Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

In the study reported by van Esch, 1955 rats were fed propyl gallate in the diet at concentrations equivalent to doses of 18.2, 104 or 260 mg/kg bw/day for 2 successive generations. No effects on reproduction performance nor on indices of reproduction were reported, and at autopsy no abnormalities were observed in the organs or tissues of the rats. This result is in line with additional data presented in the EFSA publication "Scientific Opinion on the re-evaluation of propyl gallate (E310) as a food additive" from 2014. Moreover, no adverse effects on reproductive organs of male and female animals were reported in the e.g. key repeated dose toxicity study (Speijers, 1993, see IUCLID section 7.5.1). It can be concluded that propyl gallate does not warrant classification for reproductive toxicity based on an assessment of the available data in a weight-of-evidence approach.

Link to relevant study records

Referenceopen allclose all

Endpoint:
two-generation reproductive toxicity
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
1955
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study
Reference:
Composition 0
Composition 0
Composition 0
Qualifier:
no guideline followed
Principles of method if other than guideline:
Rats were fed propyl gallate in the diet at concentrations equivalent to doses of 18.2, 104 or 260 mg/kg bw/day for two successive generations.
GLP compliance:
no
Limit test:
no
Test material information:
Composition 1
Species:
rat
Strain:
not specified
Sex:
male/female
Route of administration:
oral: feed
Dose / conc.:
18.2 mg/kg bw/day
Dose / conc.:
104 mg/kg bw/day
Dose / conc.:
260 mg/kg bw/day
Details on study design:
Rats were fed propyl gallate in the diet at concentrations equivalent to doses of 18.2, 104 or 260 mg/kg bw/day for two successive generations.
No effects on reproduction performance nor on indices of reproduction were reported. At autopsy no abnormalities were observed in the organs or tissues of the rats.
Key result
Dose descriptor:
NOAEL
Effect level:
260 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no adverse effects observed
Remarks on result:
other: no adverse effects observed
Critical effects observed:
not specified
No effects on reproduction performance nor on indices of reproduction were reported. At autopsy no abnormalities were observed in the organs or tissues of the rats.
Key result
Dose descriptor:
NOAEL
Effect level:
260 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no adverse effects observed
Remarks on result:
other: no adverse effects observed
Critical effects observed:
not specified
No effects on reproduction performance nor on indices of reproduction were reported. At autopsy no abnormalities were observed in the organs or tissues of the rats.
Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
260 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no adverse effects observed
Remarks on result:
other: no adverse effects observed
Critical effects observed:
not specified
Key result
Reproductive effects observed:
no
Conclusions:
In the study reported by van Esch, 1955 rats were fed Propyl gallate in the diet at concentrations equivalent to doses of 18.2, 104 or 260 mg/kg bw/day for 2 successive generations. No effects on reproduction performance nor on indices of reproduction were reported, and at autopsy no abnormalities were observed in the organs or tissues of the rats.
Executive summary:

In the study reported by van Esch, 1955 rats were fed Propyl gallate in the diet at concentrations equivalent to doses of 18.2, 104 or 260 mg/kg bw/day for 2 successive generations. No effects on reproduction performance nor on indices of reproduction were reported, and at autopsy no abnormalities were observed in the organs or tissues of the rats.

No effects on reproduction performance nor on indices of reproduction were reported. At autopsy no abnormalities were observed in the organs or tissues of the rats.

Endpoint:
reproductive toxicity, other
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
secondary literature
Reference:
Composition 0
Composition 0
Composition 0
Composition 0
Test material information:
Composition 1
Conclusions:
Based on the presented data in the EFSA publication "Scientific Opinion on the re-evaluation of propyl gallate (E310) as a food additive" from 2014 it can be concluded that Propyl gallate does not warrant classification for reproductive toxicity.
Executive summary:

In the EFSA publication "Scientific Opinion on the re-evaluation of propyl gallate (E310) as a food additive", 2014 several reproductive toxicity studies conducted with Propyl gallate were presented.

For rats, the results from the study reported by van Esch, 1955 were summarized. In this study, rats were fed Propyl gallate in the diet at concentrations equivalent to doses of 18.2, 104 or 260 mg/kg bw/day for 2 successive generations. No effects on reproduction performance nor on indices of reproduction were reported, and at autopsy no abnormalities were observed in the organs or tissues of the rats.

In the CIR review, 2007 data from van Esch, 1955 was cited. It was reported that rats were fed Propyl gallate in the diet at concentrations equivalent to 31.5, 180 or 450 mg/kg bw/day for more than 3 months until a few litters had been produced. Propyl gallate was reported not to have produced any significant changes in growth or reproduction and no significant abnormalities were attributed to treatment at necropsy. At 31.5 mg/kg bw/day, organ weights and haematological values did not differ significantly from control.

