Assessment of the feed additive consisting of choline chloride for all animal species for the renewal of its authorisation (Andrés Pintaluba S.A., Taminco B.V., Balchem Italia S.r.l.)

TL;DR

This paper assesses the safety of choline chloride as a feed additive for all animal species and concludes it remains safe under current conditions.

Contribution

The paper confirms the safety of choline chloride for animals, consumers, and the environment under existing authorization conditions.

Findings

Choline chloride is safe for target species, consumers, and the environment under current use conditions.

Choline chloride is a potential skin and respiratory sensitiser, posing risks with exposure through these routes.

Eye irritation potential for concentrated forms of choline chloride could not be determined.

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 choline chloride as a nutritional additive for all animal species. The additive is already authorised for use in all animal species (3a890). The applicant provided evidence that the additive currently in the market complies with the existing conditions of authorisation. The EFSA Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) concluded that the use of the feed additive in animal nutrition under the proposed conditions of use remains safe for the target species, the consumers and the environment. Regarding user safety, the FEEDAP Panel concluded that the active substance choline chloride should be considered as a potential skin and respiratory sensitiser; therefore, any exposure via skin or respiratory tract is considered a risk. Although aqueous solutions of up to 70% choline chloride are considered non‐irritant to eyes, no conclusion can be reached on the eye irritation potential for more concentrated forms. These conclusions would apply, in principle, to any preparations produced with the active substance. The present application for renewal of the authorisation does not include any modification proposal that would have an impact on the efficacy of the additive and therefore there is no need for re‐assessing the efficacy.

Tables

TABLE 1. Analysed active substance and impurities of the solid preparations expressed as average (range) [#batches].

	70% choline chloride in corn cob	60%–70% choline chloride in corn cob	50% choline chloride in silica	50% choline chloride in silica
Batch‐to‐batch variation	[5]	[5]	[5]	[5]
Choline chloride (%)	70.3 (68.2–71.2)	60.4 (60.3–60.6)	50.3 (49.9–50.5)	50.5 (50.2–50.8)
Loss on drying (%)	0.6 (0.8–0.5)	0.7 (0.8–0.6)	15.4 (15.8–14.9)	16.5 (16.9–16.0)
Impurities	[8]	[3]	[4]	[3]
Lead (mg/kg)	< 0.05–0.17	< 2.0	< 0.5–0.4	< 2.0
Mercury (mg/kg)	< 0.005	0.013–0.5	< 0.05–0.01	< 0.01–0.033
Cadmium (mg/kg)	< 0.1–0.05	< 0.2	< 0.01	< 0.2–< 0.5
Arsenic (mg/kg)	≤ 0.1	< 0.05–0.128	< 0.1–< 0.5	0.01–< 0.05
Dioxins and PCBs (upper bound,1 88% DM)	[8]	[3]		[3]
PCDD/Fs (ng WHO2005‐TEQ/kg)	0.0593–0.0610	0.068–0.085	–	0.03–0.058
PCDD/F + PCBs (ng WHO2005‐TEQ/kg)	0.0950–0.0974	–	–	–
nDL‐PCBs (μg/kg)	0.345–0.354	–	–	–
Mycotoxins (μg/kg)	[7]	[2]
Aflatoxins B1 + B2 + G1 + G2	< 0.5	< 2.0	–	–
Ochratoxin A	1.2–5.9	–	–	–
Deoxynivalenol	56–280	–	–	–
Zearalenone	30–120	643–1110	–	–
T‐2 toxin	< 10–10	< 2.0	–	–
HT‐2 toxin	< 10–17	–	–	–
Fumonisin B1	190–760	–	–	–
Fumonisin B2	24–170	–	–	–
Microbial contamination		[3]		[3]
Total plate counts (CFU/g)	–	110–780	–	< 10
Salmonella spp. (per 25g)	–	Not detected	–	Not detected
Coliforms (MPN/100g)	–	< 30	–	< 30
Physical properties	[3]	[1]	[3]	[1]
Dusting potential (mg/m3)	135–160	65	815–925	125
Particle size distribution (% of particles <)	50 μm: < 1 100 μm: 2.5–3	26 μm: 10 516 μm: 50 1071 μm: 90	10 μm: 9–13 50 μm: 54–71 100 μm: 73–89	38 μm: 10 132 μm: 50 264 μm: 90

