Registration Dossier

Administrative data

Endpoint:
sensitisation data (humans)
Type of information:
other: Assessment of medical records and human patch testing results
Adequacy of study:
weight of evidence
Study period:
1960 - Present day.
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Medical data from the site of point manufacture has been reviewed for a period of 50 years, in order to assess sensitisation. In addition, research has determined a human patch test that assessed aryl phosphate exposure for both irritation and sensitisation. The data is considered appropriate for inclusion due to the fact that this is used as part of due diligence occupational exposure monitoring, and is an accurate representation of endpoint effects (lack of) at the point of key exposure. Both studies are presented together here as they are supportive of the occupational works conducted at the site. Full reports are appended below.
Cross-reference
Reason / purpose:
reference to other study

Data source

Referenceopen allclose all

Reference Type:
other company data
Title:
Unnamed
Year:
2011
Reference Type:
study report
Title:
Unnamed

Materials and methods

Type of sensitisation studied:
skin
Study type:
other: survey and case study with volunteers.
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Assessment in humans was conducted as an evaluation of site specific data, spanning some 50 years. Evaluation of occupational skin complaints was undertaken and reviewed.

In addition, a human patch test on aryl phosphates was also conducted by a former owner of the site. The testing followed a standard procedure for human patch testing. This encompassed the following in the assessment of irritation and sensitisation.

1) The "non-occluded" type in which the substance under test is applied to the skin, rubbed in gently and covered by a small dressing to allow a certain amount of evaporation on the surface and air circulation around the test area. The reaction of the skin is noted after forty-eight hours.

2) The "occluded" patch test which consists of exposing the skin to the action of a supposed irritant, the area in question "being covered by polythene which is kept in position by an adhesive dressing so that the air is excluded. The test period is similar to (1).

3) The "sensitisation" test in which it is necessary to apply the irritant again after about a fortnight following a negative reaction to see whether the skin has, in fact, developed antibodies. This can be difficult as patients are not always willing to undergo such, a test or indeed to spare the time to come back for the result to be assessed.
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Not applicable for medical data screening - general exposure to the workforce was evaluated.

For human patch testing, Reofos 95, Reofos 65 and Reofos 50 where evaluated, plus the analogue TXP. Reofos products all contain the substance to be registered at an appropriate concentration.

Method

Type of population:
occupational
Ethical approval:
confirmed and informed consent free of coercion received
Subjects:
Medical Data
Of the 78 staff evaluated, the starting dates were as follows;

• 4 started employment in the 1960’s

• 37 started employment in the 1970’s

• 19 started employment in the 1980’s

• 12 started employment in the 1990’s

• 6 started employment since 2000.

Human Patch Data

The subjects were divided into two series, Series 1 being those with naturally hypersensitive skins who do or have suffered from eczema or other allergic conditions. Series 2 consists of normal subjects and those who have unrelated skin disease.

From Series 1, 28 individuals where tested (sex and age unspecified).
From Series 2, 14 individuals where tested (sex and age unspecified).

Clinical history:
Clinical history of both the workforce and subjects of the skin patch testing is not reported.
Controls:
None
Route of administration:
dermal
Details on study design:
As part of a due diligence exercise, the site occupational doctor at Chemtura Manufacturing UK Ltd has undertaken a review of the records of epidemiological data at the site. The records of some 78 employees, all whom have been or are in production or maintenance of aryl phosphate materials where assessed as historical data. Of the 78 staff evaluated, the starting dates were as follows;

• 4 started employment in the 1960’s

• 37 started employment in the 1970’s

• 19 started employment in the 1980’s

• 12 started employment in the 1990’s

• 6 started employment since 2000.

Hence there is reasonable spread of potential exposure over time available for review as historical data. The ‘total years employment’ of all employees amount to 1968 years and 2 months (including all past and present employees). Making various assumptions, this equates to approximately 90 years potential exposure in the workplace. As such, the criteria specified in Annex XI, Para 1.1.3:

1) the proper selection and characterisation of the exposed and control groups;

2) adequate characterisation of exposure;

3) sufficient length of follow-up for disease occurrence;

Are considered to be more than adequately met for the purposes of data evaluation of human health at this particular site.

Human Patch Data
The subjects were divided into two series, Series 1 being those with naturally hypersensitive skins who do or have suffered from eczema or other allergic conditions. Series 2 consists of normal subjects and those who have unrelated skin disease.

From Series 1, 28 individuals where tested (sex and age unspecified).
From Series 2, 14 individuals where tested (sex and age unspecified).

Results and discussion

Results of examinations:
The following data and information was determined from the site historical medical records:

1) All employees were seen regularly in the medical centre for various reasons as part of due diligence health monitoring at the site.