At doses of 4 mg/kg bw/day in rats for 6 months followed by 8 mg propyl gallate per kg bw/day for a further 6 months, degenerative changes in the testes were observed (Karplyuk, 1960). This study was judged to be inadequately reported and thus not considered for the assessment.

For guinea pigs, the results from the study reported by Orten et al., 1948 were provided. Male and female guinea pigs (14 males and 6 females/group, 3 -4 weeks old) were dosed in the diet with 0 or 4.68 mg Propyl gallate/kg bw/day. After 12 months, the six females in each group were mated with males from the same group. Only one litter with three offspring was obtained from the six control females while three litters of three offsprings were obtained from the six dosed females. There was no effect on gross appearance or rate of growth and no gross abnormalities were found at autopsy. Histological examination of liver, kidney, spleen, testes ovaries, adrenals, heart and lungs did not disclose any pathological effects. It was not specified if mothers and/or offspring were examined. There was no compound effect on the growth of one litter of the dosed females when compared to one litter of the control animals.

For pigs, the results provided by van Esch, 1955 were reported in the EFSA review publication. Pigs fed with Propyl gallate in the diet with concentrations of 0.0035, 0.2 or 200 mg/kg diet for more than three months until a few litters had been produced. Propyl gallate was reported not to have produced significant changes in growth or reproduction and no significant abnormalities were attributed to treatment at necropsy. At 14 mg/kg bw/day 0.0035 diet, organ weights and haematological values did not differ significantly from control.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

In the EFSA publication "Scientific Opinion on the re-evaluation of propyl gallate (E310) as a food additive", 2014 several reproductive toxicity studies conducted with propyl gallate were presented.

For rats, the results from the study reported by van Esch, 1955 were presented. In this study, rats were fed propyl gallate in the diet at concentrations equivalent to doses of 18.2, 104 or 260 mg/kg bw/day for 2 successive generations. No effects on reproduction performance nor on indices of reproduction were reported, and at autopsy no abnormalities were observed in the organs or tissues of the rats.

Data presented in the CIR review, 2007 from van Esch, 1955 was cited in the publication by EFSA. It was reported that rats were fed propyl gallate in the diet at concentrations equivalent to 31.5, 180 or 450 mg/kg bw/day for more than 3 months until a few litters had been produced. Propyl gallate was reported not to have produced any significant changes in growth or reproduction and no significant abnormalities were attributed to treatment at necropsy. At 31.5 mg/kg bw/day, organ weights and haematological values did not differ significantly from control.

At doses of 4 mg/kg bw/day in rats for 6 months followed by 8 mg propyl gallate per kg bw/day for a further 6 months, degenerative changes in the testes were observed (Karplyuk, 1960). This study was judged to be inadequately reported and thus not considered for the assessment.

For guinea pigs, the results from the study reported by Orten et al., 1948 were provided. Male and female guinea pigs (14 males and 6 females/group, 3 -4 weeks old) were dosed in the diet with 0 or 4.68 mg propyl gallate/kg bw/day. After 12 months, the six females in each group were mated with males from the same group. Only one litter with three offspring was obtained from the six control females while three litters of three offsprings were obtained from the six dosed females. There was no effect on gross appearance or rate of growth and no gross abnormalities were found at autopsy. Histological examination of liver, kidney, spleen, testes ovaries, adrenals, heart and lungs did not disclose any pathological effects. It was not specified if mothers and/or offspring were examined. There was no compound effect on the growth of one litter of the dosed females when compared to one litter of the control animals.

For pigs, the results provided by van Esch, 1955 were reported in the EFSA review publication. Pigs fed with propyl gallate in the diet with concentrations of 0.0035, 0.2 or 200 mg/kg diet for more than three months until a few litters had been produced. Propyl gallate was reported not to have produced significant changes in growth or reproduction and no significant abnormalities were attributed to treatment at necropsy. At 14 mg/kg bw/day 0.0035 diet, organ weights and haematological values did not differ significantly from control.

Moreover, no adverse effects on reproductive organs of male and female animals were reported in the e.g. key repeated dose toxicity study (Speijers, 1993, see IUCLID section 7.5.1).

Effects on developmental toxicity

Description of key information

Tanaka et al., 1979 presented data from a developmental toxicity study, in which propyl gallate was administered orally in a feeding study to 20 pregnant female Wistar rats per dose group in dose levels of 0%, 0.4%, 1% and 2.5% corresponding to 350 mg/kg, 880 mg/kg and 2040 mg/kg bw from day 0 of gestation until the end of pregnancy in order to examine the teratogenic effects and effects on postnatal development.

