Abstract
Following a request from the European Commission, EFSA was asked to deliver a scientific opinion on the assessment of the application for the renewal of the authorisation of biotin as a nutritional feed additive for all animal species. The applicants provided evidence that the additive currently on the market complies with the existing conditions of authorisation. There is no new evidence that would lead the FEEDAP Panel to reconsider its previous conclusions regarding the safety of the additive. The FEEDAP Panel concluded that biotin remains safe for all animal species, consumers and environment under the authorised conditions of use. Regarding the user safety, the Panel concluded that biotin is not irritant to skin or eyes and is not a dermal sensitiser. Exposure to the additive by inhalation is likely. There is no need for assessing the efficacy of the additive in the context of the renewal of the authorisation.
Keywords: all animal species, efficacy, nutritional additives, safety, vitamins
1. INTRODUCTION
1.1. Background and Terms of Reference
Regulation (EC) No 1831/2003 1 establishes the rules governing the Community authorisation of additives for use in animal nutrition. In particular, Article 14(1) of that Regulation lays down that an application for renewal shall be sent to the Commission at the latest one year before the expiry date of the authorisation.
The European Commission received a request from ADISSEO, DSM Nutritional Products Ltd. represented in the EU by DSM Nutritional Products Sp.z.o.o. and NHU Europe GmbH 2 for the renewal of the authorisation of the additive consisting of biotin, when used as a feed additive for all animal species (category: nutritional additives; functional group: vitamins, pro‐vitamins, and chemically well‐defined substances having a similar effect).
According to Article 7(1) of Regulation (EC) No 1831/2003, the Commission forwarded the application to the European Food Safety Authority (EFSA) as an application under Article 14(1) (renewal of the authorisation). The dossier was received on 29 May 2024 and the general information and supporting documentation are available at https://open.efsa.europa.eu/questions/EFSA‐Q‐2024‐00320. The particulars and documents in support of the application were considered valid by EFSA as of 30 August 2024.
According to Article 8 of Regulation (EC) No 1831/2003, EFSA, after verifying the particulars and documents submitted by the applicant, shall undertake an assessment in order to determine whether the feed additive complies with the conditions laid down in Article 5. EFSA shall deliver an opinion on the safety for the target animals, consumer, user and the environment and on the efficacy of the feed additive consisting of biotin, when used under the proposed conditions of use (see Section 3.1.3 ).
1.2. Additional information
The additive is currently authorised for use in feed and water for drinking for all animal species (3a880). 3 EFSA issued two opinions on the safety and efficacy of this product when used in feed for all animal species ( EFSA FEEDAP Panel, 2012a, 2012b).
2. DATA AND METHODOLOGIES
2.1. Data
The present assessment is based on data submitted by the applicant in the form of a technical dossier 4 in support of the authorisation request for the use of biotin as a feed additive.
The confidential version of the technical dossier was subject to a targeted consultation of the interested Member States from 3 September 2024 to 3 December 2024; the comments received were considered for the assessment.
In accordance with Article 38 of the Regulation (EC) No 178/2002 5 and taking into account the protection of confidential information and of personal data in accordance with Articles 39 to 39e of the same Regulation, and of the Decision of EFSA's Executive Director laying down practical arrangements concerning transparency and confidentiality, 6 a non‐confidential version of the dossier has been published on Open.EFSA.
According to Article 32c(2) of Regulation (EC) No 178/2002 and to the Decision of EFSA's Executive Director laying down the practical arrangements on pre‐submission phase and public consultations, EFSA carried out a public consultation on the non‐confidential version of the technical dossier from 3 December to 24 December 2024 for which no comments were received.
The FEEDAP Panel used the data provided by the applicant together with data from other sources, such as previous risk assessments by EFSA or other expert bodies, peer‐reviewed scientific papers, other scientific reports and experts' knowledge, to deliver the present output.
