Bos taurus, milk, pasteurized, homogenized, skimmed, fermented, spray-dried

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

There is a long history of safe yoghurt consumption. No reports have ever linked yoghurt consumption with toxicity effects, including toxicity effects on reproduction.

A sub-acute exposure of 2’400 mg/kg body weight (bw) of the substance Bos taurus, milk, pasteurized, homogenized, skimmed, fermented, spray-dried (EC 917-734-0) is considered safe in humans and does not have any toxic effect on reproduction.

There is no test available for reproductive toxicity for "Bos taurus, milk, pasteurized, homogenized, skimmed, fermented, spray dried." However there is a reliable data for "Powdered Lactobacillus helveticus-fermented milk". The test material used to test the toxicological properties of the substance on reproductive parameters described in this study is not exactly the same as Bos taurus, milk, pasteurized, homogenized, skimmed, fermented, spray-dried. However, the process used to prepare ‘Powdered Lactobacillus helveticus-fermented milk’ (FM) is qualitatively similar to that used in the production of ‘Bos taurus, milk, pasteurized, homogenized, skimmed, fermented, spray dried’ and is based on the same natural material (cow milk) and biological production process (bacterial fermentation). The components that are additionally removed from FM, lactic acid and casein, occur naturally in milk and milk that has been naturally exposed to microorganisms and are not expected to have important toxicological effects regarding acute oral toxicity, repeated dose oral toxicity, reproduction, or genotoxicity at the concentrations present in fermented milk products. Therefore, the toxicological properties reported on this study can be used in combination with the long historical safe consumption of yogurt and yogurt-derived products by humans assess the toxicological properties of 'Bos taurus, milk, pasteurized, homogenized, skimmed, fermented, spray dried' for this endpoint. Under the conditions of these experiments, orally administered powdered FM possesses little potential to (1) alter either the mating behavior or fertility of male or female Sprague-Dawley rats; (2) cause embryo or fetal toxicity; or (3) adversely affect pre- or postnatal development of offspring of dams administered powdered FM during pregnancy and lactation. The maximally tolerated dose (MTD) is >2000 mg/kg BW/day in both breeding/pregnant rats and the rat embryo-fetus.

Link to relevant study records

Reference

Reference 1

Endpoint:

reproductive toxicity, other

Type of information:

calculation (if not (Q)SAR)

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Calculation based on various sources of information and common knowledge.

Justification for type of information:

A sub-acute exposure of 2’400 mg/kg body weight (bw) of the substance Bos taurus, milk, pas teurized, homogenized, skimmed, fermented, spray-dried (EC 917-734-0) is considered safe in humans. Therefore, animal testing of the oral, toxicity to reproduction of the substance is not necessary.

Reasoning:
The Swiss Food Pyramid proposes a daily consume of 200 g Yoghurt per day (BLV, 2017). Under the assumption of a water content of 86 % of yoghurt, the dry substance of yoghurt and therefore yoghurt powder is 14 % of wet weight of yoghurt (BLV, 2018). This results in a proposed intake of 28 g dry weight of yoghurt powder per day. Applied to an average person (70 kg) results in a daily intake of yoghurt of 400 mg/kg bw/day. This value represents a safe, chronic intake of yoghurt per day without adverse effects.
For the derivation of a chronic Derived No Effect Level (DNEL) for human health, the ECHA provides guidance on the extrapolation from shorter studies to chronic studies (ECHA, 2012). For the extrapolation of a sub-acute study to a chronic study ECHA proposes an assessment factor of 6 to more serious adverse effects with increasing exposure times into account. The inverse conclusion suggests that the extrapolation of a chronic duration to a sub-acute duration with a factor of 6 is also possible.
Under these circumstances a sub-acute exposure to yoghurt powder of 2’400 mg/kg bw can be considered safe for humans.
The same value can be assumed for the exposure of animals to yoghurt powder. Since, according to the OECD guidelines the highest tested concentrations in rats for toxicity to reproduction should be 1’000 mg/kg bw, testing the toxicity to reproduction of yoghurt powder is not considered necessary.