2) Between 1985 and 1988 all production staff were screened for skin disease (potential exposure to di-tert butyl phenol) every 6 months (complete body scan with a Woods light). Since 2003 (ongoing) all staff screened with Woods light every 6 months (potential exposure to butylated phenol). No cases of occupational vitiligo have been identified. Screening is performed because occupational vitiligo is a “Prescribed Disease” in the UK (where exposure occurs to catechols, hydroquinones or, as at Trafford Park, potential exposure to butyl phenols. A Woods Light is a light source of specific wavelength that shows skin depigmentation very early to the observer. As a ‘by product’ of the screening programme, other skin diseases can be identified and treated.
.
3) Examination of the medical records revealed isolated episodes of constitutional skin disorders such as fungal rashes, transient eczema, impetigo and urticaria. The employee was diagnosed with urticaria (by Dr Fyans) on 20th January 1997; the rash affected his arms and back and had been present for 10 days, and it was advised that it was causing irritation (itching). In this case, there was no history of chemical contact. The employee was treated with Triludan (an oral antihistamine) and was reviewed on 29th January, at which point the rash had improved. The employee was told to re-attend if recurrence occurred. He did not. He was examined for a company placement abroad on 28th August 1997. All was well at that time.

Causes of urticaria are many, and substances including asparin, shellfish, codeine, food colouring agents, ‘E’ number etc. Chronic urticaria has many complex causes which do not apply here. Dermatologists rarely find a cause (sometimes it can be obvious with responses to ingested food) but most cases are idiopathic.

In this case, the skin disorder was self limiting and did not recur. The employee remained in the production area (and still works at the location). There have been no recurrences, suggesting a non occupational causation.

4) Other skin conditions seen include a case that was referred to a dermatologist because of failure to respond to treatment, in 1980. The diagnosis was psoriasis (a constitutional skin disorder). An additional incident related to accidental dermal exposure to phenol causing minor burns treated in the usual way (PEG swabbing/drenching/dressings). One case of skin injury in 2010 was severe and required assessment by the Burns Unit.

As stated above, the results of the dataset subject to the evaluation equates statistically to some 90 years worth of occupational monitoring data. Within this dataset, no identification of employees with a diagnosis of Industrial Dermatitis or Sensitivity was made. If such a condition was suspected by a GP or dermatologist then the likelihood is that the Company would have been contacted for information re exposure. The conclusion is therefore that industrial dermatitis and/or sensitization at the manufacturing site has not been present within the workforce overall. This would indicate that sensitization and/or skin irritation is not associated with the production of aryl phosphates, nor cumulative effects associated with exposure to aryl phosphates in conjunction with other chemical substances is anticipated.

Human Patch Testing
In support of the above, a study of human contact sensitization was also conducted at the site when under the management of Geigy UK Limited. The study was conducted by the consultant dermatologist of the Manchester and Salford Hospital Centre for Skin Diseases, and utilised human patch testing. In this study, a range of Reofos products plus the substance TXP where assessed for irritation and sensitization, under both occluded and non-occluded conditions.

The outcome of this study was negative in all aspects. This further reinforces the fact that the aryl phosphates are not sensitisers by skin contact.

The full report supporting these statements is attached below under "attached background material".

Any other information on results incl. tables

Results of Human Patch testing - Reofos 95, 65, 50 and TXP

Sensitive Skins – Series 1

No. Tested

Positive

False Positive

Negative

Non-occluded

50

-

-

50

Occluded

50

-

-

50

Sensitisation

28

-

-

28

Normal skins – Series 2

No. Tested

Positive

False Positive

Negative

Non-occluded

48

-

-

48

Occluded

48

-

-

48

Sensitisation

14

-

-

14

Applicant's summary and conclusion

Conclusions:
On the basis of the available human data, both historical and study specific, it is concluded that the aryl phosphate substances manufactured by Chemtura do not cause skin sensitization in man. The evidence presented in the historical data on epidemiological effects detail that skin effects are not prevalent within the workforce involved in the production, handling and maintenance of the areas associated with the aryl phosphates. This conclusion is reinforced by the study specific data where irritation and sensitization effects in man where studied via the use of human patch testing. The results of this study where negative, with no effects seen in any of the volunteers assessed.
Executive summary:

On the basis of the available human data, both historical and study specific, it is concluded that the aryl phosphate substances manufactured by Chemtura do not cause skin sensitization in man. The evidence presented in the historical data on epidemiological effects detail that skin effects are not prevalent within the workforce involved in the production, handling and maintenance of the areas associated with the aryl phosphates. This conclusion is reinforced by the study specific data where irritation and sensitization effects in man where studied via the use of human patch testing. The results of this study where negative, with no effects seen in any of the volunteers assessed.

  

Aryl phosphates are therefore not considered to be skin sensitisers in man on the basis of the evidence available.