties of, orally administered, acetic acid within the gastrointestinal tract of female rabbits. - Dose descriptor:
- NOAEL
- Effect level:
- 16 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Basis for effect level:
- body weight and weight gain
- dead fetuses
- number of abortions
- Remarks on result:
- other:
- Remarks:
- Maternal effects considered consequence of the bactericidal properties of, orally administered, acetic acid within the gastrointestinal tract of female rabbits.
- Fetal body weight changes:
- no effects observed
- Reduction in number of live offspring:
- effects observed, treatment-related
- Description (incidence and severity):
- Reduction in the number of live offspring observed at 16, 345 and 1600 mg/kg/day.
- Changes in sex ratio:
- no effects observed
- Changes in litter size and weights:
- no effects observed
- Changes in postnatal survival:
- no effects observed
- External malformations:
- no effects observed
- Skeletal malformations:
- no effects observed
- Visceral malformations:
- no effects observed
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:no effects
Details on embryotoxic / teratogenic effects:
The administration of up to 1600 mg/kg (body weight) of the test material to pregnant rabbits for 13 consecutive days had no clearly discernible effect on fetal survival. The number of abnormalities seen in either soft or skeletal tissues of the test groups did not differ from the number occurring spontaneously in the sham-treated controls. - Dose descriptor:
- NOAEL
- Effect level:
- 1 600 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- reduction in number of live offspring
- changes in sex ratio
- fetal/pup body weight changes
- changes in litter size and weights
- changes in postnatal survival
- external malformations
- skeletal malformations
- visceral malformations
- Abnormalities:
- not specified
- Developmental effects observed:
- not specified
- Conclusions:
- The administration of up to 1600 mg/kg (body weight) to pregnant rabbits for 13 consecutive days had no clearly discernible effect on nidation or on maternal or fetal survival. The number of abnormalities seen in either soft or skeletal tissues of the test groups did not differ from the number occurring spontaneously in the sham-treated controls.
- Executive summary:
In a developmental toxicity study in rabbits, apple cider vinegar, that contains 5% acetic acid, was administered by gavage at dose levels of 0, 16, 74.3, 345 and 1600 mg/kg/day for 13 consecutive days. The authors reported that administration of up to 1600 mg/kg bodyweight of the test material to dams for 13 days revealed no discernible effect on maternal or foetal survival, or on soft of skeletal tissues.
There was a reduction in pregnancy rate at the high dose and from 74.3 mg/kg/day, a dose-dependent decrease in maternal bodyweight gain in dams. Some deaths or abortions occurred in all treated groups and some litter losses were reported at 345 and 1600 mg/kg/day. Maternal effects were much more noticeable than effects on foetal development. It has been concluded that these findings are a consequence of the bactericidal properties of, orally administered, acetic acid within the gastrointestinal tract of female rabbits (EU, 2008). These effects are considered not to be a direct effect on embryonic implantation and development of acetic acid (EU, 2008). It is likely that this accounts for the apparent increased sensitivity of this species to oral administration of acetic acid.
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Study period:
- 5 Jan 1994 - 1 Feb 1994
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: GLP compliant, near guideline study, available as unpublished report. Minor restrictions in design and/or reporting but otherwise adequate for assessment.
- Reason / purpose for cross-reference:
- reference to same study
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Deviations:
- yes
- Remarks:
- No skeletal or soft tissue examinations
- Principles of method if other than guideline:
- Preliminary range findings study in 5 male and 5 time-mated females per group, exposed to vapours of acetic anhydride for 6h/day for 5 days/week (males) or from days 6-15 post coitum (females).
- GLP compliance:
- yes
- Species:
- rat
- Strain:
- other: Crl:CD BR
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River (UK) Ltd, Manston Road, Margate, Kent
- Age at study initiation: Males - approximately 8 weeks old. Females - 9-11 weeks old.
- Housing: 5 / cage in suspended cages with stainless steel mesh floors. The cages of each group were housed on a rack in a separate ventilated chamber to avoid cross contamination following exposures.
- Diet (e.g. ad libitum): SDS Rat and Mouse No. 1 SQC modified maintenance diet. Available in home cages.
- Water (e.g. ad libitum): Tap water available from polypropylene bottles ad libitum in home cages.
- Acclimation period: Males - 12 days, females - 5 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-24°C
- Humidity (%): 40-70%
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light): 12 h light (08.00-20.00) and 12 h dark/24 h.
