COMMENTS ON AN ANNEX XV DOSSIER FOR IDENTIFICATION OF A SUBSTANCE AS SVHC AND RESPONSES TO THESE COMMENTS

Substance name: Cadmium nitrate
CAS number: 10325-94-7
EC number: 233-710-6

The substance is proposed to be identified as meeting the following SVHC criteria set out in Article 57 of the REACH Regulation: Carcinogenic (Article 57a), Mutagenic (Article 57b), Specific target organ toxicity after repeated exposure (Article 57(f) - human health)

Disclaimer: Comments provided during public consultation are made available as submitted by the commenting parties. It was in the commenting parties own responsibility to ensure that their comments do not contain confidential information. The Response to Comments table has been prepared by the competent authority of the Member State preparing the proposal for identification of a substance of very high concern. RCOM has not been agreed by the Member State Committee nor has the document been modified as result of the MSC discussion.

PART I: Comments and responses to comments on the SVHC proposal and its justification

General comments on the SVHC proposal
Number / Date	Submitted by (name, submitter type, country)	Comment	Responses	
4911
2017/10/20	International Cadmium Association,
Industry or trade association,
Belgium	Attachment:
4911_20 Oct _CdNO3 Annex XV_Master Comments Document_2017_Oct Final .pdf
	Thank you for your comments and the information provided.
Comments regarding use, exposure, alternatives and risks may, where relevant, be considered at later stages of the risk management process.

The justification for SVHC identification is based on intrinsic properties of the substance, not on use, exposure and risk. 

For responses to specific comments, please see embedded file. 

Attachment: RCOM_Attachment CdNO3	
4941
2017/10/27	Finland,
Member State	In line with the previous inclusion to the SVHC candidate list for cadmium and cadmium salts, the Finnish CA agrees that Cadmium nitrate meets the criteria as SVHC according to Article 57 a, b and f. The substance has a harmonized classification as carcinogenicity category 1B (H350: may cause cancer) and germ cell mutagenicity category 1B (hazard statement H340: “May cause genetic defects”). The proposal for identification of substance as SVHC in accordance with Article 57 f is based on effects on kidney and bone after repeated exposure (classified as STOT RE 1). The Finnish CA agrees that Cadmium nitrate is a substance for which there is scientific evidence of probable serious effects to human health which gives rise to an equivalent level of concern to those substances listed in points (a) to (e) of Article 57 REACH.	Thank you for the support.	

Specific comments on the justification
Number / Date	Submitted by (name, submitter type, country)	Comment	Responses	
4858
2017/10/19	ChemSec,
International NGO,
Sweden	ChemSec supports the inclusion of the proposed three cadmium compounds on the Candidate List, based on the properties of the cadmium ion as carcinogenic, mutagenic and having specific organ toxicity. These cadmium compounds are also on the SIN List.	Thank you for the support.	
4872
2017/10/20	Germany,
Member State	The German CA supports the SVHC identification of cadmium nitrate.	Thank you for the support.	
4875
2017/10/20	Norway,
Member State	The Norwegian CA supports that cadmium nitrate should be identified as a substance of very high concern and should be included in the Candidate List.	Thank you for the support.	
4898
2017/10/20	ANSES,
National Authority,
France	Cadmium nitrate is included in the Annex VI of CLP (index number 048-014-00-6) with an harmonised classification Carc. 1B, Muta. 1B and STOT RE 1(kidney, bone).
Cadmium nitrate therefore fulfils the criteria for identification as SVHC according to article 57 (a) and (b).
In addition, the effects of the cadmium ion on bone and kidney are considered to rise an Equivalent Level of Concern (ELoC) as it has been established with previous cadmium compounds identified as SVHC under article 57(f) on this basis. In relation to its classification STOT RE 1 (kidney, bone), an identification of cadmium nitrate as an SVHC under art 57(f) is therefore supported.	Thank you for the support.	
4911
2017/10/20	International Cadmium Association,
Industry or trade association,
Belgium	The Annex XV report on Cadmium nitrate highlights two areas of risks:
1. risk of increased bone and kidney effect on the general population due to exposure to Cd and its compounds from the environment and to releases of cadmium nitrate from cadmium containing articles,
2. risk to a large number of EU workers occupationally exposed to cadmium compounds.
These risks are taken forward as a basis to request that cadmium nitrate be submitted to the REACH authorization process, which links the right for industry to “use” cadmium nitrate to the granting of a permit (the “Authorization”).
The general population is exposed to Cd essentially by the ingestion route, with regimen including Cd containing food. Food contains Cd because (a) of the wide-use of cadmium containing fertilizers and (b) of air deposition of cadmium to the ground.
It is therefore important to estimate the fraction or Cd content in air which is linked to industrial uses of cadmium nitrate.
In these comments, industry will show that:
1. The contribution of the industry deliberately using cadmium nitrate to general population exposure is negligible as compared to the contribution of the industry manipulating goods in which cadmium is present as an impurity.  In other words, the manufacture and formulation of cadmium nitrate has no influence on general population cadmium exposure,
2. The use of articles containing Cd and Cd compounds is already under many restrictions, prohibitions and limitations within the EU. Industry will show that exposure from the remaining articles, including their end of life, is negligible
3. Sectors where there is workforce exposure to Cd and its compounds have a solid record of risk management and risk reduction; formalized in 2006 (and regularly updated since) in an Official Industry Guidance based on the Swedish Occupational Risk Agency management tools, and implemented a DNEL based on the heath-based OEL proposed by SCOEL in 2010 (SUMDOC 136 2010).
4. Cd(NO3)2 has no use other than intermediate and this has a relevance to any authorization consideration. Intermediate uses are out of the scope of the REACH Authorisation process.

In clarifying these points, it will become clear that authorization of Cd(NO3)2 uses will not lead to any influence on general population and worker exposure, and as such will be insignificant to “ensure that the risks posed by the substance of very high concern will be properly controlled” (REACH art 55).  Indeed, it will be clear that any Risks are already properly controlled.
Some claim that the candidate listing of cadmium nitrate is quasi automatic, as that substance has now recently been classified CMR. According to the findings of the Board of Appeal, though, ECHA is expected to assess “all the information which must be taken into account in order to assess a complex situation”, and all the evidence, which “is capable of substantiating the conclusions drawn from it“
We trust ECHA will take into account “all the relevant factors and circumstances of the situation the act is intended to regulate”, as we feel that position is also part of ECHA’s duty of sound administration – a general principle of EU law according to which, before they take any decision, institutions and bodies of the European Union with decision-making power have a duty to prepare it carefully and in particular to verify all the elements of fact which may have an impact on it.

In the following, a number of comments on the Annex XV document on cadmium nitrate are given. More details (figures, tables) on some of these comments are provided in the master-file (uploaded under IV Attachment).