Treatment-related maternal effects were observed at the highest dose in form of a significant suppression of maternal body weight gain and food consumption and a slight retardation in fetal development were observed. No evidence of an increase in fetal death or of malformation attributable to the dietary treatment with propyl gallate was observed, though some apparently spontaneous changes were found in a few fetuses. In the highest dose level group, a significantly low number of caudal vertebrae. However, all the newborns from 1 dam in the 1% group and from 2 dams in the 2.5% group were cannibalised by their dams within 2 days after birth. The postnatal development of the offspring of other dams of both groups showed no indication of morphological or behavioral changes.

Thus, the maternal and the developmental NOAEL is 880 mg/kg/day.

In the review publication on the Safety Assessment of propyl gallate by the Cosmetic Ingredient Review (CIR) Expert Panel, 2007 it was reported that in one study, female rats fed 0.5 g propyl gallate had substantially increased fetal resorption rates when compared to controls, but in four other studies, propyl gallate at doses up to 2.04 g/kg was nonteratogenic in rats, rabbits, mice, and hamsters. In addition, it has been shown in further studies that propyl gallate has a protective effect on developmental and reproductive toxicity induced by certain chemicals. It has been shown that propyl gallate reduce teratogenic effects in vitamin E-deficient pregnant rats. Also, hydroxyurea (HU)-induced teratogenesis was reduced by propyl gallate.

In the EFSA publication "Scientific Opinion on the re-evaluation of propyl gallate (E310) as a food additive", 2014 several developmental toxicity studies conducted with propyl gallate were presented. For mice, the study from Food and Drugs Research Labs (FDRL) (also cited in CIR, 2007) was summarized. In this prenatal developmental toxicity study mice were given 3 -300 mg/kg bw/day on gestation days (GD) 6 -15 (22 -25 animals/group). The dams were killed and fetuses were removed on GD17. Doses of up to 300 mg/kg bw given for 10 consecutive days had no effect on implantation or on maternal or fetal survival. The number of visceral, skeletal and external abnormalities in the test item treated fetuses did not differ to the control animals receiving corn oil.

For rats, the EFSA report cited and summarized data from several studies. In the study by Telford et al., 1962 Walter Reed-Carworth rats (9 animals) with an average body weight of 200 g were given propyl gallate at a dose of 0.5 g via the diet (possibly equivalent to 100 mg/kg bw/day) during pregnancy. Increased fetal resorption rates were observed. As in this study only one dose was tested and the animal number was low the study was considered as a very limited study.

Similar to mice, FDRL also conducted a prenatal developmental toxicity study in rats given orally 3 -300 mg/kg bw on gestation days 6 -15 (22 -25 animals/group). Dams were killed and fetuses removed on GD 20. Propyl gallate up to 300 mg/kg bw for 10 consecutive days had no effect on implantation or on maternal or fetal survival. The number of visceral, skeletal and external abnormalities in the test group fetuses did not differ to control animals.

In the study by Tanaka et al., 1979 (see study specific IUCLID entry in section 7.8.2) female Wistar rats (20 animals/group, except 18 animals/high dose group) were given propyl gallate in the diet at doses of 0, 0.4, 1 and 2.5% (approximately equivalent to 0, 350, 880 and 2000 mg/kg bw/day) throughout pregnancy. On GD 20, at least 13 dams per group were sacrificed for fetal examination. The remaining animals were allowed to deliver their litters which were autopsied at week of age. The high dose caused a decrease in total number of offspring’s and induced a slight retardation in fetal development, a marked suppression of maternal body weight gain and food consumption was also noted. There were no evidence of increases in fetal deaths or malformations due to propyl gallate at any concentration. Also, there was no evidence of developmental toxicity for the groups received 350 or 880 mg/kg bw/day. Five females per group were allowed to deliver normally and appearance, behaviour and organ weights were normal in the dams and offspring.

For rabbits, the study from FDRL, 1973 (also cited in CIR, 2007) was presented. No increase in fetal abnormalities or evidence of embryotoxicity were in observed in rabbits (20 -50/group). The animals received daily doses of up to 250 mg/kg bw by stomach tube on GD days 6 -18.

For hamsters, the study from FDRL, 1972 (also cited in CIR, 2007) was summarized. Propyl gallate was tested in a prenatal developmental toxicity study in hamsters given orally 2.5 -250 mg/kg bw on GD 6 -10 (22 -25 animals/group). Dams were killed and fetuses removed on GD14. The treatment with the test item had no effect on implantation or on maternal or fetal survival. The number of visceral, skeletal and external abnormalities in the test group fetuses did not differ to control animals fed with corn oil.

EFSA concluded, that doses around 300 mg/kg bw/day did not appear to be associated with adverse effects and could be regarded as NOAEL for developmental toxicity.