IN-LIFE DATES: From: 5 January 1994 To: 1 February 1994. - Route of administration:
- inhalation: vapour
- Type of inhalation exposure (if applicable):
- whole body
- Vehicle:
- unchanged (no vehicle)
- Details on exposure:
- pressure of 10mm H2O below ambient.
- Air flow rate: approximately 150L/min.
- Air change rate: Not reported
- Treatment of exhaust air: Drawn through an activated charcoal scrubbing system by an extract fan before being vented to atmosphere.
TEST ATMOSPHERE
- Brief description of analytical method used: Gas chromatography.
- Samples taken from breathing zone: yes - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Acetic anhydride concentration was determined 6 times during each exposure (approximately hourly intervals), using gas chromatography. Samples were also analysed for acetic acid.
The absence of test substance aerosol was confirmed on one occasion during the study using a Royco Particle Monitor. - Details on mating procedure:
- - Impregnation procedure: purchased timed pregnant (day 1 post coitum)
- Duration of treatment / exposure:
- 5 days/week for 2 weeks (males)
Days 6-15 post coitum (females) - Frequency of treatment:
- 6h/day
- Duration of test:
- 2 weeks (except at 400 ppm).
Males were exposed to the high dose concentration on one occasion only, due to toxicity and females were not exposed to this concentration (Table 1) - No. of animals per sex per dose:
- 5
- Control animals:
- yes, sham-exposed
- Details on study design:
- - Dose selection rationale: randomly assigned, stratified by bodyweight
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: During exposure
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Twice daily
BODY WEIGHT: Yes
- Time schedule for examinations: day 1 of pregnancy and then on days 2, 3, 6, 8, 10, 12, 14, 16, 18 & 20 post coitum.
FOOD CONSUMPTION: Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/rat/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No
WATER CONSUMPTION : Yes
- Time schedule for examinations: Daily, from day 1 of pregnancy in females.
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs examined: Ovaries and uteri
OTHER Litter data and foetal examination: for groups 1 and 2 (killed on day 20 of pregnancy) only. Females killed on day 13 (Groups 3 & 4) were examined in a similar way although embryos were not examined or weighed because they were too immature - Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Other: individual foetal weight was recorded (from which litter weight was calculated). Foetal abnormalities were recorded.
Uteri withiout visible implantations were examine dfor evidence of implantation using a modified Salewski technique.
. - Fetal examinations:
- - External examinations: Yes: [all per litter]
- Soft tissue examinations: No
- Skeletal examinations: No
- Head examinations: No
Live young were examined externally and then discarded. - Statistics:
- None - in view of small group sizes.
- Indices:
- Pre and post -implanation losses were calculated as percentages .
Pre-implantation loss was calculated as a percentage from the formula:
(No. of corpora lutea - no. of implantations / No. of corpora lutea ) x 100
Post implantation loss was calculated from the formula:
(No. of implantations - no. of live young / No. of implantations) x 100
- Details on maternal toxic effects:
- Maternal toxic effects:yes
Details on maternal toxic effects:
At 100 ppm, during the first exposure, females showed halfclosed/closed eyes, licking of the inside of the mouth and lachrymation. After further exposures, gasping and/or exaggerated respiration and occasional twitching of the head was seen.
After exposure, noisy respiration, occasional sneezing and gasping respiration, arching of the back and occasional twitching of the head were seen in all /most animals. Severe weight loss was seen at this exposure level along with noticeably lower food and water intake values. Consequently , this group of animals was terminated on day 13 after 7 exposures.
At 25 ppm, half closed/closed eyes were observed during each exposure. Licking of the inside of the mouth and occasional head twitching were also observed predominantly on the last 3-4 days of exposure.
Noisy respiration was noted post exposure and persisted until the day prior to sacrifice (4 days after completion of the last exposure). Bodyweight gain was depressed from day 2 onwards along with food and water intake, compard to controls, but all showed some recovery on cessation of exposures. - Dose descriptor:
- LOAEC
- Effect level:
- 24 ppm (analytical)
- Basis for effect level:
- other: maternal toxicity
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:yes
Details on embryotoxic / teratogenic effects:
At 100 ppm, females were killed on day 13 and were compared with the unexposed Group 4 females (also killed on day 13 post coitum). Four out of five females were pregnant in each group. Two females exposed to 100 ppm showed total resorption of their litters, compared to none in the control group. The other two pregnant females in this group were supporting live litters of comparable size with those of the unexposed concurrent control group. Examination of foetuses for visual abnormalities was not possible given the age at sacrifice.