Comments
Comment 1
Section “Summary of how the substance meets the criteria set out in article 57 of the REACH Regulation, heading “equivalent level of concern-57(f)”, 3rd paragraph, 5th line -
Annex XV states that ”Deposition from air is an important source to the input of cadmium to soil and must therefore be reduced. In order to achieve this all uses of cadmium and cadmium compounds should wherever possible, be substituted”. This statement ignores (a) the one major source of Cd-input to soil, i.e. use of P-fertilizer (see below), and (b) makes the wrong assumption that (REACH) uses of cadmium contribute to human exposure, which is not the case (see comment 5).
- the major single source of Cd input to agricultural soils, i.e. the use of P-fertilizer, is ignored in the Annex XV dossier. P-fertilizer which may have significant Cd-content of natural origin (3-90ppm, ICdA 2012), is directly applied on the soil and as such is the main direct source of Cd into the food chain. The contribution of P-fertilizer to human exposure is estimated to be significant, as is explained below (see figure 1.1 ) This was also recognized by Sweden where, at one time, taxes on fertilizers with high cadmium contents were imposed. (These taxes were dropped later for unknown reasons)
- Industrial emissions to atmosphere are also important. These are mainly related to the cadmium that is present as an impurity in mineral commodities that are processed/combusted by industry (see comment 5).
- Last but not least, it is emphasized that manufacturing and use of Cd-containing products (including end of life) does not lead to exposure to the general population, as is demonstrated in comment 5.
In figure 1.1 the main sources categories of Cd to the general population are presented for non-smokers (Van Assche 2011). Based on quantitative modeling of the transfer pathways of Cd from the environment into the food chain , it is estimated that the main inputs to soils (and, consequently, to the food) are P-fertilizer (37% of total human exposure), and sources of Cd-emission to the atmosphere (42% of total human exposure). In a conservative approach, natural soil Cd is contributing for about 15%, and exposure from water-related sources is rather limited (6%). These results correspond to data given for a number of member states in the human health risk reduction strategy (OJ 2008/C 149/03)

Fig 1.1: Relative contribution of different Cd sources to human exposure – general population-non-smokers (after Van Assche 2011).

As follows from figure 1.1, atmospheric emissions are important as source to general population exposure (apart from P-fertilizers) because of the direct relationship with crop Cd-content (atmospheric deposition on edible plant parts and deposition on soil, resulting in root uptake). Given this importance of this relationship, a correct assessment of the emissions sources of cadmium to atmosphere is key for understanding sources of general population exposure. This analysis will be presented under comment 5.
In comment 5, it is estimated that, taking all EU emissions together from the production, processing, use and end-of-life incineration of all Cd products account for less than 1% of the anthropogenic Cd-emissions to the EU-atmosphere. Accordingly, it can be calculated that <0.42% of the Cd-exposure of the general population could originate from the Cd industry as a whole (sum of Cd-industry emissions + emissions from incineration <1% x 0.42, cfr figure 5.1).
It is emphasised that the assessment given above relates to all uses of Cd and Cd compounds.  Cadmium nitrate as such is not directly used by consumers. Therefore, the contribution from Cd(NO3)2 production and use to general population Cd exposure is considered insignificant, and consequently any measures related to this source are considered insignificant and not proportional too.
The major sources of Cd to atmosphere are detailed in comment 5. The dossier provides no support of how these sources would relate to Cd(NO3)2.

Comment 2
Section “summary of how the substance meets the criteria set out in article 57 of REACH Regulation”, heading “equivalent level of concern 57(f)”, 4rd paragraph, 4rd line -
Reference is being made to the Council resolution on cadmium of 25 January 1988 -almost 30 years ago- to justify further action on cadmium. The Annex XV fails to consider a) extensive EU legislation that was implemented since then on restrictions of the main cadmium uses, b) the extensive work that has been undertaken by the Commission since then on cadmium, with the EU risk assessment, as a result of which further measures were decided, c) the marked progress that was achieved on limiting documented Cd-emissions to air, water and soil. As such, the annex XV document ignores the significant reduction that has been observed since 1988 related to the cadmium exposure of the general population through the atmosphere (see comment 5 for data).

Comment 3
Section “summary of how the substance meets the criteria set out in article 57 of the REACH Regulation” (cont.), Uncertainties on safe exposure -
The annex XV document mentions rightfully that there is a continuous publishing of new information on cadmium. It states that this demonstrates that “what can be considered as a safe exposure level is steadily decreasing”. This statement however ignores a number of recent publications that challenge the significance of Cd-U as a marker of cadmium exposure in situations of very low exposure (e.g. at or below Cd-U = 1 µg Cd/g creatinine) for both kidney and bone effects (see comment 8 & 9 for details). It is emphasized that the current exposure of the general population is below this very low level (EU mean value for female adults ~= 0.22µg/l), as is demonstrated by recent Cd-U monitoring data in the EU (see comment 25 for details).

Comment 4
Section “summary of how the substance meets the criteria set out in article 57 of the REACH Regulation” (cont.). Societal concern and impairment of quality of life, 2nd paragraph -
The estimation of annual costs of cadmium exposure in Sweden is based on the lowest estimation of the safe exposure level, measured by Cd-U. Cd-U is however recently challenged by academic research as a biomarker of Cd-exposure in situations of very low exposure (see comment 8).  The estimation of annual costs therefore needs to be considered with great caution.

Comment 5
Section 3.1, Anthropogenic and natural sources of cadmium exposure
As follows from the analysis under comment 1 on sources of cadmium to general population exposure, the Cd inputs to atmosphere are an important contributing factor, because they are a direct source of crop/food cadmium content. The annex XV fails to make a quantitative analysis of the relative weight of the different origins of cadmium going into the atmosphere and being deposited on/taken up by the crops. As such, Annex XV fails to assess the importance of the different atmospheric Cd-sources in the perspective of human exposure. This analysis is presented here.
The current atmospheric emissions from the different sources in the EU are presented in figure 5.1 (EMEP inventory (2012)). From this inventory, the relative contributions of deliberate uses of cadmium and cadmium as impurities to atmospheric depositions can be determined:
It follows from figure 5.1 that the main Cd sources to atmosphere are: a) public power generation, b) industrial combustion, c) small combustion; d) industrial processes, e) waste incineration. These sectors emitted 20, 50, 5, 30, and 13,8 Tonnes of Cd per year into the atmosphere in 1990, respectively.
In 2010, they were (with the exception of waste incineration) still the main sources, but important decreases in emissions were observed by that time: Cd-emissions for these sectors were by then 7, 19, 6.6, 10.4, and 0.45 T/y respectively (EMEP 2012). The significant decrease of waste incineration emissions is noted (-97% compared to 1990 emissions).
Overall, Cd emissions to the atmosphere decreased by >60% over the period 1990-2010 (EMEP 2012). It follows from these data that the major part of cadmium emissions to atmosphere is from anthropogenic use where Cd is an impurity. The emissions from deliberate Cd production and use are further discussed below.
It should be noted that the EMEP inventory does not report natural emissions. These have been estimated at ca. 15T/yr (Cd/CdO RAR ECB 2008).
The emissions from the companies manufacturing Cd-products (Cd-production, Cd-recycling, production of Cd compounds, manufacture of NiCd batteries, pigments, and thin-film photovoltaic panels) are very low. They are given in table 5.1., based on recent company data reported by industry.
Figure 5.1.: Cd-emissions to the atmosphere (T/y) by sector in the EU-15 during the period 1990-2015 (EMEP 2017).