The European Union Reference Laboratory (EURL) considered that the conclusions and recommendations reached in the previous assessment regarding the methods used for the control of the biotin in animal feed are valid and applicable for the current application. 7
2.2. Methodologies
The approach followed by the FEEDAP Panel to assess the safety and the efficacy of biotin is in line with the principles laid down in Regulation (EC) No 429/2008 8 and the relevant guidance documents: Guidance on the renewal of the authorisation of feed additives (EFSA FEEDAP Panel, 2021).
3. ASSESSMENT
Biotin is currently authorised as a nutritional additive (functional group: vitamins, pro‐vitamins and chemically well‐defined substances having a similar effect) in feed and water for all animal species. The assessment regards the renewal of the authorisation.
The data submitted in this dossier was generated by a consortium of three companies involved in its production/distribution.
3.1. Characterisation
Biotin may be placed on the market and used as an additive consisting of a preparation. The applicant provided analytical data on biotin (min. 97%), and two preparations (2% and 10%). 9
3.1.1. Characterisation of the active substance
Biotin (Chemical Abstract Service (CAS) number 58‐85‐5; molecular formula C10H16N2O3S; molecular weight 244.3 g/mol) is currently authorised as D‐(+)‐biotin with a purity of at least 97%. 10 Biotin is produced by chemical synthesis using dibenzyl‐biotin as starting material. Biotin is a white or almost white, crystalline powder or colourless crystals, very slightly soluble in water (220 mg/L (25°C)). The applicant declared that the manufacturing process has not been changed since the previous authorisation. 11
Analytical data from 15 production batches (five per company) confirmed compliance with the specifications set by the authorisation, with values for purity ≥ 99% (99%–100.7%). 12 In addition, loss on drying (10 batches), optical rotation (15 batches), sulphated ash (10 batches) and related impurities (10 batches) (Impurity A, C and E) 13 were measured. Loss on drying was on average 0.15% (range 0.05%–0.4%), optical rotation was on average 90.6° (range: 89.1–91.5°).
Impurity A was on average 0.21% (range 0.18%–0.28%), impurity C was 0.06% (range 0.04%–0.08%) and impurity E was 0.1% (range 0.06%–0.21%). Sulfated ash was on average 0.8% (range 0.04%–0.1%). The FEEDAP Panel noted that these values comply with the specifications set for biotin in the European Pharmacopoeia (Ph. Eur., 2022).
Arsenic, lead, cadmium and mercury (15 batches), 14 , 15 fluorine (5 batches) 16 and nickel (2 batches) 17 were all below the limit of detection (LOD).
Polychlorinated dibenzo‐p‐dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs) and dioxin‐like polychlorinated biphenyls (DL‐PCBs) were analysed in three batches 18 and were below the limit of quantification. The calculated upper bound (UB) concentration was 0.0769 ng WHO2005‐TEQ/kg for the sum of PCDD/Fs, and 0.136 ng/kg WHO2005‐TEQ/kg the sum of PCDD/Fs and DL‐PCBs. The UB for the sum of non DL‐PCBs was 0.53 μg/kg (all values are expressed based on 88% dry matter). 19
In the same batches, fluoride, chloramphenicol, polycyclic aromatic hydrocarbons (PAHs) and ethylene oxide (pesticide) were analysed: results were all below the limits of quantification (LOQ). 20 Melamine and cyanuric acid were below the LODs. 21
Tetrahydrofuran, ethanol, dimethylformamide, 22 methanol and isobutyl acetate 23 were measured in five batches each. Toluene was measured in 10 batches. Ethanol and dimethylformamide were not detected 24 ; methanol amounted to 4.02 mg/kg (2.2–6.3 mg/kg); isobutyl acetate 1.4 mg/kg (0.9–2.8 mg/kg), tetrahydrofuran 0.027 mg/kg (0.025–0.028 mg/kg). Toluene was not detected in five batches, 25 while in other batches amounted to 0.6 mg/kg (0.4–0.7 mg/kg). The analysed values comply with the limits of the International Cooperation on Harmonisation of Technical Requirements for Registration of Veterinary Medicinal Products (VICH) Guideline (EMA, 2023).