Sources:
Bundesamt für Lebensmittelsicherheit und Veterinärwesen (BLV). Fachinformation Ernährung: Milch und Milchproduktekonsum in der Schweiz 2014/2015. März 2017.
Bundesamt für Lebensmittelsicherheit und Veterinärwesen. Schweizer Nährwertdatenbank, Lebensmittelsuche für Joghurt. State of knowledge: 04.05.2018.
European Chemicals Agency (ECHA). Guidance on information requirements and chemical safety assessment: Chapter R.8: Characterization of dose [concentration]-response for human health. Version 2.1. November 2012.

Qualifier:

no guideline required

Principles of method if other than guideline:

See Field Justification for type of information

Key result

Dose descriptor:

NOEL

Effect level:

> 2 400 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Remarks on result:

not determinable due to absence of adverse toxic effects

Key result

Dose descriptor:

NOAEL

Effect level:

> 2 400 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Remarks on result:

not determinable due to absence of adverse toxic effects

Key result

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

> 2 400 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Remarks on result:

not determinable due to absence of adverse toxic effects

Key result

Reproductive effects observed:

no

Conclusions:

A sub-acute exposure of 2’400 mg/kg body weight (bw) of the substance Bos taurus, milk, pasteurized, homogenized, skimmed, fermented, spray-dried (EC 917-734-0) is considered safe in humans, including no toxic effects to reproduction.

Executive summary:

A sub-acute exposure of 2’400 mg/kg body weight (bw) of the substance Bos taurus, milk, pas teurized, homogenized, skimmed, fermented, spray-dried (EC 917-734-0) is considered safe in humans. Therefore, animal testing of the oral toxicity to reproduction of the substance is not necessary.

Reasoning:

The Swiss Food Pyramid proposes a daily consume of 200 g Yoghurt per day (BLV, 2017). Under the assumption of a water content of 86 % of yoghurt, the dry substance of yoghurt and therefore yoghurt powder is 14 % of wet weight of yoghurt (BLV, 2018). This results in a proposed intake of 28 g dry weight of yoghurt powder per day. Applied to an average person (70 kg) results in a daily intake of yoghurt of 400 mg/kg bw/day. This value represents a safe, chronic intake of yoghurt per day without adverse effects.

For the derivation of a chronic Derived No Effect Level (DNEL) for human health, the ECHA provides guidance on the extrapolation from shorter studies to chronic studies (ECHA, 2012). For the extrapolation of a sub-acute study to a chronic study ECHA proposes an assessment factor of 6 to more serious adverse effects with increasing exposure times into account. The inverse conclusion suggests that the extrapolation of a chronic duration to a sub-acute duration with a factor of 6 is also possible.

Under these circumstances a sub-acute exposure to yoghurt powder of 2’400 mg/kg bw can be considered safe for humans.

The same value can be assumed for the exposure of animals to yoghurt powder. Since, according to the OECD guidelines the highest tested concentrations in rats for toxicity to reproduction should be 1’000 mg/kg bw, testing the  toxicity to reproduction of yoghurt powder is not considered necessary.

Reference 2

Endpoint:

extended one-generation reproductive toxicity - with developmental neurotoxicity (Cohorts 1A, 1B without extension, 2A and 2B)

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

Not reported

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Non-GLP, near guideline, published in peer reviewed literature, adequate for assessment

Justification for type of information:

The test material used to test the toxicological properties described in the study used for this RSS is not exactly the same as Bos taurus, milk, pasteurized, homogenized, skimmed, fermented, spray-dried. However, the process used to prepare ‘Powdered Lactobacillus helveticus-fermented milk’ (FM) is qualitatively similar to that used in the production of ‘Bos taurus, milk, pasteurized, homogenized, skimmed, fermented, spray dried’ and is based on the same natural material (cow milk) and biological production process (bacterial fermentation). The components that are additionally removed from FM, lactic acid and casein, occur naturally in milk and milk that has been naturally exposed to microorganisms and are not expected to have important toxicological effects regarding acute oral toxicity, repeated dose oral toxicity, reproduction, or genotoxicity at the concentrations present in fermented milk products. Therefore, the toxicological properties reported on this study can be used in combination with the long historical safe consumption of yogurt and yogurt-derived products by humans assess the toxicological properties of 'Bos taurus, milk, pasteurized, homogenized, skimmed, fermented, spray dried' for this endpoint.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 443 (Extended One-Generation Reproductive Toxicity Study)