Table 5.1.: Industry supplied data (2012) on Cd emissions to air (T/y) in the EU covering all EU sites with deliberate uses of cadmium (Cd refiners, specialty cadmium compounds manufacturers, Ni-Cd battery manufacturers, thin film PV manufacturers, recyclers).
The data presented above all relate to cadmium and cadmium compounds in general. They demonstrate that the contribution from the whole of the Cd-related industry (production, processing to compounds, manufacturing into products, recycling) to the total anthropogenic atmospheric Cd-emissions are minimal (0.18% of EU total). Consequently, the contribution of this industrial activity to the total anthropogenic Cd-exposure of the general population is 0.08% (= 0.18 x 0.42; cfr fig 1.1).
Considering the above, it is emphasised that the production and use of Cd(NO3)2 is only a small fraction of this industrial activity related to cadmium in general. Therefore, the contribution of the Cd(OH)2 production and use to cadmium exposure of the general population is entirely insignificant.
During service life, emissions from Cd-containing products are negligible: e.g. with NiCd batteries, the main application, there is no emission or consumer exposure at all. Cd-pigments and Cd-compounds for photovoltaic applications are also contained in a matrix and do not cause emission or consumer exposure, neither.
At end of life, most of the Cd in products is recycled (e.g. industrial NiCd batteries, photovoltaic panels). A small amount ends up in the municipal waste stream and can be incinerated, thus resulting in Cd-emissions to atmosphere, together with Cd from other sources. The total Cd-emissions from municipal waste incinerators in the EU was 453 kg/y in 2010 (EMEP 2012). It is noted a significant part of this Cd is of natural origin, e.g. the contribution from food and garden waste is estimated to be recently of the order 15% (Arche 2012). Moreover, part of the emissions originates from Cd-traces in non-Cd products. Considering this, the Cd emissions from incineration of Cd-products/impurities can be estimated to be <85% of total, which is <0.8% of total Cd-emissions to the atmosphere (48.4 T/y; EMEP 2012).
In general, the decrease of the Cd-emissions from municipal waste incineration is partly due to the decrease of the Cd-content in municipal waste over the last decades, e.g. in a study from the French agency on environment and energy, it was observed that the Cd-content of MSW in France (which can be taken as relevant for the EU), decreased from 4 mg/kg DW in 1993 to 1.3 mg/kg DW in 2007 (ADEME 2007).
All EU Cd-emissions taken together i.e. from production, processing, use and end-of-life incineration of Cd products account for <1% (= 0.18% + <0.8%) of the anthropogenic Cd-emissions to the atmosphere and, accordingly, for <0.42% of the Cd-exposure of the general population (sum of Cd-industry emissions + emissions from incineration <1% x 0.42, cfr figure 1.1).
In other words, the emissions from deliberate Cd production and use are minimal compared to the total emissions. Notably the emission from the production and use of Cd(NO3)2 is very low and therefore its impact on general population exposure is considered negligible.
In conclusion, a) emissions to atmosphere from Cd-production, processing and use are minimal, b) most Cd in products is recycled and emissions from incineration of municipal solid waste are also limited.  Since all combined emissions related to deliberate anthropogenic cadmium activity amounts only to less than 0.42% of general population exposure, the effect of measures taken against the use of Cd-products on general population as a whole and, notably, the effects of measures taken against Cd(NO3)2 are considered to be insignificant and disproportionate.

Comment 6
Section 3.2: “food”
This paragraph makes reference to EFSA (2012) report to conclude that “children and adults at the 95 percentile exposure can exceed health-based guidance values”. As is indicated in the EFSA report itself, this 95 percentile estimate is “speculative and potentially unrealistic” (section 3.2 page 17 of EFSA 2012) because it is based on the unlikely assumption that the same individuals retain the same high exposure throughout their whole life. This 95 percentile should thus be considered as clearly overestimated. The average Cd intake value calculated in this EFSA study is considered conservative as it is higher than recently published values in EU countries. However, it remains below the EFSA dietary intake standard, which is itself lower than the WHO dietary intake standard. Therefore, even following conservative assumptions, current observed dietary intakes in the EU can be considered safe in a life time perspective. See comment 25 for more detail.

Comment 7
Section 3.2: “food”
The Annex XV document makes reference to the current TWI of 2.5 µg/kg bw as defined by EFSA (EFSA 2009, 2012).
Both WHO’s Joint expert committee on food additives (JECFA 2010) and the European food safety authority (EFSA 2012) have derived a provisional tolerable weekly intake (PTWI) value for cadmium. In spite of the fact that the same epidemiological dataset was used by both organisations, and that they use similar toxicokinetic models to relate urinary cadmium to dietary cadmium intake, the outcome of both exercises is different: while JECFA derives a tolerable weekly intake of 5.8µg Cd.kgBW.w, EFSA sets the limit at 2.5µg Cd/kg BW.w. EFSA (2012), on request of the EU Commission, re-evaluated the evidence and models and identified a number of differences possibly explaining the different outcome. One of those is the methodology used for transforming urinary cadmium concentrations into dietary intake values. We will here comment further on this aspect of the assessment.
To determine dietary exposure corresponding to a (critical) Cd-U, EFSA used the paper by Amzal et al (2009), based on the data from a Swedish population based study on non-smoking, post-menopausal women. Using a reference point (RP) of 1µg/gC for Cd-U, EFSA calculated that the average daily intake should not exceed 0.36µg/kgBW.d, and this daily intake was used to calculate the tolerable weekly intake of 2.5µg/kgBW.w.
When looking at the Amzal et al paper in more detail, it can be observed that the RP of 1µgCd/gC is exceeded in only 2 individuals of the 680 participating in the study. The maximum intake observed in the study is 0.4µg/kg.BW. In other words, at this highest intake, only 2/680 or <<1% of the population is exceeding the RP, while the critical intake following from the analysis is set at the 95% protection level. At the same time, we observe that the highest dietary intake (0.4µg/kgBW.d) is equal to the critical intake value derived to protect the 95percentile of the population.
So, there are reasons to assume that the Amzal et al assessment is overly conservative. The main reason for this seems to be the assumption, in Amzal et al (2009), and taken over in EFSA (2009) that the highest Cd-intake can correspond to the highest bioavailability in the body, resulting in the highest Cd-body burden (measured as Cd-U). As indicated below, this assumption does not correspond to measured Cd-uptake (as Cd-B or Cd-U) data, as follows from the detailed overview made in the EU risk assessment RA (ECB 2007).
The EU risk assessment report (ECB 2007) discussed in detail the evidence related to the relationship between Cd-intake and Cd-uptake in the body. The evidence suggested that higher Cd intake due to a higher consumption of food groups with elevated Cd-content, e.g. shellfish and mushrooms, is not reflected in a proportional increase in systemic dose of Cd.  The data show that other factors than food Cd-content, e.g. iron status and fiber intake, have a more important effect on Cd-B. Some case examples:
• In the duplicate meal study of Vahter et al. (1996), a group of 17 non-smoking women, consuming shellfish at least once a week, was compared with a group of 34 non-smoking women with a mixed diet low in shellfish. The average dietary Cd intake in the shellfish group was 28 µg Cd while it was 11 µg Cd for the mixed diet group. The Cd-B was not significantly different between both groups (0.28 µg/l and 0.24 µg/l respectively). The Cd-concentration in the blood was strongly influenced by the body iron stores of the test persons and increased sharply when serum ferritin was below about 20 µg/l.
• A study from New Zealand on oyster consumers showed that, in spite of very high Cd intake via oysters (group averages 15-233 µg/day), Cd-B and Cd-U were significantly elevated, however, not to the same extent as the dietary intake (McKenzie-Parnell et al., 1988). Smoking had a more pronounced effect on Cd-B than intake of Cd via oysters.
• The gastrointestinal availability of Cd from mushrooms is most probably also low. The Cd concentrations in blood, urine and faeces was monitored daily for eight adults (5 male and 3 female, 2 moderate smokers) that consumed 290-500 g wild mushrooms (Agaricus species) daily during three consecutive days (Schellman et al., 1984). Monitoring started 2-3 days before the mushroom consumption and was continued for 4 days after the last mushroom meal. The extra Cd intake due to the mushroom consumption varied between 315 and 908 µg Cd/day. The faecal excretion of Cd sharply increased on the first day of mushroom consumption and, although it decreased progressively the following days, it was still elevated up to four days after the last mushroom meal. In contrast, Cd-B did not show any trend during the whole experimental period for any individual. The Cd-B varied between 0.2 and 2.9 µg/l and the Cd-B variance among individuals was larger than that within individuals. No increase in Cd-U was found during or after mushroom consumption.
• By analysing data on observed Cd-U, the RA concluded that model calculations assuming a GI absorption rate of 10% at t1/2=13.6 years are generally overestimating uptake by the body. Moreover, the largest calculated Cd-U at the GI absorption rate 5% (at same t1/2) is 0.76 µg Cd/g creatinine, which is still >2 fold above the largest observed value. Citing the RA (ECB 2007): “This indicates that either the 5% GI absorption rate also overestimates the body burden in this group or that groups with the largest Cd intake have a lower average GI absorption rates as often found in feeding studies. The latter suggestion effectively means that it would be inappropriate to estimate upper percentiles of Cd-U from upper percentile of dietary Cd with average toxicokinetic parameter values”
The RA noted “that the upper ranges are best described when selecting a 3% GI absorption rate for a kidney Cd half-life of 13.6 years. This might reflect the fact that, while increased GI absorption rates up to 10% may exist during certain periods of iron deficiency (e.g. late pregnancy), this status does not persist constantly during the whole life. Considering a constant fu of 10% during 50 years would therefore be inadequate for a risk characterisation.”
Considering the above, it is concluded that the accumulation of worst case assumptions (highest intake together with highest bioavailability) used in the EFSA paper to set the PTWI does not seem to be valid and results in an overly conservative PTWI.
It is noted that the assumption of combined high intake with high bioavailability was not validated in the Amzal et al paper (2009); actually, it is contradicted by the observed Cd-U values presented in fig 5 of the paper. In other words, the toxicokinetic model parameters used in Amzal et al. are dependent of dietary intake, and not independent as assumed in the paper.
Based on the elements above, it is concluded that the EFSA derived PTWI value of 2.5µg Cd/kgBW.w is overly conservative. This has consequences for the annex XV statement that ‘the margin between the average weekly intake of cadmium from food by the general population and the health-based guidance values is too small (EFSA 2009)’.