Full text

INTRODUCTION

1

Background and Terms of Reference

1.1

Regulation (EC) No 1831/20031 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 Andrés Pintaluba S.A.,2 Taminco B.V.,3 and Balchem Italia S.r.l.4 for the renewal of the authorisation of the additive consisting of choline chloride, when used as a feed additive for all animal species (category: nutritional additives; functional group: vitamins, pro‐vitamins and chemically well‐defined substances having 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 13 September 2022 and the general information and supporting documentation are available at https://open.efsa.europa.eu/questions/EFSA‐Q‐2022‐00554. The particulars and documents in support of the application were considered valid by EFSA as of 31 May 2023.

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 choline chloride, when used under the proposed conditions of use (see Section 3.1.4).

Additional information

1.2

The additive choline chloride is currently authorised for use in feed and water for drinking for all animal species (3a890).5 EFSA issued an opinion on the safety and efficacy of this product when used in feed for all animal species (EFSA FEEDAP Panel, 2011).

DATA AND METHODOLOGIES

2

Data

2.1

The present assessment is based on data submitted by the applicant in the form of a technical dossier6 in support of the authorisation request for the use of choline chloride as a feed additive.

In accordance with Article 38 of the Regulation (EC) No 178/20027 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,8 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 1 September to 22 September 2023 for which no comments were received.

In addition, the confidential version of the technical dossier was subject to a target consultation of the interested Member States from 31 May to 31 August 2023 for which the received comments were considered for the assessment.

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 choline chloride in animal feed are valid and applicable for the current application.9

Methodologies

2.2

The approach followed by the FEEDAP Panel to assess the safety and the efficacy of choline chloride is in line with the principles laid down in Regulation (EC) No 429/200810 and the relevant guidance documents: Guidance on the renewal of the authorisation of feed additives (EFSA FEEDAP Panel, 2021).

ASSESSMENT

3

The additive choline chloride is currently authorised as a nutritional additive (functional group: vitamins, pro‐vitamins and chemically well‐defined substances having similar effect) for use in feed and water for all animal species. The present application is for the renewal of the authorisation. The data submitted in this dossier was generated by a consortium of three companies involved in its production/distribution.

Characterisation

3.1

Characterisation of the active substance

3.1.1

Choline chloride [IUPAC name: ethanaminium 2‐hydroxy‐N,N,N‐trimethyl‐, chloride; synonyms: (2‐hydroxyethyl)trimethylammonium chloride; (β‐hydroxyethyl) trimethylammonium chloride; ammomium, (2‐hydroxyethyl)trimethyl‐ chloride; choline hydrochloride; cholinium chloride; trimethyl(2‐hydroxyethyl) ammonium chloride], is identified with the Chemical Abstracts Service (CAS) number 67‐48‐1 and European Inventory of Existing Chemical Substances (EINECS) number 200‐655‐4. The molecular formula is C_5_H_14_Cl^.^NO and its molecular weight 139.63 Da. Choline chloride is reported to be freely soluble in water.

The current authorisation sets a minimum purity content of choline chloride in the active substance of 99% on anhydrous basis. The applicants state that the manufacturing process has not been changed since the original authorisation.

The active substance choline chloride is manufactured as an aqueous solution of choline chloride with a minimum content of 75% choline chloride as is.

Analytical data were provided from 20 batches (at least five from each company) of the aqueous solution of choline chloride containing a minimum 75%, and 5 batches (from one company) with a minimum of 78%. The results showed a choline chloride content in the range 75.1%–78.6%,11 in compliance with the specifications.

