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

Skin sensitisation

Administrative data

Endpoint:

skin sensitisation, other

Remarks:

human exposure-related information from milk powder

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

September 2006 - January 2007

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Justification for type of information:

Bos taurus, milk, pasteurized, homogenized, skimmed, fermented, spray-dried (EC 917-734-0) is a UVCB substance originating from biochemical changes produced in milk by various species of bacteria or yeast, where the main constituents are raw proteins (approx. 34.1% w/w), lactose (approx. 40.3% w/w) and lactic acid (>=2.5 to <=5% w/w); minor constituents include water (3 – 10% w/w), raw ash (>3 to <10% w/w), raw fat (>0.25 to <1.5% w/w), and other carbohydrates (>=2 to <=3% w/w). Raw ash contains various inorganic constituents like calcium (>=7 to <=26% w/w), sodium (>=0 to <=13% w/w), potassium (>=13 to <=26% w/w) or magnesium (>=0 to <=13% w/w). These constituents are all of natural origin and common to food products consumed by humans for millennia (see Composition).
The proteinaceous components of the dried ‘milk powder’ are expected to be qualitatively and quantitatively similar to those of Bos taurus, milk, pasteurized, homogenized, skimmed, fermented, spray-dried.
Moreover, according to the toxicokinetic analysis of the Bos taurus, milk, pasteurized, homogenized, skimmed, fermented, spray-dried is not easily absorbed through the skin.
Therefore, since milk derived protein is the main component of Bos taurus, milk, pasteurized, homogenized, skimmed, fermented, spray-dried, it is safe to conclude that dermal exposure to ‘Bos taurus, milk, pasteurized, homogenized, skimmed fermented, spray-dried’ (EC 917-734-0) would also not induce any skin sensitization and this study can be used to assess the skin sensitizing properties of this substance.

Cross-reference

Cross-reference 1

Reason / purpose for cross-reference:

reference to same study

Reference

Endpoint:

respiratory sensitisation, other

Remarks:

human exposure-related information from milk powder

Type of information:

experimental study

Adequacy of study:

key study

Study period:

September 2006 - January 2007

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Justification for type of information:

Bos taurus, milk, pasteurized, homogenized, skimmed, fermented, spray-dried (EC 917-734-0) is a UVCB substance originating from biochemical changes produced in milk by various species of bacteria or yeast, where the main constituents are raw proteins (approx. 34.1% w/w), lactose (approx. 40.3% w/w) and lactic acid (>=2.5 to <=5% w/w); minor constituents include water (3 – 10% w/w), raw ash (>3 to <10% w/w), raw fat (>0.25 to <1.5% w/w), and other carbohydrates (>=2 to <=3% w/w). Raw ash contains various inorganic constituents like calcium (>=7 to <=26% w/w), sodium (>=0 to <=13% w/w), potassium (>=13 to <=26% w/w) or magnesium (>=0 to <=13% w/w). These constituents are all of natural origin and common to food products consumed by humans for millennia.
This study reported the relationship between worker inhalation exposure to dried ‘milk powder’ and development of respiratory sensitization. The mechanism of sensitization is thought to proceed via induction of immunoglobulin (Ig)E-mediated hypersensitivity by proteins common to milk products. The proteinaceous components of the dried ‘milk powder’ are expected to be qualitatively and quantitatively similar to those of Bos taurus, milk, pasteurized, homogenized, skimmed, fermented, spray-dried. Therefore, since milk derived protein is the main component of Bos taurus, milk, pasteurized, homogenized, skimmed, fermented, spray-dried, it is safe to conclude that inhalation exposure to ‘Bos taurus, milk, pasteurized, homogenized, skimmed fermented, spray-dried’ (EC 917-734-0) would also produce respiratory sensitization in the same manner as has been reported for worker inhalation exposure to dried ‘milk powder’.
Therefore, this study can be used to assess the respiratory sensitizing potential of ‘Bos taurus, milk, pasteurized, homogenized, skimmed fermented, spray-dried’ (EC 917-734-0)

Qualifier:

no guideline followed

Principles of method if other than guideline:

In four milk powder factories in Thailand, a cross-sectional study was performed among all workers (factory and office workers) between September 2006 and January 2007. All participants answered to a questionnaire and performed spirometry. The ethics committee of Mahidol University, Bangkok, Thailand approved the study. Before participation, an informed consent was signed by all participants.

