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Key value for chemical safety assessment

Effects on fertility

Description of key information
No further information available.
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

No guideline reproduction studies are available for acetic acid.

This 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; EFSA, 2013).

Systemic and local effects - inhalation exposure

Humans may be exposed to acetic acid via inhalation, oral or dermal routes of exposure. Occupational exposure occurs through inhalation and dermal contact. The principle concerns relating to exposure to concentrated forms of this material are local effects at the site of first contact and have been discussed in detail within the endpoint summary for irritation. An atmospheric concentration of 10 ppm (25 mg/m3) acetic acid is the proposed NOAEC for local irritation effects. Systemic exposure at this concentration is insignificant. For an 8 hour day spent at light work, and assuming 100% absorption of acetic acid for a worker would be 25 mg/m3* wRV m3/kg bw = 25 * 0.144 = 3.6 mg/kg bw. 

To put this intake into perspective with the known removal of acetate, 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, in humans 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 estimated as average human (infant) dietary intake (Ishiwata et al., 2002), with peak excursions up to 240 mg/kg bw /day (EU DAR, 2008).

In more dilute solutions, below the threshold for irritation and hence local effects, systemic availability from dermal exposure may be relevant. However for the same arguments as above, the systemic availability of acetate from dermal exposure to dilute solutions of acetic acid are insignificant.

Citation:

EFSA (2013): Conclusion on the peer review of the pesticide risk assessment of the active substance acetic acid; EFSA Journal 2013;11(1):3060


Short description of key information:
Sufficient information exists to conclude that there is no evidence of fertility effects associated with human exposure to acetic acid.

Effects on developmental toxicity

Description of key information
There is no evidence of a direct embryo toxicity or teratogenic potential of acetic acid derived from studies in rats, mice and rabbits.  Nor is there any information of adverse effects in humans exposed to this substance, via foodstuffs,  throughout their lifespan.
Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
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
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.
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 nidation or on maternal survival.
Dose descriptor:
NOAEL
Effect level:
345 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: developmental toxicity
Dose descriptor:
NOAEL
Effect level:
74.3 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
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
Basis for effect level:
other: developmental toxicity
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.
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 of 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. 

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 study available
Quality of whole database:
There are no developemental toxicity studies via the inhalation route.
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Quality of whole database:
There are no developemental toxicity studies via the dermal route.
Additional information

Non-human data

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). For each species they reported that administration of up to 1600 mg/kg bodyweight of the test material to dams (10 consecutive days for rats & mice, 13 for rabbits) revealed no discernable effect on maternal or foetal survival, or on soft of skeletal tissues.

They reported that in rats there was no effect on maternal or foetal toxicity, with the NOAEL for maternal and developmental toxicity reported as 1600 mg/kg/day. There was no effect on the foetal development, in the presence of slight maternal toxicity, in mice (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. In rabbits there was a reduction in pregnancy rate at the high dose and from 74 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 DAR, 2008). These effects are considered not to be a direct effect on embryonic implantation and development of acetic acid (EU DAR, 2008). It is likely that this accounts for the apparent increased sensitivity of this species to oral administration of acetic acid.

The NOAEL values for maternal and developmental toxicity in mice of 74 and 345 mg/kg/day, respectively.

Human data

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).


Justification for selection of Effect on developmental toxicity: via oral route:
This is one of three summaries detailing the results of a single published paper with apple cider vinegar (5% acetic acid). This summary is selected as the mouse is more sensitive than the rat. Note effects in rabbit are considered to be a consequence of the bactericidal properties of, orally administered, acetic acid within the gastrointestinal tract of female rabbits (EU, 2008).

Justification for classification or non-classification

There is sufficient direct information for acetic acid developmental studies and weight of evidence information relating to both developmental and fertility effects to conclude that there is no reproductive or developmental potential for this substance and that classification is not warranted.

Additional information