GLP compliance:

no

Limit test:

no

Justification for study design:

The specific goals of the experiments were (1) to determine the effects of fermented milk (FM) on (a) fertility and reproductive behavior in both sexes of rats, (b) embryo-fetal development in pregnant rats, and (c) pre- and postnatal development of rats exposed to FM in utero and during lactation; and (2) to estimate the no-observable-adverse-effect doses of FM in maternal and fetal rats. During the conduct of these classical segment I, II, and III studies, the test material was powdered Lactobacillus helveticus–fermented milk (FM). FM (0, 500, 1000 or 2000 mg/kg bodyweight [BW]/day) was administered to males by oral gavage from 4 weeks prior to mating until sacrifice, and to females from 2 weeks prior to mating through day 20 of lactation. Evaluative parameters included monitoring grossly observable clinical signs; food consumption and body weight gains; mating behavior and fertility indices of both sexes; implantation and maintenance of embryos; sex ratio of live pups; fetal viability; incidences of external, visceral or skeletal variations; growth and behavioral development; as well as reproductive capabilities of F1 offspring exposed to FM during gestation and lactation.

Specific details on test material used for the study:

Reconstituted skim milk (9%, w/w) was pasteurized and fermented with L. helveticus CM4 at 37°C for 22 h. Casein was removed by centrifugation and lactic acid was eliminated from the supernatant by electrodialysis. The residual supernatant was converted to fermented milk whey powder by using maltodextrin as a bulking agent and spray drying.

Species:

rat

Strain:

Sprague-Dawley

Details on species / strain selection:

Crj: CD (SD) IGS

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River, Japan
- Females (if applicable) nulliparous and non-pregnant: [yes/no]
- Age at study initiation: (P) males 7-11, females 8-10 wks
- Weight at study initiation: (P) Males: 292 to 330 g; Females: 201 to 229 g
- Fasting period before study:
- Housing: Except during mating periods, individually in stainless steel cages. During mating trials, single males and single females were cohabited. The female rats were housed in plastic cages with bedding individually or together with litters during the terminal phase of gestation and lactation period.
- Diet: olid diet for experimental animals (CE-2; CLEA Japan Inc.) ad libitum
- Water: tap water ad libitum
- Acclimation period: one week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 3
- Humidity (%): 50 +/- 20
- Air changes (per hr): approx. 10
- Photoperiod (hrs dark / hrs light): 12h/12h

Route of administration:

oral: gavage

Vehicle:

water

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
Prepared weekly in water for injection (J.P. Fuso Pharmaceutical Industries, Ltd., Lot No.00512D). Prepared dosing solutions were stored and frozen at approximately -20°C in screw-capped plastic tubes in quantities sufficient for a single day’s administration. Frozen
aliquots were brought to room temperature before administration. Oral doses of the powdered FM employed in these studies were 0, 500, 1000, and 2000 mg/kg BW/day

Details on mating procedure:

-One male and one female from the same dose group were
housed together after powdered FM administration (treatment day 29 for the male and treatment day 15 for the female). They cohabited for a maximum of 2 weeks, during which time daily vaginal smears were executed to determine the presence of sperm.
Sperm-positive females were considered to have had successful copulation and that day was defined as gestation day 0. After successful copulation, females were separated from males. In the case of unsuccessful copulation (after 2 weeks of cohabitation), the male was remated with an untreated female, and the female was remated with a dosed male that had previously succeeded in copulating. If untreated females succeeded in copulating with a previously unsuccessful male, they were observed daily then sacrificed on gestation day 13. The females were then examined for the presence or absence of implantations in order to verify male fertility. Copulation and fertility indices were computed as the percent of males successfully copulating and the percent of copulated females impregnated.