Link to relevant study records

Referenceopen allclose all

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Reference:
Composition 0
Qualifier:
no guideline followed
Principles of method if other than guideline:
Propyl gallate was given ad libitum to pregnant rats during pregnancy at levels of 0, 0.4, 1, 2.5% in the diet and its teratogenic effect and effect on postnatal development were examined.

- Principle of test: Propyl gallate was given ad libitum to pregnant rats during pregnancy at levels of 0, 0.4, 1, 2.5% in the diet and its teratogenic effect and effect on postnatal development were examined.

- Short description of test conditions: The concentrations of Propyl gallate were selected based on the results obtained from a preliminary test in pregnant rats. On the 20th day of gestation, 13 out of 18 animals in the highest dose level group and 15 out of 20 in other groups were sacrificed for fetal examination. Fetuses were removed from the dams.

- Parameters analysed / observed: Implantation sites and numbers of live and dead fetuses, body weight, skeletal bone anomalies, organ anomalies. The remaining 5 dams in each group were allowed to give birth and postnatal development of the newborn animals was examined in each case. The offspring were weaned on the 4th week after birth and autopsied on the 8th week for examination of visceral and skeletal anomalies. During the postnatal life of the offspring, the general appearance, behavior and survival were checked daily, and body weight was measured weekly.
GLP compliance:
not specified
Limit test:
no
Test material information:
Composition 1
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material:
Nakarai Chemical Co. Ltd., Kyoto
Species:
rat
Strain:
Wistar
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Nihon Rat Co. Ltd., Tokyo
- Age at study initiation: more than 11 weeks
- Weight at study initiation: approx. 220 g
- Fasting period before study: no data
- Housing: Animals were housed in an air-conditioned animal. Each pregnant rat was housed individually.
- Diet (e.g. ad libitum): basal diet (NMS, manufactured by Oriental Yeast Co. Ltd., Tokyo), ad libitum
- Water (e.g. ad libitum): no data
- Acclimation period: no data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 25 ± 2 °C
- Humidity (%): 55 ± 5%
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): no data
Route of administration:
oral: feed
Vehicle:
not specified
Details on exposure:
DIET PREPARATION
Propyl gallate diet was prepared to contain 0, 0.4, 1 and 2.5% levels of the compound in a basal diet.
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused: The primiparous female rats were caged with males overnight.
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy
Duration of treatment / exposure:
During pregnancy
Frequency of treatment:
ad libitum
Dose / conc.:
0 other: % in diet
Remarks:
equals to 0 mg/kg bw
Dose / conc.:
0.4 other: % in diet
Remarks:
equals to 350 mg/kg bw
Dose / conc.:
1 other: % in diet
Remarks:
equals to 880 mg/kg bw
Dose / conc.:
2.5 other: % in diet
Remarks:
equals to 2040 mg/kg bw
No. of animals per sex per dose:
20 pregnant rats
Control animals:
yes, concurrent no treatment
Details on study design:
- Dose selection rationale: The concentrations of propyl gallate in the diet were selected based on the results obtained from a preliminary test in pregnant rats. Net amounts of Propyl gallate ingested were calculated from the daily food consumptions.
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: weekly

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Time schedule for examinations: daily
- Net amounts of Propyl gallate ingested were calculated from the daily food consumption
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: daily