GLP compliance:

no

Specific details on test material used for the study:

Evaluation of the respiratory effects of occupational exposures in milk powder factory

Route of induction exposure:

inhalation

Vehicle:

unchanged (no vehicle)

Details on study design:

Study design:
In four milk powder factories in Thailand, a cross-sectional study was performed among all workers (factory and office workers) between September 2006 and January 2007. All participants answered to a questionnaire and performed spirometry. The ethics committee of Mahidol University, Bangkok, Thailand approved the study. Before participation, an informed consent was signed by all participants
Study population: With a response rate of 77%, 167 out of 245 workers working in these milk powder factories participated in the study. Among these 130 worked in the production and packing, 22 in the process of adding vitamin to the mixture and 15 in the quality control. The 76 office employees (response rate 73%) formed the unexposed reference population. This number includes 24 office workers from the milk powder factory, 18 from a microfibre factory, 18 from a wood furniture factory and 16 from a tile factory. These 76 office employees were represented by managers, administrative staff, chauffeurs and gate security staff.
 
Measurement methods :
-Questionnaire: The questionnaire on respiratory health, occupational exposures and lifestyle provided by the Finnish Environment and Asthma Study was used and modified. The questions enquired about job history and specific exposures in current and previous jobs. The questionnaire was translated into Thai and then translated back into English.
-Spirometry Participants: spirometry was performed according to the standards of the American Thoracic Society using a Minato Autospiro PAL spirometer (Minato Medical Sciences, Osaka, Japan). The following variables were measured: the best forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) out of a minimum of three acceptable forced expirations. Predicted values from a Thai population were used to calculate FEV1 and FVC as a percentage of the predicted value.
-Outcome assessment:The outcomes of interest included the occurrence of respiratory symptoms within the past 12 months, and asthma ever and within the past 12 months, based on questionnaire information. These outcomes were defined as:
1) cough: recurrent or prolonged cough;
2) phlegm production: recurrent or prolonged phlegm production;
3) wheezing: wheezing or whistling of the chest;
4) breathlessness: chest tightness or difficulty breathing;
5) nasal symptoms: dryness, itching or smarting of nose, stuffy nose, runny nose or repeated sneezing;
6) eye symptoms: dryness of eyes, itchy eyes, irritation or smarting of eyes, watering of eyes or redness of eyes;
7) skin symptoms: dryness or flaking of skin, itchy skin, irritation, smarting or redness of skin, sore or tender skin, or urticaria;
8) current asthma: asthma diagnosed by a physician within the previous 12 months;
9) asthma ever: asthma diagnosed by a physician ever during lifetime. Lung function outcomes included FEV1 and FVC (absolute values and percentage of predicted) based on the best values of FEV1 and FVC obtained on spirometry.
 
Exposure assessment: The aim of this assessment was the occupational exposures in the milk powder factory were the exposures of interest.
Firstly, exposure was assessed based on whether the subject was a factory or office employees. Secondly, exposure among factory workers was assessed based on their job tasks and work location, classified into three groups: production line and packing staff, workers adding vitamins, and quality control staff. Production line workers were exposed to milk powder. Workers adding vitamin mixture and packing workers were also exposed to a mixture of vitamins, corn syrup and minerals. Additionally, vitamin-adding workers and quality control workers were exposed to natural rubber latex (NRL). Workers responsible for quality control of the milk powder were exposed to many other chemicals. Indicator variables were formed for the three job categories (coded 1 if the participant belonged to the job category in question; 0 if not), whereas the office workers formed the common reference category. Thirdly, exposure was assessed based on reported exposure to specific substances given in a list in the questionnaire. The most commonly reported specific exposures were milk (60%) and NRL (27%). Quality control workers reported exposure to several chemicals, including sulphuric acid (0.6 %), ethanol (6.6%), methanol (1.2%), sodium hydroxide (3.6%) and ammonium hydroxide (1.8%). Since numbers were low for these specific exposures, only exposure to milk powder (yes51; no50) and NRL (yes51; no50) were investigated separately, adjusted for each other in regression models. In addition, the specific exposures were categorised into sensitisers and irritants. Sensitisers included milk powder, welding fumes, cutting oils, NRL, tetrahydrofuran and glues. Irritants included sulphuric acid, urea, sodium hydroxide, ammonium hydroxide, ethyl acetate, ethanol, methanol, nitric acid, glacial acetic acid, acetone,thinner, microfibres, solvents, paints, acetonitrile and hexane.
Additional information on exposures was provided by annual measurements of dust and chemicals in the air of the factory, performed by an independent consulting company (W. Phanprasit is a member of the monitoring team) for the previous 3 yrs (2003–2005). Respirable dust concentrations were measured following the method of the US National Institute for Occupational Safety and Health (method number 0600).
 