Duration of treatment / exposure:

Males 28 consecutive days before mating until the day of necropsy (conclusion of the mating period).
Females: 14 days before mating until gestation day 7.

Frequency of treatment:

Daily

Dose / conc.:

500 mg/kg bw/day (nominal)

Dose / conc.:

1 000 mg/kg bw/day (nominal)

Dose / conc.:

2 000 mg/kg bw/day (nominal)

No. of animals per sex per dose:

21 animals of each sex.

Control animals:

yes, concurrent vehicle

Positive control:

No

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: Yes / No / No data
- Time schedule: observed daily for mortality, morbidity and clinical signs (before and after powdered FM administration). Dosed females were examined twice daily. When dosing was terminated, animals were observed once a day.

BODY WEIGHT: Yes / No / No data
- Time schedule for examinations:
Males were weighed on treatment days 1, 5, 9, 12, 16, 19, 23, and 26, then weekly until sacrificed.
Females were weighed on treatment days 1, 5, 9, and 12, then on gestation days 0, 4, 8, and 13.

FOOD CONSUMPTION:
males: on treatment days 4, 8, 11, 15, 18, 22, and 25,
females: on treatment days 4, 8, and 11 and gestation days 0, 3, 7, and 12.

Litter observations:

PARAMETERS EXAMINED
The following parameters were examined in [F1] offspring:
[number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain, physical or behavioural abnormalities, anogenital distance (AGD), presence of nipples/areolae in male pups, other:]

ASSESSMENT OF DEVELOPMENTAL NEUROTOXICITY:

Postmortem examinations (parental animals):

SACRIFICE
After successful mating, males were euthanized by carbon dioxide inhalation and necropsied. On gestation day 13, females were similarly euthanized and subjected to complete necropsy and examination of ovarian and uterine contents. Major organs
(brain; pituitary gland; liver; kidneys; spleen; and adrenal
glands of male and female rats; ovaries and uterus with neck
and oviduct for females; and testes, epididymes, seminal vesicles,
and prostate for males) were dissected and weighed. Bilateral
organs were weighed together. The organ weight data were
expressed as absolute and relative (to body weight) weights.
Animals proven to be infertile were excluded from statistical
analysis.

GROSS NECROPSY
- Gross necropsy consisted examination of ovarian and uterine contents. Uteri were removed and examined to determine the numbers
of implantation sites and living and dead embryos. Ovaries from all gravid females were examined to determine the number of corpora lutea. The implantation index and percent postimplantation loss were computed as the percent of corpora lutea resulting in implantation sites and the percent of implantation sites yielding living embryos, respectively.

HISTOPATHOLOGY / ORGAN WEIGHTS
Brain; pituitary gland; liver; kidneys; spleen; and adrenal glands of male and female rats; ovaries and uterus with neck and oviduct for females; and testes, epididymes, seminal vesicles, and prostate for males) were dissected and weighed. Bilateral organs were weighed together.
In addition to the organs listed for organ weight measurement, vagina and mammary glands
of females, and all macroscopically abnormal organs were removed and preserved in 10% neutral-buffered formalin solution. The testes were immersed in Bouin’s solution and then washed in a solution of 70% ethanol saturated with lithium carbonate, and similarly preserved.
The testes and epididymes from the first ten males in each group were embedded in paraffin, sectioned and stained for histopathological examination. Similarly, the ovaries of
infertile females were preserved, sectioned, and stained for examination. For the testes, two transverse sections were made in two sites; one was stained with periodic acid Schiff’s reagent (PAS) and the other with hematoxylin and eosin (H&E). The head, body, and tail of the epididymes were divided longitudinally, sectioned, and stained with H&E. Ovaries were divided longitudinally into four sections, and stained with H&E. All macroscopically abnormal organs and the corresponding organs from vehicle-control animals of the same sex were embedded in paraffin, sectioned, and stained with H&E.