POST-MORTEM EXAMINATIONS: No
- Sacrifice on gestation day 20 (13 out of 18 in the highest dose level group and 15 out of 20 in other groups were sacrificed for fetal examination)
Ovaries and uterine content:
The ovaries and uterus was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: No data
- Number of late resorptions: No data
Fetal examinations:
- External examinations: Yes: (13 out of 18 animals in the highest dose level group and 15 out of 20 in other groups)
- Soft tissue examinations: Yes
- Skeletal examinations: Yes
- Head examinations: Yes
13 out of 18 animals in the highest dose level group and 15 out of 20 in other groups were sacrificed for fetal examination. After gross observations, live fetuses from each dam were weighed and then divided into two groups. One group was fixed with 80% alcohol solution to clear the bones and stained with alizarine red S9) for examination of skeletal bone anomalies, and the other was fixed in 10% neutral formalin solution for 2 weeks, then internal organ anomalies were examined by the method of Wilson.
Statistics:
Statistical analysis of the results obtained was performed according to the method of Weil.
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):
At the highest dose level, a marked body weight loss and low food consumption were observed following the commencement of the treatment. However, these parameters began to increase gradually in a few days and the
food consumption was comparable with that of the control group after 8 days, though the body weight did not regain the level of the control group throughout the treatment. Maternal body weight gains in the 0.4 and 1% groups were similar to those of the control group during pregnancy.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Food and water consumptions in the 0.4 and 1% groups were similar to those of the control group during pregnancy. At the highest dose level of 2.5%, a low food consumption were observed following the commencement of the treatment. However, this parameter began to increase gradually in a few days and the food consumption was comparable with that of the control group after 8 days.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not specified
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not examined
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
not examined
Details on results:
No effects except changes in body weights were observed in pregnant female rats. The mean amounts of propyl gallate ingested daily during pregnancy were 0.35g/kg for the 0.4% group, 0.88g/kg for the 1% group and 2.04 g/g/kg for the 2.5% group
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:
not specified
Dead fetuses:
no effects observed
Changes in pregnancy duration:
not specified
Changes in number of pregnant:
no effects observed
Details on maternal toxic effects:
No significant differences between the control and Propyl gallate groups were found in the uterine weight with fetuses, number of corpora lutea or implantations and rate of nidation.
Key result
Dose descriptor:
NOAEL
Effect level:
880 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
body weight and weight gain
food consumption and compound intake
Abnormalities:
not specified
Fetal body weight changes:
no effects observed
Description (incidence and severity):
At the highest dose level a slightly low body weight of fetuses was obtained but the difference from the control was not statistically significant.
The body weight gains of offspring after birth showed gradual increases in all groups, and there was no evidence of growth retardation in the body weight at the 8th week in the terminal stage of the experiment.
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Description (incidence and severity):
The sex ratio was similar in all groups.
Changes in litter size and weights:
no effects observed
Description (incidence and severity):
The litter size was similar in all groups.
Changes in postnatal survival:
effects observed, non-treatment-related
Description (incidence and severity):
The viability index was significantly low in the 1 and 2.5% groups compared with that of the control because all the newborn animals obtained from 1 dam in the 1% group and 2 dams in the 2.5% group were killed by cannibalism of the dams within 2 days after birth. However, no marked differences between the control and Propyl gallate groups, including the 1% and 2.5% groups, were found in the survival indexes.
External malformations:
no effects observed
Skeletal malformations:
effects observed, treatment-related
Description (incidence and severity):
In one fetus, a cranioshisis accompanied by a patial absence of skull was observed in the 0.4% group. The cranioshisis was considered to be spontaneous, because the type and the incidence of the malformation were similar to those observed in untreated rats in the tested laboratory. Some kinds of anomaly and variation were found in a few fetuses of the Propyl gallate-treated groups. A fetus in the 0.4% group showed variations such as non-ossification of sacral and caudal vertebrae. A minor anomaly (partial fusion of the cervical arch) was observed in a fetus of the 1% group. Minor anomalies observed in the 2.5% group were absence of the 7th to 10th thoracic centrum in one case and a bipartite centrum of the 1st lumbar vertebrae in another. All fetuses with these changes were obtained from different dams. The changes observed in the skeletal system were similar in types to those in the laboratories’ cumulative control data. Moreover, the incidences of the changes noted in the present experiment were low and not significantly different from the control. It thus appears that the changes observed were spontaneous. Some fetuses with lumbar ribs were also observed in all groups, but the frequencies were low and not related to the dietary level of propyl gallate. No marked changes in the state of ossification as indicated by the numbers, shapes and stainings of sternebrae, metacarpi, metatarsi and caudal vertebrae were found in the 0.4 or 1% group, as in the control group. In the highest dose level group, however, a significantly low number of caudal vertebrae was noted. Although this finding suggests a tendency for retardation of ossification in the fetal stage of the highest dose group, no such change was found in the rats examined after weaning.
Visceral malformations:
no effects observed
Other effects:
no effects observed
Description (incidence and severity):
Organ weights: No significant differences were observed in the orgen weights of offspring sacrificed at the terminal stage.
Details on embryotoxic / teratogenic effects:
No significant differences in organ weights were observed between the control and Propyl gallate groups and no external, visceral or skeletal anomalies were found in any of the groups examined. A slight retardation in the fetal development were noted only in the highest dose level group. However, no evidence of increase in fetal death and no malformation attributable to the dietary Propyl gallate treatment were obtained, though some kinds of skeletal changes which were considered to be spontaneous were observed in a few fetuses. The postnatal developments showed no behavioral or morphological changes except for the cannibalized newborns.
Key result
Dose descriptor:
NOAEL
Effect level:
880 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
not specified
Basis for effect level:
skeletal malformations
Abnormalities:
not specified
Developmental effects observed:
not specified
Conclusions:
Administration of Propyl gallate by feed during pregnancy resulted in a NOAEL of 880 mg/kg/day for maternal and developmental toxicity.
Executive summary:

In a developmental toxicity study, Propyl gallate was administered orally in a feeding study to 20 pregnant female Wistar rats per dose group in dose levels of 0%, 0.4%, 1% and 2.5% corresponding to 350 mg/kg, 880 mg/kg and 2040 mg/kg bw from day 0 of gestation until the end of pregnancy in order to examine the teratogenic effects and effects on postnatal development.