The FEEDAP Panel considers that the detected impurities do not raise any safety concern.
Considering that no changes have been introduced in the manufacturing process and composition of the active substance, no changes in the physical properties, described in the previous opinion (EFSA FEEDAP Panel, 2012b), are expected. For the current assessment, new data on dusting potential, particle size distribution and shelf‐life of the active substance biotin were provided.
The dusting potential measured in three batches of biotin using the Stauber‐Heubach method showed values on average of 649 mg/m3 (range 526–713 mg/m3) (mg airborne dust per m3 of air). Particle size distribution was investigated by means of laser diffraction analysis in three batches of biotin. The average results showed that 2%(v/v) of the particles were < 1 μm, 28%(v/v) was < 10 μm, 92%(v/v) was below 50 μm and 99% (v/v) was below 100 μm. 26
Three batches of biotin were stored at (30°C) in plastic bags for 36 months. No significant losses were recorded at the end of the storage period. 27
3.1.2. Characterisation of biotin preparations
The authorising regulation states that biotin may be placed on the market and used as an additive consisting of a preparation.
The applicants state that biotin is marketed in the form of preparations at concentrations of 2% or 10%, by mixing the active substance biotin (min. 97%) with carriers and technological additives.
The applicants provided some analytical data on the batch‐to‐batch variation, impurities and physical properties for four different preparations containing 2% biotin and one preparation containing 10% biotin (see Table 1). 28
TABLE 1.
Data on the batch‐to‐batch variation, impurities and physical properties of preparations containing biotin. The data presented are average values, (range) and [number of batches analysed] for batch‐to‐batch variation, and ranges for all other parameters.
| Biotin 2% | Biotin 2% | Biotin 2% (spray‐dried) | Biotin 2% (spray‐dried) | Biotin 10% (spray‐dried) | |
|---|---|---|---|---|---|
| Specifications | |||||
| Biotin (%) | 2 | 2 | 2 | 2 | 10 |
| Batch‐to‐batch variation | |||||
| Biotin (%) |
2.11 (2.03–2.28) [4] |
2.31 (2.05–3.01) [5] |
2.03 (2.02–2.04) [5] |
2.0 (2) [5] |
10.3 (10.2–10.4) [5] |
| Loss on drying (%) | – |
0.2 [1] |
5.7 (5.6–5.8) [5] |
– | – |
| Impurities | |||||
| Lead (mg/kg) |
< 2 [3] |
4.21–4.31 [5] |
< 0.2 [5] |
– | – |
| Cadmium (mg/kg) |
< 0.5 [3] |
0.10–0.13 [3] |
< 0.1 [5] |
– | – |
| Arsenic (mg/kg) |
< 2 [3] |
0.53–0.95 [3] |
< 0.2 [5] |
– | – |
| Mercury (mg/kg) |
< 0.01 [3] |
< 0.01–0.001 [3] | < 0.1 [5] | – | – |
| Fluoride (mg/kg) | < 20–22 [3] | 51–92 [2] | – | – | – |
| Dioxins and furans | [3] | [1] | [3] | ||
| PCDD/Fs (ng/kg, upper bound, 88% DS) | 0.0519–0.0595 | 0.05683 | – | – | – |
| DL‐PCBs (ng/kg) | 0.0277–0.0318 | 0.05922 | – | – | – |
| PCDD/Fs + PCBs (ng/kg) | 0.0796–0.0912 | 0.11605 | – | – | – |
| nDL‐PCBs (μg/kg) | 0.0493–0.0563 | 0.53 | Not detected, < 1 | – | – |
| Mycotoxins (μg/kg) | [3] | [3] | [3] | ||
| Aflatoxins B1, B2, G1 | < 0.1 | – | < 0.2 | – | – |
| Aflatoxin G2 | < 0.2 | – | < 0.2 | – | – |
| Deoxynivalenol | < 50 | < 40 | < 10 | – | – |
| Zearalenone | < 20 | < 10 | < 5 | – | – |
| HT‐2 toxin | < 20 | < 20 | < 2 | – | – |
| T‐2 toxin | < 20 | < 2 | < 2 | – | – |
| Fumonisins B1 + B2 | – | < 40 | < 50 | – | – |
| Ochratoxin A | – | < 5 | < 0.5 | – | – |
| Microbial contamination | [3] | ||||
| Yeast and moulds (CFU/g) | – | – | < 100 | – | – |
| Enterobacteriaceae (CFU/g) | – | – | < 10 | – | – |
| Salmonella spp. (in 25g) | – | – | Not detected | – | – |