At 25 ppm, all females had a live litter at scheduled termination (day 20). There were no differences from controls in the incidence and pattern of embryofoetal loss, litter size, litter weight or foetal weight and there were no gross foetal abnormalities. - Dose descriptor:
- NOAEC
- Effect level:
- 24 ppm (analytical)
- Basis for effect level:
- other: embryotoxicity
- Abnormalities:
- not specified
- Developmental effects observed:
- not specified
- Executive summary:
In a 2 week preliminary inhalation study, exposure of time-mated females to 100 or 25 ppm acetic anhydride caused clear signs of maternal toxicity (noisy respiration, severely reduced food and water consumption and a marked bodyweight loss). At 100 ppm, females were removed from the study on day 13 after 7 exposures. Two females in this group showed total resorption, probably as a consequence of the marked maternal toxicity.
At 25 ppm, there was clear evidence of maternal toxicity similar to, but less severe than, at higher exposure levels. However, there was no evidence of embryotoxicity at this exposure level.
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: GLP status not known, near guideline study, published in peer reviewed literature, limitations in design and/or reporting but otherwise adequate for assessment.
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- EU Method B.31 (Prenatal Developmental Toxicity Study)
- GLP compliance:
- not specified
- Limit test:
- no
- Species:
- rat
- Strain:
- Wistar
- Details on test animals or test system and environmental conditions:
- Virgin adult female albino rats (Wistar derived stock) were individually housed in mesh bottom cages in temperature and humidity controlled quarters with free access to food and fresh tap water.
- Route of administration:
- oral: gavage
- Vehicle:
- water
- Details on exposure:
- The females were dosed with the indicated dosages by oral intubations. The controls were sham treated with the vehicle at a level equivalent to the group receiving the highest test dose. The test material was prepared and doses calculated according to the following table:
Dosage Dose Concentration
(mg/kg) (ml/kg) (mg/ml)
250 1 250
251 - 540 2 125 - 250
501 - 750 3 133 - 250
751 - 1000 4 187 - 250
1001 - 1250 5 200 - 250
1251 - 1500 6 208 - 250
1501 - 1600 6.4 235 - 250 - Analytical verification of doses or concentrations:
- not specified
- Details on mating procedure:
- The females were mated with young adult males, and observation of the vaginal sperm plug was considered Day 0 of gestation.
- Duration of treatment / exposure:
- Days 6 - 15 of gestation
- Frequency of treatment:
- Daily
- Duration of test:
- Days 0-20 of gestation
- Dose / conc.:
- 16 mg/kg bw/day (nominal)
- Dose / conc.:
- 74.3 mg/kg bw/day (nominal)
- Dose / conc.:
- 345 mg/kg bw/day (nominal)
- Dose / conc.:
- 1 600 mg/kg bw/day (nominal)
- No. of animals per sex per dose:
- 25 mated females
- Control animals:
- yes, sham-exposed
- Details on study design:
- An additional group of mated females was dosed with 150 mg/kg aspirin and served as a positive control
- Maternal examinations:
- Body weights were recorded on Days 0, 6, 11, 15, and 20 of gestation.
All animals were observed daily for appearance and behaviour with particular attention to food consumption and weight, in order to rule out any abnormalities which may have occurred as a result of anorexic effects in the pregnant female animal - Ovaries and uterine content:
- On Day 20 all dams were subjected to Caesarean section under surgical anesthesia, and the numbers of implantation sites, resorption sites, and live and dead fetuses were recorded. The urogenital tract of each dam was examined in detail for anatomical normality.
- Fetal examinations:
- The body weights of the live pups were recorded. All fetuses were examined grossly for the presence of external congenital abnormalities. One-third of the fetuses of each litter underwent detailed visceral examinations employing the Wilson technique. The remaining two-thirds were cleared in potassium hydroxide, stained with alizarin red S dye and examined for skeletal defects.