Data from 15 batches (five per company) were provided which confirmed compliance with the specifications with an average content of choline chloride of 99.92% on anhydrous basis (range 99.84%–99.97%).12

Analytical data for the main organic impurities resulting from choline chloride synthesis, i.e. unreacted trimethylamine (32–200 mg/kg), ethylene glycol13 (61–500 mg/kg) and chloroethanol (0.56–29.6 mg/kg)14 formed by the reaction of hydrochloric acid with ethylene oxide, were submitted for 15 batches of the aqueous choline chloride (five batches per company).15

Data on arsenic, lead, cadmium and mercury were below the limit of quantification (LOQ) LOQ16 in 10 batches from one company, while arsenic ranged 0.02–0.06 mg/kg and lead was below the LOQ17 in 5 batches of another company.

The FEEDAP Panel considers that the detected impurities do not raise safety concerns.

Characterisation of the preparations

3.1.2

The current authorisation states that the additive choline chloride can be placed in the market in the form of solid and liquid preparations.

The applicants stated that choline chloride is placed in the market in the form of two aqueous solutions of choline chloride described under Section 3.1.1 with a content of choline chloride of min 75%–78%, and five solid preparations in which the active substance is mixed with either silica (E 551) or with vegetable carriers, with a resulting content of choline chloride ranging between min 50% and 80%.

The applicants provided data on the composition and impurities of four example solid preparations: two formulated with a vegetable carrier (corn cob) with a minimum content of 60% and 70% choline chloride, and two formulated with silica with a minimum content of 50% choline chloride. The applicant provided also data from two companies on dusting potential (determined using the Stauber‐Heubach method) and particle size distribution of the solid choline chloride preparations (60%–70%) in vegetable carrier and choline chloride (50%) in silica. The data on batch‐to‐batch variation, impurities and physical properties are reported in Table 1.18 The applicant provided also analyses of impurities for the carriers, but these are considered not relevant for the assessment.

The FEEDAP Panel considers that the microbial contamination and the amounts of the detected impurities do not raise safety concerns.

Stability and homogeneity

3.1.3

Since no changes were introduced in the manufacturing process of the active substance, the data described in the previous opinion still apply (EFSA FEEDAP Panel, 2011).

The applicant has provided new data on the shelf life and the capacity for homogeneous distribution of the choline chloride in the aqueous solution and/or solid preparations, which support the previous data.

The shelf life of the aqueous choline chloride (75%) was measured in seven batches when stored after 24 months in closed drums or HDPE plastic containers under ambient conditions (0–35°C). Losses at the end of the storage period were below 0.3%.19

The shelf life of solid preparation of choline chloride (50% in silica, four batches; 60% in corn cob, six batches; and 70% in corn cob, six batches) was assessed when stored for 24 months at 25°C in net bags. Losses were ≤ 0.2% in all cases.20 ^,^ 21

The capacity for homogeneous distribution of the choline chloride in the solid preparations was studied in 6 subsamples of choline chloride (60%) in vegetable carrier and 10 subsamples of choline chloride (50%) in silica. The coefficient of variation was 0.7% and 1.2%, respectively.22

Conditions of use

3.1.4

Choline chloride is currently authorised for use in all animal species and categories without a maximum limit. The authorising regulation states under other provisions:

1. If the preparation contains a technological additive or feed materials for which a maximum content is set or which is subject to other restrictions, the feed additive manufacturer shall provide this information to the customers.
2. In the directions for use of the additives and premixture indicate the storage and stability conditions.
3. Choline chloride may be used via water for drinking.
4. The labelling of feed for poultry and pigs containing choline chloride should indicate in the instructions of use: ‘simultaneous use with water for drinking in which choline chloride has been added should be avoided’.
5. Recommended not to exceed supplemental levels of 1000 mg of choline chloride/kg of complete feed for poultry and pigs.
6. For safety: breathing, eye and skin protection shall be used during handling.

The applicants did not request any change in the current conditions of the authorisation.