Comment 8
Section 4.2.1 Kidney toxicity, para 2
Annex XV makes reference to KemI (2011), in which a number of studies were cited, “showing significant associations between cadmium in urine and/or blood and markers of impaired kidney function, mostly impaired tubular function”.
However, recent evidence, questions the causality of these associations between U-Cd and biomarkers of kidney effects (urinary proteins) in populations with low levels of exposure.
Recent literature, as discussed in Annex XV, is showing that the association between Cd and protein excretion probably represents normal variability in renal physiology resulting in a temporarily increased or decreased Cd excretion, independent of kidney cadmium concentration (Kidney Cd) (Chaumont et al., 2012, Akerstrom et al., 2013a). The excretion of Cd and proteins is assumed to change in the same direction due to temporary changes in the renal activity, since Cd bound to metallothionein and LMW proteins share the same tubular binding site (Christensen et al., 2009), thus resulting in an association between U-Cd and urinary proteins excretion.
Overall, Akerstrom concludes that “these associations are unlikely to be caused by Cd toxicity but rather reflect temporary changes in urinary flow or other sources of normal physiological variability that affect the excretion of U-Cd and urinary proteins in the same direction, resulting in an overestimation of the risk of renal toxicity from low-level Cd exposure” (Akerstrom et al. 2013a). These recent findings suggest that at low environmental exposures, U-Cd would be more a reflection of the functional integrity of the nephron than of the Cd exposure or of the Cd body burden (Chaumont 2012).
These reverse causality mechanisms might have important implications in the risk assessment of Cd for the general population, which currently largely relies on the use of U-Cd as exposure indicator (Chaumont et al 2012).
See also comment 20 for more details.
In conclusion, the scientific debate on the causal effect of low Cd exposures (measured as Cd-U) on kidney function is ongoing. Taking this debate into account, it is strongly recommended to consider the anticipated effects on kidney at low Cd exposure with caution. It is emphasized that at higher exposures, the causal relationship is not questioned (Chaumont et al 2011). The use of biological indicators in e.g. worker environment is thus justified.
Referring to the recent study of (Åkerström et al, (2013b) showing a strong association between kidney Cd and urinary Cd (healthy kidney donors), we would like to emphasize this study should be interpreted very cautiously.
In summary, in the study of Akerström et al (2013b), the associations shown between concentrations of Cd in urine (or in blood) and the concentration of Cd in kidney are based on the whole population with no distinction between never and ever smokers. The association in ever-smokers is certainly confounded by the influence of recent exposure as the authors have not considered separately current and former smokers. The study would have been much more conclusive by showing that U-Cd correlates with K-Cd when considering only former smokers.  The authors have not excluded the possibility that the association in smokers is mainly driven by the current exposure to tobacco smoke.
The only place where a correlation appears between U-Cd and K-Cd in never-smokers is in Table 3, model 2. This correlation is based on only 31 subjects and is shown with U-Cd expressed per 24 h (output and not concentration) and with K-Cd expressed in total amount of Cd. As these important results are not illustrated by a Figure, it is difficult to judge of the robustness of this association based on few data and perhaps some outliers. These units are not those classically adopted in most studies. What determines the risk is the concentration of Cd in kidney cortex and not the total amount of the metal in the kidney (estimated using the body surface).
The authors have not reported the correlations calculated with U-Cd in µg/g creatinine and with K-Cd in ppm or µg/g kidney weight, which are the units commonly used in biomonitoring for deriving thresholds of Cd toxicity. By using these more classical units, the authors would have eliminated the influence of body size/surface which thus determines the uptake and the kidney weight.

Furthermore, it is interesting to note that U-Alb emerges as a determinant of U-Cd in this study of Akerstrom et al, confirming the physiological link between U-Cd and protein excretion reported now by several authors. This is an important point as urinary protein excretion and in particular albuminuria has recently been found to be a significant predictor of bone disease (Barzilay et al. 2013). Further studies should check whether the associations between U-Cd and bone persists after adjustment for albumin excretion.

And in conclusion, if one takes the study by Akerstrom et al. 2013b as an evidence that U-Cd reflects reliably the body burden of Cd and in particular the K-Cd, then one has to take also into consideration that in another study by the same group (Wallin et al. 2013) based that time of the concentration of Cd in kidney cortex, there was no significant association between K-Cd and bone mineral density after adjustment for confounders. In other terms if one assumes that U-Cd reflects the K-Cd, according to Wallin et al. (2013) U-Cd would reflect an indicator that does not correlate with the BMD.

Comment 9
Section 4.2.2. Bone toxicity, para 3, line 9
Annex XV suggests “that even a urinary concentration around 0.5 µg/g creatinine is associated with increased risk of osteoporosis and fractures”.
It is emphasized (see also comments 8, 20) that the significance of Cd-U as an exposure marker in situations of very low exposure to Cd, has recently been questioned (Chaumont 2012, Akerstrom 2013a). Consequently, this association between urinary Cd and bone effects must be questioned too.
Therefore, considering these recent elements of scientific knowledge, the suggested threshold for bone effects of Cd ‘at a level around 0.5 µg/g creat for the general population’ exposed by the oral route, is considered highly questionable.
There is evidence suggesting that low-level urinary Cd in the general population is more a reflection of the recent intake and of the physiological variations in the urinary excretion of creatinine. This is relevant for all studies using urinary Cd as cumulative exposure indicator.
Therefore, considering these new elements, a cautious interpretation of Cd-U data is needed because it is noted that the link between proteinuria and albuminuria at low Cd-U is physiological rather than causal (Cd-MT and LMW proteins share the same binding sites in the tubuli) (Akerstrom et al 2013a).  Moreover, since proteinuria and albuminuria are well known predictors of bone diseases (Barzilay et al., 2013), a causal relationship between CdU (at low levels) and bone effects is questionable.