Treatment-related maternal effects were observed at the highest dose in form of a significant supression of maternal body weight gain and food consumption and a slight retardation in fetal development were observed. No evidence of an increase in fetal death or of malformation attributable to the dietary treatment with Propyl gallate was observed, though some apparently spontaneous changes were found in a few fetuses. In the highest dose level group, a significantly low number of caudal vertebrae. However, all the newborns from 1 dam in the 1% group and from 2 dams in the 2.5% group were cannibalised by their dams within 2 days after birth. The postnatal development of the offspring of other dams of both groups showed no indication of morphological or behavioral changes.

Thus, the maternal and the developmental NOAEL is 880 mg/kg/day.

The developmental toxicity study in the rat is classified acceptable, since the study is well documented and meets generally accepted scientific principles which are acceptable for assessment.

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Reference:
Composition 0
Composition 0
Composition 0
Composition 0
Test material information:
Composition 1

Several studies on developmental toxicity of Propyl gallate has been cited in the EFSA report.

Propyl gallate was tested in a prenatal developmental toxicity study in mice given orally 3-300 mg Propyl gallate /kg/bw on gestation days (GD) 6-15 (22-25 animals/group) (FDRL, 1972, as reported in CIR, 2007). Dams were killed and fetuses removed on GD 17. Propyl gallate up to 300 mg/kg bw for 10 consecutive days had no effect on implantation or on maternal or fetal survival (CIR, 2007). The number of visceral, skeletal and external abnormalities in the test group fetuses did not differ to control animals (fed corn oil) (FDRL, 1972, as reported in CIR, 2007).

In Walter Reed-Carworth Farms rats (9 animals; average body weight 200 g) fed Propyl gallate at a dose of 0.5 g in diet (possibly equivalent to 100 mg/kg bw/day) during pregnancy, increased fetal resorption rates were observed (Telford et al., 1962, as reported in BIBRA, 1989a, CIR, 2007). In this study only one dose was tested and the number of animals per group was low. This study was therefore considered as a very limited study.

 

Propyl gallate was tested in a prenatal developmental toxicity study in rats given orally 3-300 mg Propyl gallate /kg/bw on gestation days (GD) 6-15 (22-25 animals/group). Dams were killed and fetuses removed on GD 20. Propyl gallate up to 300 mg/kg bw for 10 consecutive days had no effect on implantation or on maternal or fetal survival. The number of visceral, skeletal and external abnormalities in the test group fetuses did not differ to control animals (fed corn oil) (FDRL, 1972, as reported in CIR, 2007).

 

Female Wistar rats (20 animals/group, except 18 animals/highest dose-group) were given Propyl gallate in the diet at doses of 0, 0.4, 1 and 2.5 % (approximately equivalent to 0, 350, 880 and 2000 mg/kg bw/day) throughout pregnancy (Tanaka et al., 1979, BIBRA, 1989a). On GD 20, at least 13 dams per group were sacrificed for fetal examination (Tanaka et al.,1979); the remaining animals were allowed to deliver their litters which were autopsied at week 8 of age. The highest dose (2000 mg/kg bw/day) caused a decrease in the total number of offspring and induced a slight retardation in fetal development; a marked suppression of maternal body weight gain and food consumption was also noted (Tanaka et al., 1979). There was no evidence of increases in fetal deaths or malformations due to Propyl gallate at any concentration. Also, there was no evidence of developmental toxicity for the groups which received 350 or 880 mg/kg bw/day. Five females per group were allowed to deliver normally and appearance, behaviour and organ weights were normal in the dams and offspring (Tanaka et al., 1979 as reported in BIBRA, 1989a).

No increase in fetal abnormalities or evidence of embryotoxicity were observed in rabbits (20-50/group) given daily doses of up to 250 mg Propyl gallate /kg bw by stomach tube on GD days 6-18 (FDRL, 1973 as reported in BIBRA, 1989a, CIR, 2007).

Propyl gallate was tested in a prenatal developmental toxicity study in hamsters given orally 2.5-250 mg Propyl gallate /kg/bw on gestation GD 6-10 (22-25 animals/group) (FDRL, 1972, as reported in CIR, 2007). Dams were killed and fetuses removed on GD 14. Propyl gallate up to 250 mg/kg bw for 5 consecutive days had no effect on implantation or on maternal or fetal survival (CIR, 2007). The number of visceral, skeletal and external abnormalities in the test group fetuses did not differ to control animals (fed corn oil) (FDRL, 1972, as reported in CIR, 2007).