Safety

3.2

Safety for the target species, consumers and environment

3.2.1

In its previous opinion, the FEEDAP Panel concluded that ‘recommended and use levels of choline chloride supplementation to feed are safe for the target animals. However, studies indicate that the margin of safety compared to the use level in poultry and pigs is small. The limited and inconsistent dataset available together with the uncertainties arising from differences in diet composition do not allow the FEEDAP Panel to conclude on the maximum safe content in feed. The simultaneous use of supplemental choline in feed and water for drinking should therefore be avoided’. The Panel also concluded that the use of choline chloride in feed is safe for the consumers and the environment (EFSA FEEDAP Panel, 2011).

The applicants stated that no adverse effects regarding the safety for the target animals, consumers, users and the environment have been notified since the original authorisation,23 and provided an updated extensive literature search to further support the safety of the additive.24 Two literature searches were performed, the second one with a modified search strategy to improve sensitivity and specificity, in both cases limited to the period between 2010 and 2022.25 Overall, 78 publications were assessed for their safety relevance by three reviewers. The FEEDAP Panel concluded that none of the hits described safety concerns related with the use of choline chloride in animal nutrition.

Considering the above, and the fact that the manufacturing and composition of the active substance have not been modified since the original authorisation, the FEEDAP Panel concludes that choline chloride remains safe for all animal species, consumers and the environment under the authorised conditions of use.

Safety for the user

3.2.2

In the previous opinion (EFSA FEEDAP Panel, 2011), the FEEDAP Panel concluded that the risk of choline chloride preparations to cause inhalation toxicity is low. Aqueous solutions of up to 70% choline chloride were considered non‐irritant to skin and eyes, but no evidence that more concentrated and/or solid choline chloride formulations would be irritant were provided, hence this possibility could not be excluded. The possibility that occupational exposure to choline chloride might cause skin sensitisation could not be excluded either.

The applicant provided three papers (two scientific articles and one abstract) to support the safety of the user. However, they were not further considered relevant for the assessment as they were intended to evaluate the beneficial effects of the substance and the test item was not representative of the additive under assessment.

No additional data were submitted by the applicant for the active substance or any of the preparations. Therefore, the FEEDAP Panel concludes that the active substance choline chloride should be considered as a potential skin and respiratory sensitiser. Therefore, any exposure via skin or respiratory tract is considered a risk. Although aqueous solutions of up to 70% choline chloride are considered non‐irritant to eyes, no conclusion can be reached on the eye irritation potential for more concentrated forms. These conclusions would apply, in principle, to any preparations produced with the active substance.

Efficacy

3.3

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.

CONCLUSIONS

4

The applicant has provided evidence that the additive currently in the market complies with the existing conditions of authorisation.

The use of choline chloride in animal nutrition remains safe for the target species, the consumers and the environment under the approved conditions of use.

Regarding user safety, the FEEDAP Panel concludes that the active substance choline chloride should be considered as a potential skin and respiratory sensitiser; therefore, any exposure via skin or respiratory tract is considered a risk. Although aqueous solutions of up to 70% choline chloride are considered non‐irritant to eyes, no conclusion can be reached on the eye irritation potential for more concentrated forms. These conclusions would apply, in principle, to any preparations produced with the active substance.

There is no need to assess the efficacy of the additive in the context of the renewal of the authorisation.

ABBREVIATIONSCASChemical Abstracts ServiceCFUcolony forming unitsDMdry matterEINECSEuropean Inventory of Existing Chemical SubstancesEURLEuropean Union Reference LaboratoryFEEDAPEFSA Panel on Additives and Products or Substances used in Animal FeedLOQlimit of quantificationMPNmost probable numberPCBspolychlorinated biphenylsPCDDspolychlorinated dibenzo‐p‐dioxinsPCDFspolychlorinated dibenzofuransnDL‐PCBsnon‐dioxin‐like PCBsTEQtoxic equivalentWHOWorld Health Organization

REQUESTOR

European Commission

QUESTION NUMBER

EFSA‐Q‐2022‐00554

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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.