- Clinical signs:
- no effects observed
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- no effects observed
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- not examined
- Histopathological findings: neoplastic:
- not examined
- Other effects:
- not examined
- Number of abortions:
- no effects observed
- Pre- and post-implantation loss:
- no effects observed
- Total litter losses by resorption:
- no effects observed
- Early or late resorptions:
- no effects observed
- Dead fetuses:
- no effects observed
- Changes in pregnancy duration:
- no effects observed
- Changes in number of pregnant:
- no effects observed
- Other effects:
- not examined
- Details on maternal toxic effects:
- Details on maternal toxic effects:
The administration of up to 1600 mg/kg (body weight) of the test material to pregnant rats for 10 consecutive days had no clearly discernible effect on nidation or on maternal survival. - Dose descriptor:
- NOAEL
- Effect level:
- 1 600 mg/kg bw/day
- Basis for effect level:
- body weight and weight gain
- changes in number of pregnant
- changes in pregnancy duration
- dead fetuses
- early or late resorptions
- effects on pregnancy duration
- gross pathology
- histopathology: non-neoplastic
- mortality
- necropsy findings
- number of abortions
- organ weights and organ / body weight ratios
- pre and post implantation loss
- total litter losses by resorption
- Fetal body weight changes:
- no effects observed
- Reduction in number of live offspring:
- no effects observed
- Changes in sex ratio:
- no effects observed
- Changes in litter size and weights:
- no effects observed
- Changes in postnatal survival:
- no effects observed
- External malformations:
- no effects observed
- Skeletal malformations:
- no effects observed
- Visceral malformations:
- no effects observed
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:no effects
Details on embryotoxic / teratogenic effects:
The administration of up to 1600 mg/kg (body weight) of the test material to pregnant rats for 10 consecutive days had no clearly discernible effect on fetal survival. The number of abnormalities seen in either soft or skeletal tissues of the test groups did not differ from the number occurring spontaneously in the sham-treated controls. - Dose descriptor:
- NOAEL
- Effect level:
- 1 600 mg/kg bw/day (nominal)
- Basis for effect level:
- reduction in number of live offspring
- changes in sex ratio
- fetal/pup body weight changes
- changes in litter size and weights
- changes in postnatal survival
- external malformations
- skeletal malformations
- visceral malformations
- Abnormalities:
- not specified
- Developmental effects observed:
- not specified
- Conclusions:
- The administration of up to 1600 mg/kg (body weight) to pregnant rats for 10 consecutive days had no clearly discernible effect on nidation or on maternal or fetal survival. The number of abnormalities seen in either soft or skeletal tissues of the test groups did not differ from the number occurring spontaneously in the sham-treated controls.
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: GLP status not known, near guideline study, published in peer reviewed literature, limitations in design and/or reporting but otherwise adequate for assessment.
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- EU Method B.31 (Prenatal Developmental Toxicity Study)
- GLP compliance:
- not specified
- Limit test:
- no
- Species:
- mouse
- Strain:
- CD-1
- Details on test animals or test system and environmental conditions:
- Virgin adult female albino CD-1 outbred mice were gang-housed in disposable plastic cages in temperature and humidity-controlled quarters with free access to food and fresh tap water.
- Route of administration:
- oral: gavage
- Vehicle:
- water
- Details on exposure:
- Dose volume 10 ml/kg body weight
- Analytical verification of doses or concentrations:
- not specified
- Details on mating procedure:
- The females were mated with young adult males, and observation of the vaginal sperm plug was considered Day 0 of gestation.
- Duration of treatment / exposure:
- Days 6 - 15 of gestation
- Frequency of treatment:
- Daily
- Duration of test:
- Days 0-17 of gestation
- Dose / conc.:
- 16 mg/kg bw/day (nominal)
- Dose / conc.:
- 74.3 mg/kg bw/day (nominal)
- Dose / conc.:
- 345 mg/kg bw/day (nominal)
- Dose / conc.:
- 1 600 mg/kg bw/day (nominal)
- No. of animals per sex per dose:
- 25 mated females
- Control animals:
- yes, sham-exposed
- Details on study design:
- An additional group of mated females was dosed with 150 mg/kg aspirin and served as a positive control
- Maternal examinations:
- Body weights were recorded on Days 0, 6, 11, 15, and 17 of gestation.
All animals were observed daily for appearance and behaviour with particular attention to food consumption and weight, in order to rule out any abnormalities which may have occurred as a result of anorexic effects in the pregnant female animal - Ovaries and uterine content:
- On Day 17 all dams were subjected to Caesarean section under surgical anesthesia, and the numbers of implantation sites, resorption sites, and live and dead fetuses were recorded. The urogenital tract of each dam was examined in detail for anatomical normality.