 

The Panel considered that the reproduction studies were not appropriate for hazard characterisation since they are old, poorly described and lack information about reproductive performance.

Data for developmental toxicity were less limited. Oral studies in mice, rats, rabbits and hamsters were available. Doses around 300 mg/kg bw/day did not appear to be associated with adverse effects and could be regarded as a NOAEL for developmental toxicity.

Conclusions:
Based on the assessment of available data in a weight-of-evidence approach EFSA concluded, that doses around 300 mg/kg bw/day did not appear to be associated with adverse effects and could be regarded as NOAEL for developmental toxicity.
Executive summary:

In the EFSA publication "Scientific Opinion on the re-evaluation of propyl gallate (E310) as a food additive", 2014 several developmental toxicity studies conducted with Propyl gallate were presented. For mice, the study from Food and Drugs Research Labs (FDRL) (also cited in CIR, 2007) was summarized. In this prenatal developmental toxicity study mice were given 3 -300 mg/kg bw/day on gestation days (GD) 6 -15 (22 -25 animals/group). The dams were killed and fetuses were removed on GD17. Doses of up to 300 mg/kg bw given for 10 consecutive days had no effect on implantation or on maternal or fetal survival. The number of visceral, skeletal and external abnormalities in the test item treated fetuses did not differ to the control animals receiving corn oil.

For rats, the EFSA report cited and summarized data from several studies. In the study by Telford et al., 1962 Walter Reed-Carworth rats (9 animals) with an average body weight of 200 g were given Propyl gallate at a dose of 0.5 g via the diet (possibly equivalent to 100 mg/kg bw/day) during pregnancy. Increased fetal resorption rates were observed. As in this study only one dose was tested and the animal number was low the study was considered as a very limited study.

Similar to mice, FDRL also conducted a prenatal developmental toxicity study in rats given orally 3 -300 mg/kg bw on gestation days 6 -15 (22 -25 animals/group). Dams were killed and fetuses removed on GD 20. Propyl gallate up to 300 mg/kg bw for 10 consecutive days had no effect on implantation or on maternal or fetal survival. The number of visceral, skeletal and external abnormalities in the test group fetuses did not differ to control animals.

In the study by Tanaka et al., 1979 (see study specific IUCLID entry in section 7.8.2) female Wistar rats (20 animals/group, except 18 animals/high dose group) were given Propyl gallate in the diet at doses of 0, 0.4, 1 and 2.5% (approximately equivalent to 0, 350, 880 and 2000 mg/kg bw/day) throughout pregnancy. On GD 20, at least 13 dams per group were sacrificed for fetal examination. The remaining animals were allowed to deliver their litters which were autopsied at week of age. The high dose caused a decrease in total number of offspring’s and induced a slight retardation in fetal development, a marked suppression of maternal body weight gain and food consumption was also noted. There were no evidence of increases in fetal deaths or malformations due to Propyl gallate at any concentration. Also there was no evidence of developmental toxicity for the groups received 350 or 880 mg/kg bw/day. Five females per group were allowed to deliver normally and appearance, behaviour and organ weights were normal in the dams and offspring.

For rabbits, the study from FDRL, 1973 (also cited in CIR, 2007) was presented. No increase in fetal abnormalities or evidence of embryotoxicity were in observed in rabbits (20 -50/group). The animals received daily doses of up to 250 mg/kg bw by stomach tube on GD days 6 -18.

For hamsters, the study from FDRL, 1972 (also cited in CIR, 2007) was summarized. Propyl gallate was tested in a prenatal developmental toxicity study in hamsters given orally 2.5 -250 mg/kg bw on GD 6 -10 (22 -25 animals/group). Dams were killed and fetuses removed on GD14. The treatment with the test item had no effect on implantation or on maternal or fetal survival. The number of visceral, skeletal and external abnormalities in the test group fetuses did not differ to control animals fed with corn oil.

EFSA concluded, that doses around 300 mg/kg bw/day did not appear to be associated with adverse effects and could be regarded as NOAEL for developmental toxicity.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
880 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
Comparable to guideline study
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

Tanaka et al., 1979 presented data from a developmental toxicity study, in which propyl gallate was administered orally in a feeding study to 20 pregnant female Wistar rats per dose group in dose levels of 0%, 0.4%, 1% and 2.5% corresponding to 350 mg/kg, 880 mg/kg and 2040 mg/kg bw from day 0 of gestation until the end of pregnancy in order to examine the teratogenic effects and effects on postnatal development.