| Physical properties | [3] | [3] | [4] | [4] | |
| Bulk density (kg/m3) | 1425–1472 | ||||
| Dusting potential (mg/m3) | 1533–1750 | – | 2098–3069 | 5360–9940 | 3750–8830 |
| Particle size distribution (% of particles below, v/v) | |||||
| 100 μm | 31.2–32.6 | – | 56.7–58.3 | 66.3–92.0 | 74.4–83.4 |
| 50 μm | 15.2–18.7 | – | 24.3–26.5 | 32.4–60.5 | 37.9–48.3 |
| 10 μm | 8.6–10.7 | – | 2.1–2.3 | 1.8–5.1 | 2.4–4.4 |
| 1 μm | – | 0.3 | 0 | 0 | |
| Stability in feed (% recovery) | [3] | ||||
| 25°C/60% RH 24 months | – | 98 | – | – | – |
| 40°C/75% RH 6 months | – | 98 | – | – | – |
| Homogeneity (coefficient of variation, %) Pelleted feed, 0.4 mg biotin/kg feed | – | – | – | 5 | 3 |
Abbreviations: <, means below the limit of quantification; –, not analysed; RH, relative humidity.
The Panel considers that the microbial contamination and the levels of the impurities analysed in these preparations are of no concern.
3.1.3. Conditions of use
Biotin (97%) is currently authorised for use as nutritional additive in feed for all animal species without a minimum or maximum level. Under other provisions of the authorisation, it is specified that:
Biotin may be placed on the market and used as an additive consisting of a preparation.
In the directions for use of the additive and premixture, indicate the storage and stability conditions.
For safety: breathing protection shall be worn during handling.
The additive may be used in water for drinking.
The applicants did not request any change in the current conditions of the authorisation.
3.2. Safety
In the previous assessment, the FEEDAP Panel concluded that biotin is safe for the target animals with a margin of safety that is probably at least 10 times the requirements and use levels, as already reported in the EFSA Panel opinion issued in 2012 (EFSA FEEDAP Panel, 2012a, 2012b). Biotin has a low toxicity and shows a limited retention in edible tissues and products. Current levels of intake of biotin arising from consumption of animal tissues and products from biotin‐treated animals do not represent a health risk. The FEEDAP Panel considered that the use of biotin in animal nutrition does not pose a concern for the consumers and environment. Regarding the user safety, the FEEDAP Panel considered biotin not irritant to skin, eyes or mucous membranes and not a dermal sensitiser, but concluded that inhalation exposure resulting from handling biotin could be hazardous.
The applicants declared that no incidents or safety issues for target animals, consumers, users and/or the environment have been documented or reported regarding the additive since its first authorisation. 29
In support of the safety of the additive, the applicants submitted the results of a literature search performed in accordance with the requirements of the Guidance on the renewal of the authorisation of feed additives (EFSA FEEDAP Panel, 2021). 30 The search period covered the full period since the authorisation (from January 2011 to February 2024). Several databases were searched (e.g. LIVIVO, OVID, PubMed, ACS pub, Elsevier, CSIR‐NISCAIR, Ingenta, Kluwer/LWW). A secondary manual search in Google Scholar was performed. A total of 31 references were selected by the applicants as relevant for the current assessment. Fifteen papers were related on the safety for the target species, eleven on the safety for the consumers and three on the safety for the users. No relevant papers regarding the safety for the environment were found. The FEEDAP Panel reviewed the papers and considered that none of them provides information that would modify the conclusions previously reached.