Postmortem examinations (offspring):

Live fetuses were separated according to sex, individually weighed, and examined for external anomalies. Fetuses with grossly observable external malformations were fixed in 10% neutral-buffered formalin solution without being subjected to either skeletal or visceral examination. With the exception of
any externally malformed fetuses, about half of each litter was allocated to skeletal examination and the remaining animals to visceral examination. Visceral and skeletal observations were performed on the fetuses of all groups. Visceral examinations were conducted by microdissection techniques after fixation of fetuses in Bouin’s solution. Stereomicroscopic examinations of skeletons were conducted on alizarin red S-stained specimens. Examinations were performed on all skeletons.

Statistics:

Computed statistics, such as copulation, implantation, and fertility indices, were analyzed with Fisher’s one-sided exact test.
The percentage data for litters in the second generation of the pre- and postnatal development study (live birth index; incidence of external abnormality; sex ratio; achievement of landmarks of physical development during the lactation period; viability index on day 4; lactation index; implantation index; and post implantation loss) were compared by Steel’s method (1959) and, if significant differences resulted, the Jonckeere-Terpstra test (Jonckheere 1954) was performed for trends in dose-response relationship.
Body weight; food consumption; duration of pregnancy; number of implantations; number of live neonates; mean body weights of offspring; data of open-field and learning tests; organ weight and weight ratio; number of corpora lutea; and number of live fetuses were tested for homogeneity by Bartlett’s method (Sokal 1969). If the variance was homogeneous, Dunnett’s test (Dunnett 1955) was performed for pairwise comparison of mean values. If Dunnett’s test detected a significant difference,Williams’s test (1971, 1972)was performed for doseresponse relationship. If Bartlett’s test (Sokal 1969) detected an inhomogeneous variance, Steel’s method (Steel 1959) was performed, and if Steel’s method detected a significant difference, the Jonckeere-Terpstra test (Jonckheere 1954) was performed for trends in dose-response relationship. Data on clinical signs and gross observations during necropsy were not statistically analyzed.

Clinical signs:

no effects observed

Dermal irritation (if dermal study):

not examined

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Ophthalmological findings:

not examined

Haematological findings:

not examined

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:

no effects observed

Reproductive function: oestrous cycle:

no effects observed

Reproductive function: sperm measures:

not examined

Reproductive performance:

no effects observed

Key result

Dose descriptor:

NOAEL

Effect level:

> 2 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Remarks on result:

not determinable due to absence of adverse toxic effects

Clinical signs:

no effects observed

Reproductive function: oestrous cycle:

no effects observed

Reproductive function: sperm measures:

not examined

Reproductive performance:

no effects observed

Key result

Dose descriptor:

NOAEL

Effect level:

> 2 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Remarks on result:

not determinable due to absence of adverse toxic effects

Clinical signs:

no effects observed

Mortality / viability:

no mortality observed

Body weight and weight changes:

no effects observed

Sexual maturation:

no effects observed

Organ weight findings including organ / body weight ratios:

effects observed, non-treatment-related

Description (incidence and severity):

Significantly decreased absolute weights of male and female brains, male prostate, and female uterus were observed in the highest doses group animals. The decrease in absolute brain weight appeared dose-related down to 1000 mg FM/kg BW/day for males, and 500 mg FM/kg
BW/day for females. The decrease in absolute prostate weight down to 1000 mg FM/kg BW/day for males also appeared dose-related.
They were not considered to be treatment-related as the change was either in the absolute or relative weight.

Gross pathological findings:

effects observed, non-treatment-related

Description (incidence and severity):

dilated renal pelvis, were observed in all experimental groups and were considered to be naturally occurring changes in this strain of rats.

Behaviour (functional findings):

no effects observed

Key result

Dose descriptor:

other: maximally tolerated dose (MTD)

Generation:

F1

Effect level:

> 2 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Remarks on result:

not determinable due to absence of adverse toxic effects

Key result

Reproductive effects observed:

no

Conclusions:

Under the conditions of these experiments, orally administered powdered FM possesses little potential to (1) alter either the mating behavior or fertility of male or female Sprague-Dawley rats; (2) cause embryo or fetal toxicity; or (3) adversely affect pre- or postnatal development of offspring of dams administered powdered FM during pregnancy and lactation.
The maximally tolerated dose (MTD) of powdered FM is >2000 mg/kg BW/day in both breeding/pregnant rats and the rat embryo-fetus.
According to the considerations previously listed on the field "justification for type of information", it can be concluded that the maximally tolerated dose (MTD) of "Bos taurus, milk, pasteurized, homogenized, skimmed, fermented, spray-dried" (EC No. 917-734-0) would likewise be >2000 mg/kg BW/day in both breeding/pregnant rats and the rat embryo-fetus.