- Fetal examinations:
- The body weights of the live pups were recorded. All fetuses were examined grossly for the presence of external congenital abnormalities. One-third of the fetuses of each litter underwent detailed visceral examinations employing the Wilson technique. The remaining two-thirds were cleared in potassium hydroxide, stained with alizarin red S dye and examined for skeletal defects.
- Clinical signs:
- no effects observed
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Reduced bodyweight gain observed in females treated with 345 and 1600 mg/kg/day.
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- no effects observed
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- not examined
- Histopathological findings: neoplastic:
- not examined
- Other effects:
- not examined
- Number of abortions:
- no effects observed
- Pre- and post-implantation loss:
- no effects observed
- Total litter losses by resorption:
- no effects observed
- Early or late resorptions:
- no effects observed
- Dead fetuses:
- effects observed, treatment-related
- Description (incidence and severity):
- There was an increase in the number of dead foetuses in females treated with 1600 mg/kg/day.
- Changes in pregnancy duration:
- no effects observed
- Changes in number of pregnant:
- no effects observed
- Details on maternal toxic effects:
- Details on maternal toxic effects:
The administration of up to 1600 mg/kg (body weight) of the test material to pregnant mice for 10 consecutive days had no clearly discernible effect on maternal survival. - Dose descriptor:
- NOAEL
- Effect level:
- 74.3 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Basis for effect level:
- body weight and weight gain
- dead fetuses
- Remarks on result:
- other: Slight toxicity (reduced bodyweight gain) at 345 and 1600 mg/kg/day
- Fetal body weight changes:
- no effects observed
- Reduction in number of live offspring:
- effects observed, treatment-related
- Description (incidence and severity):
- There was a decreased number of live offspring from females treated with 1600 mg/kg/day.
- Changes in sex ratio:
- no effects observed
- Changes in litter size and weights:
- no effects observed
- Changes in postnatal survival:
- no effects observed
- External malformations:
- no effects observed
- Skeletal malformations:
- no effects observed
- Visceral malformations:
- no effects observed
- Other effects:
- effects observed, treatment-related
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:no effects
Details on embryotoxic / teratogenic effects:
The administration of up to 1600 mg/kg (body weight) of the test material to pregnant mice for 10 consecutive days had no clearly discernible effect on fetal survival. The number of abnormalities seen in either soft or skeletal tissues of the test groups did not differ from the number occurring spontaneously in the sham-treated controls. - Dose descriptor:
- NOAEL
- Effect level:
- 345 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- reduction in number of live offspring
- other: Delyaed ossification
- Remarks on result:
- other: At the highest dose tested, 1600 mg/kg/day, there was an increase in the number of litters containing a dead foetus and some reductions in ossification.
- Key result
- Developmental effects observed:
- yes
- Lowest effective dose / conc.:
- 1 600 mg/kg bw/day (nominal)
- Treatment related:
- yes
- Relation to maternal toxicity:
- developmental effects as a secondary non-specific consequence of maternal toxicity effects
- Dose response relationship:
- not specified
- Conclusions:
- The NOAEL for maternal toxicity was determined to be 74.3 mg/kg/day, due to reduced bodyweight gain and number of dead foetuses. The NOAEL for developmental toxicity was 345 mg/kg/day, due to number of dead foetuses and delayed ossification.
- Executive summary:
In a developmental toxicity study in mice, apple cider vinegar, that contains 5% acetic acid, was administered by gavage at dose levels of 0, 16, 74.3, 345 and 1600 mg/kg/day for 10m consecutive days. The authors reported that administration of up to 1600 mg/kg bodyweight of the test material to dams for 10 days revealed no discernible effect on maternal or foetal survival, or on soft or skeletal tissues.
There was no effect on the foetal development, in the presence of slight maternal toxicity (reduced bodyweight gain) at 345 mg/kg/day. At the highest dose tested, 1600 mg/kg/day, there was an increase in the number of litters containing a dead foetus and some reductions in ossification. The NOAEL for maternal and developmental toxicity in mice were 74.3 mg/kg/day and 345 mg/kg/day, respectively.