The applicants provided updated data on dusting potential for the active substance and as a preparation (see Section 3.1). Based on these, the FEEDAP Panel considers that the exposure of users by inhalation is likely.
Considering the above and the fact that the manufacturing process of the active substance has not been changed since the previous authorisation, the FEEDAP Panel concludes that the biotin remains safe for the target species, the consumers and the environment under the authorised conditions of use. Regarding the user safety, biotin is not irritant to skin and eyes and is not a dermal sensitiser. The exposure to the additive through inhalation is likely.
3.3. Efficacy
The present application for renewal of the authorisation does not include a proposal for amending or supplementing the conditions of the original authorisation that would have an impact on the efficacy of the additive. Therefore, there is no need for assessing the efficacy of the additive in the context of the renewal of the authorisation.
4. CONCLUSIONS
The applicants have provided evidence that the additive currently on the market complies with the existing conditions of authorisation.
The Panel concludes that biotin remains safe for all target animal species, consumers and the environment under the authorised conditions of use.
Regarding the user safety, the FEEDAP Panel concludes that biotin is not irritant to skin, eyes and is not a dermal sensitiser. Exposure by inhalation is likely.
There is no need for assessing the efficacy of the additive in the context of the renewal of the authorisation.
ABBREVIATIONS
- CAS
Chemical Abstracts Service
- CFU
colony forming unit
- EURL
European Union Reference Laboratory
- FEEDAP
EFSA Scientific Panel on Additives and Products or Substances used in Animal Feed
- LOD
limit of detection
- LOQ
limit of quantification
- RH
relative humidity
REQUESTOR
European Commission
QUESTION NUMBER
EFSA‐Q‐2024‐00320
COPYRIGHT FOR NON‐EFSA CONTENT
EFSA may include images or other content for which it does not hold copyright. In such cases, EFSA indicates the copyright holder and users should seek permission to reproduce the content from the original source.
PANEL MEMBERS
Roberto Edoardo Villa, Giovanna Azimonti, Eleftherios Bonos, Henrik Christensen, Mojca Durjava, Birgit Dusemund, Ronette Gehring, Boet Glandorf, Maryline Kouba, Marta López‐Alonso, Francesca Marcon, Carlo Nebbia, Alena Pechová, Miguel Prieto‐Maradona, Ilen Röhe and Katerina Theodoridou.
ACKNOWLEDGEMENTS
The Panel wishes to thank the following for the support provided to this scientific output: Stefania Fusani.
EFSA FEEDAP Panel (EFSA Panel on Additives and Products or Substances used in Animal Feed) , Villa, R. E. , Azimonti, G. , Bonos, E. , Christensen, H. , Durjava, M. , Dusemund, B. , Gehring, R. , Glandorf, B. , Kouba, M. , López‐Alonso, M. , Marcon, F. , Nebbia, C. , Pechová, A. , Prieto‐Maradona, M. , Röhe, I. , Theodoridou, K. , Svensson, K. , Tosti, L. , … Pizzo, F. (2025). Assessment of the feed additive consisting of biotin for all animal species for the renewal of its authorisation (ADISSEO, DSM Nutritional Products Ltd., NHU Europe GmbH). EFSA Journal, 23(2), e9250. 10.2903/j.efsa.2025.9250
Adopted: 28 January 2025
The declarations of interest of all scientific experts active in EFSA's work are available at https://open.efsa.europa.eu/experts
Notes
Regulation (EC) No 1831/2003 of the European Parliament and of the council of 22 September 2003 on the additives for use in animal nutrition. OJ L 268, 18.10.2003, p. 29.
DSM Nutritional Products Ltd., Wurmisweg 576 Kaiseraugst – Switzerland (represented in the EU by DSM Nutritional Products Sp.z.o.o.); NHU Europe GmbH, Daimlerstrasse 14–16 Bardowick – Germany; ADISSEO France S.A.S, Immeuble Antony Parc II 10, place du Général de Gaulle Antony – France.