Comment 10
Section 6.3.2 Equivalent level of concern assessment, 4rd paragraph, 4rd line : ‘deposition from air…’.
Section 6.3.2 is largely similar to section “summary of how the substance meets the criteria set out in article 57 of  the REACH regulation”. The comments 1 to 4 formulated above on this section, are also relevant here. Notably the sentence in paragraph 4, 4rd line “Deposition from air is an important source to the input of cadmium to soil and must therefore be reduced. In order to achieve this all uses of cadmium and cadmium compounds should wherever possible, be substituted” is misleading, since (a) it ignores the main single source of Cd to general population exposure, i.e. the use of P-fertilizer on agricultural land (see also comment 1), and (b) the fact that cadmium (REACH) uses do not contribute to the cadmium deposition from air on crops and soil (see comment 5).
We note that the percentages provided in comment 1 are averages for the EU, and that differences between countries in Cd-sources to soil can occur. Yet, the averages are quite consistent throughout EU member states (OJ 2008/C 149/03), see for more detail comment 1.

Comment 11
Section 6.3.2, 4th paragraph
Again, this section 6.3.2 is largely similar to section “summary of how the substance meets the criteria set out in article 57 of the REACH Regulation”. Comment 1 formulated above on this section, is also relevant here.

Comment 12
Section 6.3.2, 5th paragraph
Again, this section 6.2.2 is largely similar to section “summary of how the substance meets the criteria set out in article 57 of the REACH Regulation”. Comment 2 formulated above on this section, is also relevant here.

Comment 13
Section 6.3.2 , heading “uncertainties on safe exposure” 1st paragraph.
Again, this section 6.2.2 is largely similar to section “summary of how the substance meets the criteria set out in article 57 of the REACH Regulation”. Comment 3 formulated above on this section, is also relevant here, see also comment 8 &9 for more details.

Comment 14
Section 6.3.2, heading “societal concern and impairment of quality of life”.
See comment 4 made above	Thank you for your comments and the information provided.
Comments regarding use, exposure, alternatives and risks may, where relevant, be considered at later stages of the risk management process.

The justification for SVHC identification is based on intrinsic properties of the substance, not on use, exposure and risk. 

For responses to specific comments, please see embedded file under general comments.	
		Please see attachment embedded in table 1 of Part I  
4911_20 Oct _CdNO3 Annex XV_Master Comments Document_2017_Oct Final .pdf		
4916
2017/10/20	CHEM Trust,
National NGO,
United Kingdom	CHEM Trust supports inclusion of the Cadmium nitrate in the REACH candidate list due to its classification as carcinogen and mutagen and based on the described justification under REACH 57 f. It is important to also address the other properties of concern (i.e. damage to kidneys and bones) in addition to its C and M effects. Therefore we support the inclusion in the candidate list on the basis of 57(f) as well as 57(a) and (b).	Thank you for the support.	
4925
2017/10/20	Belgium,
Member State	Belgium supports the proposal to identify cadmium nitrate as SVHC as the proposal is based on
- article 57(a) of the REACH Regulation due to the classification as carcinogen cat. 1B.
- article 57(b) of the REACH Regulation due to the classification as mutagen cat. 1B.
The substance is also classified as STOT RE 1. Following items substantiate that the substance fulfills the article 57(f) criteria :
- Serious organ dysfunction (for kidney and bone)
- The health effects  can be irreversible
- The delay of the effects is very long
- The bioaccumulation
- There is uncertainty about identifying safe exposure levels
- Huge cost for the society
- The exposure is a societal concern
Therefore, Belgium also supports the identification of Cadmium nitrate as SVHC according to article 57(f) of the REACH Regulation.	Thank you for the support.	

PART II: Comments and responses to comments on uses, exposures, alternatives and risks

Specific comments on use, exposure, alternatives and risks
Number / Date	Submitted by (name, submitter type, country)	Comment	Responses	
4881
2017/10/20	Netherlands,
Member State	Figure 1 in part II in the cadmium SVHC-dossiers indicate that the cadmium compounds are used in consumer articles.	Thank you for your comment. The figure is meant to illustrate the complexity and interrelations of the uses of the group cadmium compounds.	
4911
2017/10/20	International Cadmium Association,
Industry or trade association,
Belgium	PART II Comments
Comment 15
Section 9, heading “Information on uses of the substance”.
The figure 1 provided in the Annex XV is difficult to read and contains mistakes. The only use of Cadmium nitrate is industrial being intermediate use for manufacturing of other inorganic cadmium compounds (see registration dossier Cd(NO3)2 of the lead registrant dossier).

Comment 16
Section 9. “Table 8 - Uses by professional workers”
Indeed, we confirm there are no professional uses of cadmium nitrate

Comment 17
Section 9. “Table 8 - Consumer uses”
Indeed, we confirm there are no consumer uses of cadmium nitrate