Executive summary:

The objective of these studies was to assess the effects of FM, on reproductive capabilities of male and female rats. The specific goals of the experiments were (1) to determine the effects of orally administered FM on (a) fertility and reproductive behavior in both sexes of rats, (b) embryo-fetal development in pregnant rats, and (c) pre- and postnatal development of rats exposed in utero and during lactation; and (2) to estimate the no-observable-adverse-effect doses in maternal and fetal rats. During the conduct of these classical segment I, II, and III studies, the test material was powdered Lactobacillus helveticus–fermented milk (FM). FM (0, 500, 1000 or 2000 mg/kg body weight [BW]/day was administered to males by oral gavage from 4 weeks prior to mating until sacrifice, and to females from 2 weeks prior to mating through day 20 of lactation. Evaluative parameters included monitoring grossly observable clinical signs; food

consumption and body weight gains; mating behavior and fertility indices of both sexes; implantation and maintenance of embryos; sex ratio of live pups; fetal viability; incidences of external, visceral or skeletal variations; growth and behavioral development; as well as reproductive capabilities of F1 offspring exposed to FM during gestation and lactation. All animals were subjected to macroscopic examination at termination of their segment of the studies. Clinical signs, body weights, and food consumption were unaffected by administration of FM. During segment I, the test agent had no effect on estrus cycle, mating behavior, fertility index, or reproductive competence of either males or females. The results of segment II experiments revealed no effects of FM on postimplantation survival-loss, sex ratio or birth weights of live fetuses, and

there was no evidence of treatment-associated developmental or teratological effects. During segment III, FM was without effect on pup viability, behavioral and sexual maturation, and reproductive capability of the F1 generation. Under the conditions of these experiments, the no-observable-adverse-effect level (NOAEL) of FM on reproductive performance in male and female rats is greater than 2000 mg/kg BW/day.

The process used to prepare ‘Powdered Lactobacillus helveticus-fermented milk’ (FM) is qualitatively similar to that used in the production of ‘Bos taurus, milk, pasteurized, homogenized, skimmed, fermented, spray dried’ and is based on the same natural material (cow milk) and biological production process (bacterial fermentation).The components that are additionally removed from FM, lactic acid and casein, occur naturally in milk and milk that has been naturally exposed to microorganisms and are not expected to have important toxicological effects regarding acute oral toxicity, repeated oral dose toxicity, reproduction, or genotoxicity at the concentrations present in fermented milk products.

Therefore, taking into account the previous considerations, it is safe to assume that the the no-observable-adverse-effect level (NOAEL) of 'Bos taurus, milk, pasteurized, homogenized, skimmed, fermented, spray dried' on reproductive performance in male and female rats would also be greater than 2000 mg/kg BW/day.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Study duration:

subacute

Species:

rat

Effects on developmental toxicity

Description of key information

There is a long history of safe yoghurt consumption. No reports have ever linked yoghurt consumption with toxicity effects, including toxicity effects on reproduction.

A sub-acute exposure of 2’400 mg/kg body weight (bw) of the substance Bos taurus, milk, pasteurized, homogenized, skimmed, fermented, spray-dried (EC 917-734-0) is considered safe in humans and does not have any toxic effect on reproduction.