Referenceopen allclose all
Table 2 - Litter data
Category |
Group and Exposure (analysed concentration – ppm) |
|||||
1 - Control |
2 - 24 |
3 - 104 |
4 - Untreated |
|||
No. with live young |
5 |
5 |
2 |
(4) |
4 |
|
Corpora lutea/dam |
14.6 |
14.6 |
15 |
(14.5) |
15.3 |
|
Implantations/dam |
14.0 |
14.4 |
14.5 |
(14.3) |
14.5 |
|
Pre-implantation loss % |
3.8 |
1.3 |
3.0 |
(1.5) |
4.4 |
|
Early embryonic death |
1.4 |
0.6 |
1.0 |
(7.5) |
2.0 |
|
Late embryonic death |
0.0 |
0.0 |
- |
- |
- |
|
Total embryonic death |
1.4 |
0.6 |
- |
- |
- |
|
Post-implantation loss % |
9.9 |
4.2 |
7.7 |
(53.9) |
12.0 |
|
Live young/dam |
12.6 |
13.8 |
13.5 |
(6.8) |
12.5 |
|
Litter weight |
50.31 |
52.09 |
NR |
NR |
||
Mean foetal weight |
3.99 |
3.78 |
NR |
NR |
||
EMBRYONIC DEATHS |
||||||
Total (early) 0 |
- |
2 |
1 |
(-) |
2 |
|
1 |
3 |
3 |
- |
(-) |
1 |
|
2 |
2 |
- |
1 |
(-) |
- |
|
3 |
- |
- |
- |
(-) |
- |
|
= > 4 |
- | - | - | (2) |
1 |
NR not recordable
( ) data from all pregnant animals, inclusive of 2 showing total resorption
Effect on developmental toxicity: via oral route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 345 mg/kg bw/day
- Study duration:
- subacute
- Species:
- mouse
- Quality of whole database:
- NOTE: NOAEL is for developmental effects with apple cider vinegar (5% acetic acid). There are studies in rats, mice and rabbits considered equivalent or similar to EU Method B.31 (Prenatal Developmental Toxicity Study). These all pre-date GLP and are evaluated at Klimisch score=2.
Effect on developmental toxicity: via inhalation route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEC
- 104 mg/m³
- Study duration:
- subacute
- Species:
- rat
- Quality of whole database:
- The key study is GLP compliant. It is a preliminary study and the number of animals are insufficient for a full evaluation of developmental effects however it is reliable (Klimisch=1).
Effect on developmental toxicity: via dermal route
- Endpoint conclusion:
- no study available
Additional information
Non-human data
A range-finding study in which rats were exposed to acetic anhydride by inhalation reported irritation of the eyes and upper respiratory tract of the dams at 25 ppm (104 mg/m3), but no effects on the foetus (HRC, 1994). Increased resorptions, most likely a consequence of maternal toxicity, were reported at 100 ppm (418 mg/m3). At this dose level, over the exposure period, dams displayed continually worsening effects of eye and respiratory tract irritation and, most likely as a consequence, a decrease in food and water consumption, finally expressed as a large decrease in bodyweight. This test group was discontinued on day 13 post-coitum after only 7 exposures. Maternal toxicity following inhalation exposure occurs at relatively low concentrations (100 mg/m3). The MTD may reflect the strongly exothermic aqueous hydrolysis of acetic anhydride that may exacerbate local effects of the acetic acid produced.
Within an aqueous environment, acetic anhydride is rapidly hydrolysed to acetic acid. Developmental toxicity data are available for apple cider vinegar (containing 5% acetic acid). As acetic anhydride is rapidly and extensively transformedin vivoto acetic acid, it is reasonable to consider systemic exposure to the two substances comparable and systemic toxicity endpoints, such as reproduction and development, would be similar in animals exposed to either substance. In contrast, local toxicity effects of the two chemicals are likely to depend upon the molecular structure of the parent substance and its metabolic/chemical fate within the micro-environment of the site of first contact.
Considering the acetate metabolite, developmental toxicity studies in rats, mice and rabbits have been reported for apple cider vinegar, that contains 5% acetic acid, administered by gavage at dose levels of 0, 16, 74.3, 345 and 1600 mg/kg/day (Morgareidge, 1974). There was no evidence of a direct embryo toxicity or teratogenic potential and the NOAEL values for maternal and developmental toxicity in mice were 74 and 345 mg/kg/day, respectively.
The low systemic exposure to acetate, following administration of acetic anhydride at concentrations below the NOAEC for local effects is discussed for reproductive toxicity. Such considerations are also relevant to developmental toxicity.
Human data
No relevant human information is available.
Justification for classification or non-classification
There is no evidence to indicate adverse reproductive or developmental potential to humans for acetic anhydride. Therefore classification is not warranted.
Additional information
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.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.