Comment 18
Section 11.4.2 Work environment –SCOEL assessment
In addition to the information provided in Annex XV, ICdA wishes to provide the following additional information.
Risk management measures have been developed by industry in two stages.
Stage ONE: adopting and disseminating the Swedish legislation throughout the EU
As the RAR covering Cd/CdO (ECB, 2007) was in the process of getting near to completion, it became apparent that a conclusion would be reached indicating that there was a need for limiting the risk to workers. Industry therefore decided to build an Industry Guidance for its members explaining how to reduce and control this risk.
Industry (ICdA) built its Guidance on the basis of the Swedish legislation developed by ARBETSMILJÖVERKETS FÖRFATTNINGSSAMLING (the Swedish Work Environment Agency), amended and published in MEDICINSKA KONTROLLER I ARBETSLIVET (Medical Surveillance in Occupational Setting) publication AFR 2005:6.
Implementation of this legislation had been on-going (under version 2005, following previous versions) in a large industrial Ni-Cd battery manufacturing plant since its inception, and has proven excellent at keeping exposure of workers extremely low.
This Industry Guidance (available upon request) was published in 2006, dissemination followed, and implementation started in 2007 (ICdA 2006). A revised version of the guidance was disseminated in 2013 (ICdA 2013). ICdA has a dedicated Health and Safety Committee, organizes regular conferences for sharing best practice and manages the consolidation of EU wide industrial data (see below) meaning protection, control and monitoring is well managed and adequate.
Industry sectors who have committed to implementing this program are Zn producers, Cd refiners, specialty cadmium compound manufacturers, pigment manufacturers, Ni-Cd battery manufacturers, thin-film PV panel manufacturers, Ni-Cd battery recyclers.
This industry Guidance is built along three pillars;
 keeping the workplace clean,
 implementing collective and individual hygiene policies,
 ensuring individual exposure is properly controlled by means a medical surveillance program which takes advantage of:
o exposure bio-markers: [Cd-U] for cumulated exposure and [Cd-B] for recent exposure,
o as well as effect biomarkers: measurement of the urinary excretion of specific proteins.
CdB and CdU based action levels, taken over from this Swedish regulation, determine what added surveillance must be implemented should an employee exceed these action levels. Removal from exposure is decided should a certain threshold be exceeded.
Stage TWO: selecting risk based OEL (set by SCOEL) as the DNEL for workers
As mandated after the conclusion of the Cd/CdO RAR (ECB 2007), a COM Risk Reduction Strategy was agreed, and the setting of an OEL (and possibly a BLV) was decided. SCOEL was therefore tasked with developing a health based proposal.
SCOEL published its (health based) OEL recommendation of [Cd-air] = 4 µg/m3 (respirable fraction) in February 2010. The recommendation of SCOEL was introduced by the following comments:
Industry therefore decided to take this OEL forward as its worker DNEL in the cadmium registration dossier.
Since that date this is the workplace air quality standard that industry is legally bound to comply with.
Results of Industry Guidance implementation; current exposure of workers in industry
Two sets of Cd-U distributions (the biomarker which integrates all routes of exposure) are tracked.
First set of data (for graphs see master-file (uploaded under IV Attachment):
This data tracks the distribution of exposure of workers from 15 industrial sites whose occupational doctors have started reporting anonymous data since the inception of the program in 2008. The size of this exposed workforce is 2164  workers (in 2016).
This data shows that 1.7% of workers (37 over 2164)  have a [Cd-U] greater than the maximum value allowed under the Swedish regulation (5µgCd/g creatinine).
As strongly recommended by the Swedish regulation, most of these workers are removed from exposure. Only in limited cases will the occupational doctor allow such employees to continue work in exposed positions.
This data also shows that 8.9% of workers (192 over 2164) have a [Cd-U] greater than the BLV proposed by SCOEL in February 2010.
Both numbers are being reduced at a rapid pace.
Second set of data (for graphs see master-file (uploaded under IV Attachment):
This data tracks the distribution of exposure of all workers from all industrial sites whose occupational doctor have started reporting anonymous data, either in 2008 or at a later date. 28 sites have reported for 2016. The size of the corresponding bio-monitored workforce is 3157 workers. It is estimated that within the whole industry, the number of workers that are bio-monitored to cadmium is ca. 3,700 workers of which 3,000 are currently exposed.
This data also shows a strong decrease between 2008 and 2016 of both categories of workers, respectively from 7.7% down to 1.4%, and from 20.3% down to 8.2%.
It can be concluded from this data that as of 2016, 8.2% of the workforce under to cadmium biomonitoring in a deliberate use of this substance have a biomarker in exceedance of the SCOEL health-based threshold of 2 µg Cd/g creat. In this respect, it is noted that Cd-U is a marker for life time accumulated exposure; in other words the higher Cd-U levels observed today are a reflection of higher exposure in the past.

Comment 19
Section 11.4.3, 3rd  paragraph, line 7-9.
It is stated that “a critical review of the database on biomarkers of Cd-exposure provides no evidence for a decrease in Cd exposure over time during the last 2-3 decades in Sweden”.
The reader of this Annex XV document is referred to KemI Rapport Nr1/11 (2011). Based on this report (KemI 2011) the above statement is challenged, not only for Sweden, but also for the EU, as there is clear indication for decreasing exposure, as follows from the information below:
For Sweden, there are 3 studies available on kidney-Cd content of general population. Most relevant for comparing the general exposure are the data on the “ever non-smokers”, since the smokers/ever smokers data are dominated by smoking behaviour. The “never smoker” data show that between the 1970s and 1990s, there was a rather significant decrease in Cd-content of forensic autopsy kidney samples (compare Elinder et al 1976) with Friis et al 1998). Kidney Cd values were subsequently evaluated by Barregard et al 2010), related to the period 2003-2006. These samples had Cd content that was not different from the Friis data, and, while still lower, the differences with Elinder et al (1976) were smaller in the comparable age groups. When considering these kidney Cd data, it needs to be taken into account that the number of samples was small (order of magnitude ~=10) in all studies. Moreover, the time lapse between the period considered by Friis et al 1998 (period 1995-1996) and Barregard et al 2010 (period 2003-2006) was probably too small to allow indication of any further trend.
 No dietary intake data are presented in this section at all, so it is impossible to check this part of the statement.
 The interpretation of the Swedish Cd-U data presented in figure 2 of Kemi 2011 is odd: of the 12 populations, where a comparison was made in Cd-exposure (measured via Cd-U) between 2002-2004 and 2008-2009 (in the areas of Vastra Gotaland, Stockholm, Vaster och Naarbotten), a decrease was observed in 10 out of 12 cases; while in 2 cases there was an increase. The decreases are sometimes quite large (reductions can amount to -40%), but are put in doubt because of “analytical differences that are still under investigation”. We consider this a weak argument to refuse the data. Moreover, we consider that nowadays differences in analytical performance between labs leading to such differences would be unacceptable.
In conclusion, and in contrast to what is concluded in this section of Annex XV, the data show that the exposure of the general population in Sweden to Cd has decreased over the last 2-3 decades.
The question of time trends should however also be considered in a broader EU context. In this respect, the review of Schultz et al (2007) is particularly relevant.
Schulz et al (2007) reviewed data on urinary Cd-levels in the general population of Germany, obtained by the German Environmental Survey (GerES). These are nationwide population studies that have been repeatedly carried out in Germany since the mid-1980s. The survey monitored a.o. urinary Cd levels in adults, over the periods 1985-1986 (W-Germany only), 1990-1992, and 1998 (more recent studies focus on children only). The studies provide the absolute levels observed in the general population and allow to check on possible time trends over the period 1990-1992 to 1998. The data are considered highly representative for the EU population, given the high number of monitored persons, the wide area over which they were spread, and the care taken in analytics and the selection of representative individuals.
Comparable data for non-smokers are summarized in table 19.1. The data show a clear decrease in Cd-U over the observed time period (6-8 years). P50 values decrease with 19% and geomean values with 14% over this relatively short period. P95 values show the same time trend (-18%), and all P95 values are below 1µgCd/l. In smokers, a similar decrease in time is observed; all parameters are 50-70% higher than for non-smokers; the P95 values are >1µg Cd/l (Schulz et al 2007).
Table 19.1: Cd-U levels (µg Cd/l) in the non-smoking adult population in Germany (after Schulz et al 2007)
The Cd-U levels observed in children are, as expected, lower than in adults (table 19.2). Also for the children, a significant decreasing time trend in Cd-U levels is observed over the period 1990-1992 to 2003-2006.  The relative decrease is 18-20% over this 11-16 years’ time period. The Cd-U levels observed in the German children are very similar to the Cd-U levels recently observed for children in 17 EU countries (see comment 25 below).
Table 19.2: Cd-U levels (µg Cd/l) in children in Germany (after Schulz et al 2006)
In conclusion, the studies presented above show that average Cd-U in adults in Europe is at the level of ~= 0.22µg Cd/l. The data also show that P95 levels of the non-smoking adults are < 1 µg Cd/l.  Moreover, time series data show that the internal exposure to Cd of the general population is decreasing, as demonstrated by significant reduction of Cd-U levels. This observation is consistent with the observed decrease in Cd in major foodstuffs and in the diet that has been commented earlier by ICdA (ICdA 2014). So, the Cd-U data mentioned above confirm this decreasing trend of Cd exposure to the general population in Europe.
Dietary Cd-intake data are also an indication of the exposure of the general population. In contrast to what is stated in the Annex XV document, there is evidence showing that the dietary intake of Cd has decreased over the last decades.
This decrease in Cd exposure of the general population can be explained by the parallel decrease of Cd-emissions to atmosphere, observed over the same period. Over the period 1970-1995, the atmospheric deposition of Cd to mosses in Sweden decreased by 75%, due to the decreasing emissions from industry and fossil fuel combustion in Northern and Western Europe (Rühling and Tyler 2001). These data demonstrate the direct relationship between atmospheric Cd emissions and deposition of Cd from the atmosphere on exposed edible plant parts. Cd emissions to atmosphere have decreased significantly in the EU over the last decades as follows clearly from the yearly data between 1990 and 2010 from EMEP (2012), see figure 5.1.
Figure 5.1.: Cd-emissions to the atmosphere (T/y) by sector in the EU-15 during the period 1990-2015 (EMEP 2017).
Referring to the effect observed on Scandinavian mosses, the general decrease of atmospheric Cd-emissions in the EU (>60% reduction) over the last 2 decades is anticipated to have resulted in a decrease of Cd-deposition on exposed edible plant parts, and, as a result, in a general decrease of Cd-content of food in the EU, and consequently, a decrease in Cd-intake through food in the EU.
This progressively lower Cd-intake is confirmed by crop data over time from Sweden and Germany: the Cd content of main cereal crops show consistently a decrease of 40-50% of the Cd content since the 1990s (BfR 2009, Kirchman et al 2009). Cereals are a general basis for food products, and a main source (33% of total) of dietary Cd intake by the general population (BfR 2009). The continuing decrease of the Cd content measured in 2 base cereals (wheat and rye) with about -40% over the period 1975-2004 is clear (figure 19.1).  The observed decrease in these cereals is anticipated to have also resulted in a general decrease of the dietary Cd-intake of the European population.
This observation is also the result of the decreasing input of P-fertilizer (see below).
Given the central geographical position of Germany in the EU, notably the German data put the time trend of Cd-exposure to the general population in a broader EU-perspective.
Figure 19.1: Cd-content of cereal crops in Germany, measured during the period 1975-2005 (after Bfr 2009).
Regarding the time trend of Cd-exposure in the future, it is expected that the phenomena leading to a decrease, as described above, will continue, due to a further progressive reduction of Cd-emission from point sources.
Moreover, with respect to future exposures, the annex XV document ignores an important future modelling that was recently made by the author of the EU risk assessment on Cd and CdO. After updating the information and scenarios on Cd-inputs and outputs in EU agricultural soils with recent information, it was concluded that the current net balance of Cd in EU soils is negative, mainly due to i) decrease of P-fertilizer use, ii) decrease of atmospheric deposition, and iii) refinement of the leaching component (Six & Smolders, 2014).
Following the revision, the authors concluded that under current practice, the average Cd concentration in EU-27 + Norway soils will decrease with 15% over the next 100 years.  Key in this conclusion are the well-documented data on the pH of EU soils, studied in a systematical way with a same representative method over the whole EU area (NGU 2012).
Taking into account the prediction of -15% decrease of Cd content of agricultural soils, discussed above, the expectation is that the Cd-content of main crops and, consequently, the human Cd intake through food, will further decrease in the future.
In conclusion, the statement in annex XV that “there is no evidence for a decrease in Cd exposure over time during the last 2-3 decades in Sweden” is in conflict with the consistent evidence indicating a decrease of Cd-exposure to the general population in the EU and also in Sweden. A major factor for this is most probably the general decrease of  atmospheric Cd-emissions observed all over the EU, having resulted most probably in a decrease of Cd content of food and thus of intake through the diet. The main cause for this decrease in atmospheric emissions is the decrease of industrial Cd-emissions to the EU atmosphere. Another important factor is the decrease in Cd-input to agricultural soils via P-fertiliser. Both Phenomena are expected to continue in the future. In other words, a decrease of environmental exposure to Cd through the diet (the objective of the current Annex XV exercise) is ongoing in the EU, and is expected to continue in the future.