There is no test available for reproductive toxicity for "Bos taurus, milk, pasteurized, homogenized, skimmed, fermented, spray dried." However there is a reliable data for "Powdered Lactobacillus helveticus-fermented milk". The test material used to test the toxicological properties of the substance on reproductive parameters described in this study is not exactly the same as Bos taurus, milk, pasteurized, homogenized, skimmed, fermented, spray-dried. However, the process used to prepare ‘Powdered Lactobacillus helveticus-fermented milk’ (FM) is qualitatively similar to that used in the production of ‘Bos taurus, milk, pasteurized, homogenized, skimmed, fermented, spray dried’ and is based on the same natural material (cow milk) and biological production process (bacterial fermentation). The components that are additionally removed from FM, lactic acid and casein, occur naturally in milk and milk that has been naturally exposed to microorganisms and are not expected to have important toxicological effects regarding acute oral toxicity, repeated dose oral toxicity, reproduction, or genotoxicity at the concentrations present in fermented milk products. Therefore, the toxicological properties reported on this study can be used in combination with the long historical safe consumption of yogurt and yogurt-derived products by humans assess the toxicological properties of 'Bos taurus, milk, pasteurized, homogenized, skimmed, fermented, spray dried' for this endpoint. Under the conditions of these experiments, orally administered powdered FM possesses little potential to (1) alter either the mating behavior or fertility of male or female Sprague-Dawley rats; (2) cause embryo or fetal toxicity; or (3) adversely affect pre- or postnatal development of offspring of dams administered powdered FM during pregnancy and lactation. The maximally tolerated dose (MTD) is >2000 mg/kg BW/day in both breeding/pregnant rats and the rat embryo-fetus.

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Toxicity to reproduction: other studies

Description of key information

There is a long history of safe yoghurt consumption. No reports have ever linked yoghurt consumption with toxicity effects, including toxicity effects on reproduction.

A sub-acute exposure of 2’400 mg/kg body weight (bw) of the substance Bos taurus, milk, pasteurized, homogenized, skimmed, fermented, spray-dried (EC 917-734-0) is considered safe in humans and does not have any toxic effect on reproduction.

There is no test available for reproductive toxicity for "Bos taurus, milk, pasteurized, homogenized, skimmed, fermented, spray dried." However there is a reliable data for "Powdered Lactobacillus helveticus-fermented milk". The test material used to test the toxicological properties of the substance on reproductive parameters described in this study is not exactly the same as Bos taurus, milk, pasteurized, homogenized, skimmed, fermented, spray-dried. However, the process used to prepare ‘Powdered Lactobacillus helveticus-fermented milk’ (FM) is qualitatively similar to that used in the production of ‘Bos taurus, milk, pasteurized, homogenized, skimmed, fermented, spray dried’ and is based on the same natural material (cow milk) and biological production process (bacterial fermentation). The components that are additionally removed from FM, lactic acid and casein, occur naturally in milk and milk that has been naturally exposed to microorganisms and are not expected to have important toxicological effects regarding acute oral toxicity, repeated dose oral toxicity, reproduction, or genotoxicity at the concentrations present in fermented milk products. Therefore, the toxicological properties reported on this study can be used in combination with the long historical safe consumption of yogurt and yogurt-derived products by humans assess the toxicological properties of 'Bos taurus, milk, pasteurized, homogenized, skimmed, fermented, spray dried' for this endpoint. Under the conditions of these experiments, orally administered powdered FM possesses little potential to (1) alter either the mating behavior or fertility of male or female Sprague-Dawley rats; (2) cause embryo or fetal toxicity; or (3) adversely affect pre- or postnatal development of offspring of dams administered powdered FM during pregnancy and lactation. The maximally tolerated dose (MTD) is >2000 mg/kg BW/day in both breeding/pregnant rats and the rat embryo-fetus.

Justification for classification or non-classification

Based on the long history of safe yoghurt consumption, an estimated NOAEL >2400 mg/kg BWday for oral sub-acute exposure and no evidence of reproductive toxic effects of 2000 mg/kg BW day on 1) either the mating behavior or fertility of male or female Sprague-Dawley rats; (2) embryo or fetal toxicity; or (3) adverse effects on pre- or postnatal development of offspring of dams administered Fermented milk products during pregnancy and lactation, it is safe to conclude that Bos taurus, milk, pasteurized, homogenized, skimmed, fermented, spray-dried (EC 917-734-0) does not have any toxic effect on reproduction.