Data analysis:
The relationship between exposure and outcome were evaluated using the Odds ratios (ORs) and 95% confidence intervals (CIs).
A model was fitted for respiratory symptoms and asthma separately. Three types of exposure variables, described in the Exposure assessment section, were fitted in different sets of models. All models were adjusted for potential confounders, including age and sex (f25 yrs, 26–30 yrs or o31 yrs), educational level (primary/high school, vocational school/college or bachelor/higher university degree), parental atopy or asthma (yes or no), smoking status (current, ex- or never-smoker), exposure to second-hand smoke (SHS) at home and/or at work (yes or no) and work stress (a lot/very much stress or some/a little/no stress), on multivariate logistic regression.
Multiple linear regression was used to evaluate the effect of exposures on lung function. A separate model was fitted for each outcome, including FEV1, FVC, FEV1 % pred and FVC % pred. Models of lung function levels were adjusted for age, sex, height, educational level, smoking status, SHS exposure at home and/or at work, and parental atopy/asthma. FEV1 % pred and FVC % pred were already controlled for sex, age and height in the prediction equations.

Results:

Characteristics and symptoms of the study population:
The study population included 101 females and 142 males between 18 and 60 years old. Factory employees were more often male, younger, with a lower educational level and current smokers than the office employees. A multivariate analysis adjusted for these variables was carried out.
The occurrence of respiratory symptoms was analyzed per each work task in the factory or in the office. The number of quality control employees was so small that this worker group was excluded from the analyses. Factory workers experienced twice as much wheezing and breathlessness (24 and 33%, respectively) compared to the office workers (12 and 16%, respectively). Employees with the task of adding vitamins to milk powder showed a high occurrence of eye (41%) and skin symptoms (46%).

Air measurements:
Air concentrations in the factory had been measured monitored by an independent consulting company during the prevous 3 years (2003–2005). The mean concentrations ranged between 0.02 and 2.18 mg/m(-3). Packing areas showed the highest concentrations (up to 2.18 mg/m(-3)). Measurement in 2005 showed levels above the action level of 50% of the threshold limit value, which is 3 mg/m(-3) for respirable dust. In vitamin rooms and warehouse areas concentrations above the action level had been measured in 2004–2005. The concentrations of various chemicals were generally low in the quality control department.

Factory work and respiratory symptoms and asthma:
The ORs of respiratory symptoms and asthma in factory workers compared with office workers were calculated. The crude ORs of wheezing (2.31 (95% CI 1.06–5.05)) and breathlessness (2.58 (1.29–5.17)) were significantly increased in factory employees, and remained increased after adjustment for confounders (1.74 (0.67–4.54) and 2.20 (0.92–5.28), respectively), although no more significant. After adjustment for confounders, the risk of nasal symptoms was significantly increased (2.30 (1.00–5.29)). The risk of ever asthma was high in factory employees (OR 2.26) but, due to the small number of asthmatics in the studied population, the CI was wide. No cases of current asthma among the office workers (forming the reference group) were observed, so the OR for asthma diagnosed within the previous year could not be calculated.
ORs were calculated with the aim of comparing different job tasks within the factory with office work. Production and packing staff showed a significantly increased risk of breathlessness (OR3.05 (95% CI 1.21–7.69)) and nasal symptoms (2.57 (1.06–6.22)). They also exhibited increased risk of ever asthma (OR 10.38) but, again, due to the small number of asthmatics, the CI was wide. Vitamin-adding employees showed a significantly increased risk of skin symptoms (4.48 (1.36–14.75)).