Comment 20
Section 11.4.3 , para 5
Annex XV states that “There is the debate concerning the causality and the health significance of the associations between urine-based biomarkers of cadmium exposure and kidney effects that occur at very low cadmium concentration. Thus, it is difficult to ascertain the exact lowest effects dose for a clear adverse effect. However, several recent mechanistic studies support effects at low exposure.”
It is emphasized that there is indeed recent debate on the significance of Cd-U as indicator of exposure at very-low Cd-exposure levels: (Chaumont 2012, Akerstrom 2013a) concluded that “There is evidence of non-causal associations between low-level urinary Cd and urinary proteins.  The co-variability observed between Cd-U and urine based biomarkers would have a strong physiological basis. This evidence is suggesting that low-level urinary Cd (e.g. for Cd-U at or below 1 µg Cd/g creatinine) in the general population would be more a reflection of the recent intake and of the physiological variations in the urinary excretion of creatinine and of the renal function (diuresis, renal handling of proteins and glomerular filtration rates). This is relevant for all studies using U-Cd as cumulative exposure indicator.
In conclusion, the threshold for kidney effects of Cd < 1 µg/g creatinine for the general population exposed by the oral route should be questioned because of the non-causal associations between low-level U-Cd and urinary proteins mentioned in recent reports.
Consequently, the major hypothesis of the Annex XV document that there may be risk of impaired kidney function already at urinary Cd-levels below 1 µg/g creatinine has also to be questioned.

Comment 21
Section 11.4.3, para 7, line 4-5
The threshold for bone effects of cadmium concentration in urine around 0.5 µg/g creatinine for the general population exposed by the oral route should be questioned because of the non-causal associations between low-level U-Cd and low Cd-exposure mentioned in recent reports (see also comment 8-9)
Consequently, the major hypothesis of the Annex XV document suggesting that already a cadmium concentration in urine of around 0.5µg/g creatinine is associated with increased risk of osteoporosis and fractures and the estimated societal cost related to that (see comment 4) has also to be questioned.

Comment 22
Section 11.4.3 (cont.), para 8,  line 4-6
Annex XV suggests that results from experimental and epidemiological studies are raising concern that cadmium might have oestrogen-like effect and possibly increase the risk of hormone-related cancers.
It is emphasized that although there are indications that this is the case, this needs to be confirmed by other studies, for several reasons:
-most positive in vivo studies were conducted with acute Cadmium exposures. Kortenkamp (2011) emphasized in his review that a key issue that needs to be resolved in the context of human risk assessment is whether the estrogenic effects of Cd occur at dose levels that are lower than those known to be associated with kidney dysfunction or pulmonary carcinogenesis.
-most studies apply non-physiological routes of Cd-administration e.g. peritoneal injection. When relevant physiological routes of exposure (e.g. oral) were used, no positive effects were observed (Höfer et al 2009)
-CdCl2 is used for most studies; however, no effects were observed after oral administration of dietary Cd
-It is noted that in the general environment, humans are simultaneously exposed to metals (cadmium and others), but also to organic compounds that might also be endocrine disruptors. There is a need to study the possible additive, synergistic, or antagonistic effects on the endocrine system following exposure to such substances.
-Van Maele-Fabry et al (2016) systematically reviewed available studies on the association between dietary exposure to Cd and breast cancer focusing on postmenopausal women. Postmenopausal women represent the most appropriate population to investigate the possible impact of exogenous factors with potential estrogenic activity on breast cancer as, after menopause, their estrogenic influence is predominant. A meta-analysis combining the risk estimators was performed and potential sources of between studies heterogeneity were traced. The study did not provide support for the hypothesis that dietary exposure to Cd increases the risk of breast cancer in postmenopausal women.