Treatment-related maternal effects were observed at the highest dose in form of a significant suppression of maternal body weight gain and food consumption and a slight retardation in fetal development were observed. No evidence of an increase in fetal death or of malformation attributable to the dietary treatment with propyl gallate was observed, though some apparently spontaneous changes were found in a few fetuses. In the highest dose level group, a significantly low number of caudal vertebrae. However, all the newborns from 1 dam in the 1% group and from 2 dams in the 2.5% group were cannibalised by their dams within 2 days after birth. The postnatal development of the offspring of other dams of both groups showed no indication of morphological or behavioral changes.

Thus, the maternal and the developmental NOAEL is 880 mg/kg/day.

In the review publication on the Safety Assessment of propyl gallate by the Cosmetic Ingredient Review (CIR) Expert Panel, 2007 it was reported that in one study, female rats fed 0.5 g propyl gallate had substantially increased fetal resorption rates when compared to controls, but in four other studies, propyl gallate at doses up to 2.04 g/kg was nonteratogenic in rats, rabbits, mice, and hamsters. In addition, it has been shown in further studies that propyl gallate has a protective effect on developmental and reproductive toxicity induced by certain chemicals. It has been shown that propyl gallate reduce teratogenic effects in vitamin E-deficient pregnant rats. Also, hydroxyurea (HU)-induced teratogenesis was reduced by propyl gallate.

In the EFSA publication "Scientific Opinion on the re-evaluation of propyl gallate (E310) as a food additive", 2014 several developmental toxicity studies conducted with propyl gallate were presented. For mice, the study from Food and Drugs Research Labs (FDRL) (also cited in CIR, 2007) was summarized. In this prenatal developmental toxicity study mice were given 3 -300 mg/kg bw/day on gestation days (GD) 6 -15 (22 -25 animals/group). The dams were killed and fetuses were removed on GD17. Doses of up to 300 mg/kg bw given for 10 consecutive days had no effect on implantation or on maternal or fetal survival. The number of visceral, skeletal and external abnormalities in the test item treated fetuses did not differ to the control animals receiving corn oil.

For rats, the EFSA report cited and summarized data from several studies. In the study by Telford et al., 1962 Walter Reed-Carworth rats (9 animals) with an average body weight of 200 g were given propyl gallate at a dose of 0.5 g via the diet (possibly equivalent to 100 mg/kg bw/day) during pregnancy. Increased fetal resorption rates were observed. As in this study only one dose was tested and the animal number was low the study was considered as a very limited study.

Similar to mice, FDRL also conducted a prenatal developmental toxicity study in rats given orally 3 -300 mg/kg bw on gestation days 6 -15 (22 -25 animals/group). Dams were killed, and fetuses removed on GD 20. Propyl gallate up to 300 mg/kg bw for 10 consecutive days had no effect on implantation or on maternal or fetal survival. The number of visceral, skeletal and external abnormalities in the test group fetuses did not differ to control animals.

In the study by Tanaka et al., 1979 (see study specific IUCLID entry in section 7.8.2) female Wistar rats (20 animals/group, except 18 animals/high dose group) were given propyl gallate in the diet at doses of 0, 0.4, 1 and 2.5% (approximately equivalent to 0, 350, 880 and 2000 mg/kg bw/day) throughout pregnancy. On GD 20, at least 13 dams per group were sacrificed for fetal examination. The remaining animals were allowed to deliver their litters which were autopsied at week of age. The high dose caused a decrease in total number of offspring’s and induced a slight retardation in fetal development, a marked suppression of maternal body weight gain and food consumption was also noted. There were no evidence of increases in fetal deaths or malformations due to propyl gallate at any concentration. Also there was no evidence of developmental toxicity for the groups received 350 or 880 mg/kg bw/day. Five females per group were allowed to deliver normally and appearance, behaviour and organ weights were normal in the dams and offspring.

For rabbits, the study from FDRL, 1973 (also cited in CIR, 2007) was presented. No increase in fetal abnormalities or evidence of embryotoxicity were in observed in rabbits (20 -50/group). The animals received daily doses of up to 250 mg/kg bw by stomach tube on GD days 6 -18.

For hamsters, the study from FDRL, 1972 (also cited in CIR, 2007) was summarized. Propyl gallate was tested in a prenatal developmental toxicity study in hamsters given orally 2.5 -250 mg/kg bw on GD 6 -10 (22 -25 animals/group). Dams were killed and fetuses removed on GD14. The treatment with the test item had no effect on implantation or on maternal or fetal survival. The number of visceral, skeletal and external abnormalities in the test group fetuses did not differ to control animals fed with corn oil.

Justification for classification or non-classification

Based on the available data, it can be concluded that no classification for reproductive/developmental toxicity is warranted for the target substance propyl gallate.