Factory work and lung function:
Factory employees had significantly lower FEV1 % pred. (b -4.23 (95% CI -7.70– -0.76)). No significant effects were observed on absolute FEV1 or FVC. This may mean that predicted values control better for age and height than adjusting for them in the regression model. Factory employees included more young males than office workers, which was reflected in higher mean lung function levels when not taking into account the predicted values. Vitamin-adding employees exhibited generally lower lung function, FVC % pred. being significantly reduced (-6.26 (-11.45– -1.07)).

Specific exposures and respiratory effects:
Exposure to milk powder was related to a significantly increased risk of nasal symptoms (OR 2.35 (95% CI 1.11–5.02)), and the risks of wheezing, eye symptoms and asthma. Exposure to NRL was related to an increased risk of skin symptoms (1.73 (0.70–4.30)) and breathlessness (1.73 (0.73– 4.10)), but the CIs were wide probably due to the small sample size. This study assessing the exposure to the sensitizers observed that the ORs of phlegm production, wheezing, breathlessness, nasal symptoms, eye symptoms, skin symptoms and asthma were all increased in a consistent pattern. However only nasal symptoms reached statistical significance (2.13 (1.11–4.08)). Exposure to irritants was not consistently related to respiratory symptoms.
The employees exposed to milk powder showed lower spirometric lung function. This effect being significant for FVC (b -0.14 (95% CI -0.26– -0.01)) and FVC % pred (-4.81 (-8.13– -1.50). For the exposed employees a generally lower lung function levels were observed, the effect being significant for FVC % pred (-2.96 (-5.79– -0.13)). No effect on lung function was observed in relation to exposure to irritants.

Interpretation of results:

Category 1 (respiratory sensitising) based on GHS criteria

Conclusions:

Workers exposed to relatively low levels of milk powder by inhalation showed significantly increased risk of nasal symptoms, wheezing and breathlessness, and reduced spirometric lung function. Employees exposed to the process of adding vitamin mixtures to milk showed an increased risk of skin symptoms, which was most probably related to their use of natural rubber latex gloves.
Considering the high milk protein derived content in the Bos taurus, milk, pasteurized, homogenized, skimmed fermented, spray-dried (EC 917-734-0), it is safe to conlude that this substance would also be a respiratory sensitizer and therefore must be classified as a respiratory sensitizer (Cat 1) according to the CLP criteria.

Executive summary:

Milk powder ingestion is a well-known cause of allergies in children. However, the risks arising from exposure to inhaled milk powder have not been studied previously. The aim of this study was to assess the effects of occupational exposures to milk powder and assess the respiratory symptoms and lung function.

A cross-sectional study was conducted in four factories in Thailand. This study was conducted on 167 milk powder factory workers and 76 office workers with a response of 77% and 73%, respectively. All these 167 participants answered to a questionnaire and performed spirometry. Measurements of concentrations of dust were also collected.

The range of the means of the respirable dust concentrations were 0.02–2.18 mg*m(-3). Breathlessness cases and nasal symptoms were significantly increased in workers working int the production and packing area. The risk of skin symptoms was significantly increased in workers adding vitamin mixture to milk powder. Factory workers showed significantly lower forced expiratory volume in one second measured as percentage of predicted value. New evidences were provided by this study: workers exposed to milk powder by inhalation showed an increased risk of nasal symptoms, wheezing and breathlessness. Moreover, the workers exhibited reduced spirometric lung function, even at low air concentrations of milk dust.

Considering the high milk protein derived content in the Bos taurus, milk, pasteurized, homogenized, skimmed fermented, spray-dried (EC 917-734-0), it is safe to conlude that this substance would also be a respiratory sensitizer and  therefore must be classified as a respiratory sensitizer (Cat 1) according to the CLP criteria.