Comment  23
Section 11.4.3 (cont.), para 10, line 3-4
Annex XV states: « Causal relationships are supported by mechanistic experimental studies”.
No references are given. In comment 8, references are given which strongly suggest non-causal relationships.

Comment 24
Section 11.4.3 (cont.) para 10, line 4-6
Annex XV emphasises on bone effects of cadmium and their relationship with Cd-U as a marker for cadmium exposure.
As indicated, the significance of Cd-U as a biomarker of exposure in situations of very low Cd exposure (like in general population) is currently under scientific debate. Therefore, the relationship between bone effects and Cd-U levels in the general population is questioned.

Comment 25
Section 11.4.4.  Risk via food intake-Abstract (EFSA 2009, 2012)
The Annex XV document presents the abstract of the EFSA study on dietary Cd intake in the European population (EFSA 2012). Calculated lifetime cadmium dietary exposure was estimated at a middle bound overall weekly average intake of 2.04µg Cd/kg BW, and a potential 95 percentile value of 3.66µg Cd/kg BW.
The following comments are made on the EFSA study:
 The dietary intake was calculated from food Cd-content data and dietary information. It has been observed that such approach may overestimate the Cd-intake, since considerable loss of Cd can occur during food preparation (Fouassin & Fondu 1981).
 The authors of the EFSA-report themselves note that the 95 percentile estimate is “speculative and potentially unrealistic” because it is based on the unlikely assumption that the same individuals retained the same high exposure throughout their whole life”. The 95 percentile should thus be considered with caution, since it appears that it is clearly an overestimation.
 The EFSA-report notes also that “many of the reported results for meat and edible offal category have been sampled under directive 96/23 and might include a high proportion of samples targeting potential problem areas and thus might not reflect an average situation” (EFSA 2012, page 8). This suggests that the average may be biased towards higher levels.
When comparing the EFSA average intake value with recent (post 2000) Cd-intakes for EU countries (including Sweden) reported from different literature sources, the values are indeed generally a factor 1.5-2 lower than the EFSA calculations (table 33.1). The points raised above may explain why. Even for a country like Belgium, which has a historical contamination of Cd, the 95 percentile value is only just at the level of the EFSA-average. These country data suggest that the EFSA average is overestimating current dietary Cd-intake.

Table 25.1. Recent (post year 2000) values reported for weekly dietary intake in EU member states.

It is noted that the EFSA average Cd intake was an update from an earlier survey reported in 2009 (EFSA 2009). At that time, the average middle bound mean dietary intake of adults was calculated to be 2.27 µg/kgBW.w; in the update (with somewhat more recent and more complete data), a middle bound mean value of 1.77µg/kgBW was calculated for the same age group. This is 22% lower than the earlier estimate (EFSA 2012).
The weekly intake data mentioned above are general figures, which are related to the average exposure of general populations. Such data make sense for a cumulative toxicant such as cadmium, where critical exposure levels relate to chronic Cd accumulation at the level of the kidney cortex and therefore relate well to chronic average exposures. For that reason also, worst-case estimates may not be realistic, since such situations are unlikely to proceed for longer time. Yet, situations of consistent enhanced exposure can occur in particular related to specific dietary habits involving systematic consumption of high-Cd food.
With respect to the latter, the EU RAR discussed notably the more than average consumption of seafood (molluscs, crustaceans,...) that is observed in some local communities, e.g. of oyster cultivators. However, in spite of the fact that the Cd content of such foodstuff, and the corresponding estimated dietary Cd-intake of individuals can be quite high, it was found out that this does not translate in increased internal exposure (McKenzie et al 1982), most probably due to limited bioavailability of the Cd in these food sources. As a result, elevated dietary Cd intake due to preference of these food products may not necessarily result in proportional internal exposure.
In conclusion, recent (post-2000) weekly dietary Cd-intakes in the EU are rather at the lower end of the range 1 -2 µg/kg BW. and as such below the WHO PTWI standard of 5.8 µg Cd/kg BW, and below the more stricter EFSA standard of 2.5 µg Cd/kgBW. Calculations of dietary intake based on life-time continued worst case is considered unrealistic.
With respect to exposure of the general population , the recent EU DEMOCOPHES study is also of  relevancy (DEMOCOPHES 2014). In this EU wide study, human biomonitoring data on e.g. Cd-U were compiled using a consistent methodology over 17 EU member states (Belgium, Cyprus, Czech Republic, Denmark, Germany, Hungary, Ireland, Luxembourg, Poland, Portugal, Romania, Slovakia, Slovenia, Spain, Sweden, Switzerland, and the United Kingdom). The study used a common EU protocol, and the laboratories analyzing the samples were selected through a strict quality assurance process, comprising Interlaboratory Comparison Investigations (ICI) and External Quality Assessment Schemes (EQUAS). Important to mention in a Cd-exposure context is that the adult populations in the DEMOCOPHES study  include smokers and non-smokers , and don’t make distinction between both groups in  the first reports that are available on the study.
The results (European average) for children aged 6-11 years and their mothers aged up to 45 years are given in table below.

Table 25.2: Cd-U levels (µg Cd/l) in children and adults in 17 EU countries (after DEMOCOPHES 2014)
The mean EU result for the children corresponds very well with the P50 value observed in the German GerES study (see comment 19). The P90 for the 17 EU countries is similar to the P95 in Germany.
The adult mothers have a mean value that is also very similar to the P50 observed on the “total” = smokers + non-smokers) of the German study in 1998 (Schulz et al 2007).  It is noted that the mothers in the EU study were as group younger than the German group. The P90 and P95 of both studies are not really comparable; the higher P95 observed in 1998 in Germany could be explained by the 12-14 years difference in time of sampling (considering the decrease that is observed in Cd exposure all over the EU), and the older age of the German population.
Important is that the DEMOCOPHES report explicitly mentions that “not one mother in this study had a cadmium level in her urine which indicates an adverse health effect on the kidneys”.
The Cd-U data for each country in the study, as normalized towards the average at 100%, are presented in figure below (taken from DEMOCOPHES 2014) (for figures see master-file (uploaded under IV Attachment)
The variability between countries is rather limited (+/-25-30%), with as exceptions the lowest exposure (60% of EU-average in Denmark), and the highest exposure (almost 200% of EU-average observed in Poland). The report considers that “the main reason for this might be that farmers are still using fertilizers with high cadmium content” (DEMOCOPHES 2014).
Conclusion
Based on the extensive analysis of Cd in food and diet, EFSA (2009) stated that the margin between Cd exposure through food and the EFSA limit value is small and that limited segments of the population may exceed the value. This EFSA assessment of Cd-intake through food in the EU is challenged, because of lower values currently observed in EU countries. In addition, the limit value set by EFSA (2011) for human daily intake has been evaluated as being overly conservative (see comment 7). A main point in the latter critique was that the accumulation of worst cases (highest intakes combined with highest uptake rates) applied by EFSA for the calculations, is not corresponding to reality. As is demonstrated by the recent Cd-U data observed in the EU, average Cd-U levels are consistently well below the value used as critical for Cd exposure 1µg Cd/l) and even P95 values of non-smokers are below that level.	Thank you for your comments and the information provided.
Comments regarding use, exposure, alternatives and risks may, where relevant, be considered at later stages of the risk management process.

We agree that information on use in the Annex XV report should have been taken from the latest registration and other relevant updated sources, and regret if that has not been the case. 

For further responses to the specific comments, see embedded file above under general comments.
	
		Please see attachment embedded in table 1 of Part I  
4911_20 Oct _CdNO3 Annex XV_Master Comments Document_2017_Oct Final .pdf