Commission Implementing Regulation (EU) No 2015/723 of 5 May 2015. OJ L 115, 6.5.2015, p. 22.
Dossier reference: FEED‐2024‐26620.
Regulation (EC) No 178/2002 of the European Parliament and of the Council of 28 January 2002 laying down the general principles and requirements of food law, establishing the European Food Safety Authority and laying down procedures in matters of food safety. OJ L 31, 1.2.2002, p. 1–48.
Decision available at: https://www.efsa.europa.eu/en/corporate‐pubs/transparency‐regulation‐practical‐arrangements.
Evaluation report available on the EU Science Hub https://joint‐research‐centre.ec.europa.eu/eurl‐fa‐eurl‐feed‐additives/eurl‐fa‐authorisation/eurl‐fa‐evaluation‐reports_en.
Commission Regulation (EC) No 429/2008 of 25 April 2008 on detailed rules for the implementation of Regulation (EC) No 1831/2003 of the European Parliament and of the Council as regards the preparation and the presentation of applications and the assessment and the authorisation of feed additives. OJ L 133, 22.5.2008, p. 1.
Sect_II_2‐1_2‐2_Detailed_Identification_Biotin.
OJ L 115, 06.05.2015, p. 22.
Sect_II_2‐3_Manufacturing_Biotin.
Annex_II_02_a_CoA‐pure; Annex_II_02_b_CoA‐pure; Annex_II_02_c_CoA‐pure.
Impurity A: Di[3‐[(3aS,4S,6aR)‐2‐oxohexahydrothieno[3,4‐d]imidazol‐4‐yl]propyl]acetic acid; Impurity B: 4‐[(3aS,4S,6aR)‐2‐ Oxohexahydrothieno[3,4‐d]imidazol‐4‐yl]butane‐1,1‐dicarboxylic acid; Impurity E: 5‐[(3aS,4S,6aR)‐3‐benzy1‐2‐oxohexahydrothieno[3,4‐d]imidazol‐4‐yl]pentanoic acid and 5‐[(3aS,4S,6aR)‐1‐benzy1‐2‐oxohexahydrothieno[3,4‐d]imidazol‐4‐yl]pentanoic acid.
Annex_II_02_b_CoA‐pure; LODs: arsenic and cadmium 0.005 mg/kg, lead 0.05 mg/kg, mercury 0.03 mg/kg.
Annex_II_02_c_CoA‐pure; LODs: arsenic 0.003 mg/kg, lead 0.02 mg/kg, cadmium and mercury 0.001 mg/kg.
LOD fluorine: 40 mg/kg.
LOD nickel: 0.2 mg/kg.
Annex_II_05_c_Impurities‐pure.
Upper bound concentrations are calculated on the assumption that all values of the different congeners below the limit of quantification are equal to the limit of quantification. TEQ = toxic equivalency factors for PCDD/Fs and DL‐PCBs established by WHO in 2005 (van den Berg et al., 2006).
LOQs were: fluoride 40 mg/kg, chloramphenicol 0.00015 mg/kg, PAHs 0.2–0.5 μg/kg each, ethylene oxide 0.01 mg/kg.
LODs were: melamine 0.2 mg/kg, cyanuric acid 0.9 mg/kg.
Annex_II_02_b_CoA‐pure.
Annex_II_02_c_CoA‐pure.
LOD not indicated.
LOD not indicated.
Annex_II_09_c_DP‐PSD‐pure.
Annex_II_12_c_Stability‐pure.
Annex_II_03_a_CoA‐2p_Conf.pdf; Annex_II_03_b_CoA‐2p.pdf; Annex_II_03_c_CoA‐2pCa_Conf.pdf; Annex_II_03_c_CoA‐2p_Conf.pdf; Annex_II_04_b_CoA‐10p.pdf, Annex II 13 c Stability‐2p.
Annex_III_01_a_Monitoring_report_Conf.pdf; Annex_III_01_b_Monitoring_report_Conf.pdf; Annex_III_01_c_Monitoring_report_Conf.pdf.
Annex III 02 Literature search.
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