Cross-reference 2

Reason / purpose for cross-reference:

exposure-related information

Reference

The substance Bos taurus, milk, pasteurized, homogenized, skimmed, fermented, spray-dried (EC 917-734-0) is a UVCB substance originating from biochemical changes produced in milk by various species of bacteria or yeast, where the main constituents are raw proteins (approx. 34.1% w/w), lactose (approx. 40.3% w/w) and lactic acid (=2.5 - =5% w/w); minor constituents include water (3 – 10% w/w), raw ash (inorganic constituents) (>3 – <10% w/w), raw fat (>0.25 – <1.5% w/w), and other carbohydrates (=2 – =3% w/w). Raw ash contains calcium (=7 – =26% w/w), sodium (=0 - =13% w/w), potassium (=13 - =26% w/w) and magnesium (=0 - =13% w/w). The proteins consist mainly of caseines (80%), serum albumines, beta-lactoglobulines, immunoglobulines and lactalbumines.

After ingestion, raw proteins are generally broken down into amino acids through denaturation of the protein in the acidic environment of the stomach and hydrolysis by proteases in the intestine. They are absorbed from the intestine and distributed systemically across various compartments of the body. Since amino acids are of natural origin and form an essential part of the normal human diet, no further consideration of the toxicokinetics of raw protein is necessary

Likewise, ingested lactose is digested through the enzyme lactase, which is expressed in the brush border membrane of enterocytes in the small intestine, and cleaved into the sugar monomers, glucose and galactose which are taken up in the small intestine (Hampson et. al., 1986). Therefore, it is absorbed and distributed as glucose and galactose. Based on the long history dietary human exposure to lactose, the substance is not acute orally toxic and the evaluation of the toxicokinetics of lactose is not considered necessary. Furthermore, lactose is exempted from REACH registration requirements according to REACH Annex IV (substances included in Annex IV: sufficient information is known about these substances that they are considered to cause minimum risk because of their intrinsic properties) and can thus be considered to have non-critical properties.

Due to the low volatility (lactose: <0.1 Pa at 25°C, lactic acid: 11 Pa at 25°C) the main constituents of the substance are not present in a gaseous state and gas-phase absorption through inhalation is therefore highly unlikely at normal ambient temperatures. The 10th percentile and median size of the particles of the substance (D10 = 75.3 µm and D50 = 127.5 µm, mass based) indicates that the large majority of the particles are too big to be inhaled. If some portion of the substance should reach the respiratory tract, the main constituents could cross the alveolar and capillary membranes by a combination of active and passive uptake mechanisms. Additionally, there is human data on the respiratory effects of occupational exposure to milk powder available which, can be used as an analog to provide evidence for yoghurt powder. Although there were no signs of systemic toxicity, increased risk of nasal symptoms, wheezing, breathlessness and reduced spirometric lung function were observed; based on these findings the substance was classified as a Category 1 respiratory sensitizer.

The physical state (solid) and high molecular weight (only <100 g/mol can be readily taken up dermally) of the main constituents suggest that the substance will not be easily absorbed through skin. Additionally, the high water solubility and low log P values (-0.72 to -3.77) will further decrease the penetration into the lipid rich stratum corneum and therefore dermal absorption of the substances will be limited due to high hydrophilicity.. In a worst-case approach, based on the classification of the substance L (+) Lactic Acid (CAS-No. 79-33-4, EC-No. 201-196-2), Bos Taurus, milk, fermented, spray-dried (EC 917-734-0) was classified as “Skin Irritation Cat. 2” (H315). A damaged skin surface, induced through the substance, may enhance the penetration of the substance.

 

Sources:

Hampson, D., Kidder, DE (1986). Influence of creep feeding and weaning on brush border enzyme activities in the piglet small intestine. Res Vet Sci. 40(1):24-31.

Boiling point lactic acid: Haynes, W.M. (ed.). CRC Handbook of Chemistry and Physics. 95th Edition. CRC Press LLC, Boca Raton: FL 2014-2015, p. 3-336

Vapour pressure Lactic acid: Yaws CL; Handbook Chem Compd Data Process Saf, Houston, TX: Gulf Publishing, p. 33 (1997).

Log P Lactic acid: Hansch, C., Leo, A., D. Hoekman. Exploring QSAR - Hydrophobic, Electronic, and Steric Constants. Washington, DC: American Chemical Society

 

 

Bioaccumulation potential:

no bioaccumulation potential

A toxicokinetic assessment based on the physical properties (see ECHA Guidance on Information Requirements and Chemical Safety Assessment, R7c, version 3.0, June 2017) and toxicity data was performed. NOTE: this is mostly a generic assessment based on general statements in the guidance document that are derived from physical parameters.  

Data source

Reference

Reference Type:

publication

Title:

Respiratory effects of occupational exposures in a milk powder factory

Author:

P. Sripaiboonkij, W. Phanprasit and M.S. Jaakkola

Year:

2008

Bibliographic source:

Eur Respir J 2008; 31: 807–814

Materials and methods

Test guideline

Qualifier:

no guideline required

Principles of method if other than guideline:

In four milk powder factories in Thailand, a cross-sectional study was performed among all workers (factory and office workers) between September 2006 and January 2007. All participants answered to a questionnaire and performed spirometry. The ethics committee of Mahidol University, Bangkok, Thailand approved the study. Before participation, an informed consent was signed by all participants.

GLP compliance:

no

Type of study:

other: human exposure-related information from milk powder

Test material

Test material information

Constituent 1

Reference substance name:

Milk Powder

IUPAC Name:

Milk Powder

Test material form:

solid: particulate/powder

Results and discussion

In vivo (non-LLNA)

Results

Key result

Remarks on result:

no indication of skin sensitisation

Remarks:

see field "any other information on results"

Any other information on results incl. tables

Vitamin-adding staff (staff who adds vitamins to milk powder and who wears protective gloves) indicated that they experienced skin symptoms, whereas the other job groups (apart from the quality control staff) did not show an excess of skin symptoms.

The study concluded that skin symptoms were not a consequence of exposure to milk powder, but instead related to wearing natural rubber latex (NRL) gloves.

Since milk derived protein is the main component of Bos taurus, milk, pasteurized, homogenized, skimmed, fermented, spray-dried, it is safe to conclude that dermal exposure to ‘Bos taurus, milk, pasteurized, homogenized, skimmed fermented, spray-dried’ (EC 917-734-0) would also not induce any skin sensitization.

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Conclusions:

Vitamin-adding staff (staff who adds vitamins to milk powder and who wears protective gloves) indicated that they experienced skin symptoms, whereas the other job groups (apart from the quality control staff) did not show an excess of skin symptoms. The study concluded that skin symptoms were not a consequence of exposure to milk powder, but instead related to wearing natural rubber latex (NRL) gloves.
Since milk derived protein is the main component of Bos taurus, milk, pasteurized, homogenized, skimmed, fermented, spray-dried, it is safe to conclude that dermal exposure to ‘Bos taurus, milk, pasteurized, homogenized, skimmed fermented, spray-dried’ (EC 917-734-0) would also not induce any skin sensitization.

Executive summary:

The aim of this study was to assess the effects of occupational exposures to milk powder and assess the respiratory symptoms and lung function.

The study focussed on respiratory sensitisation, but also data was collected on skin symptoms.

Vitamin-adding staff (staff who adds vitamins to milk powder and who wears protective gloves) indicated that they experienced skin symptoms, whereas the other job groups (apart from the quality control staff) did not show an excess of skin symptoms. The study concluded that skin symptoms were not a consequence of exposure to milk powder, but instead related to wearing natural rubber latex (NRL) gloves.

Since milk derived protein is the main component of Bos taurus, milk, pasteurized, homogenized, skimmed, fermented, spray-dried, it is safe to conclude that dermal exposure to ‘Bos taurus, milk, pasteurized, homogenized, skimmed fermented, spray-dried’ (EC 917-734-0) would also not induce any skin sensitization.