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Alkanes,-C14-17,-Chloro

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					                                                                              ECBI/35/02



         Working Group on the Classification and Labelling of Dangerous Substances



 Alkanes, C14-17, Chloro (medium-chained chlorinated paraffins, MCCPs)

        C&L proposal based on ESR review: produced by UK HSE (February 2002)

Current Annex 1 position:            Not in Annex 1

UK initial position                  [Carc. Cat 3; R40] : R64 : R66

UK proposal:                         R64 : R66


Background
The human health aspects of MCCPs were discussed in-depth as part of the ESR risk assess-
ment process at Technical Meetings (TM) in September 2001 and March 2002. This discus-
sion will continue at the next TM in September 2002. Further occupational exposure informa-
tion is being evaluated but we are not aware of any ongoing or planned work on the toxicity
of MCCPs or the structurally-related SCCPs. It is possible that further work (eg. an in vitro
dermal absorption study) may be conducted to help clarify the extent of dermal absorption, al-
though this would not affect considerations of human health hazard classification. Owing to
concerns for environmental effects and human health one of the recommendations of the TM
is to refer this substance to the Competent Authorities for consideration of immediate risk re-
duction. Again, this need not affect the consideration of hazard classification.

The hazardous properties of MCCPs are briefly summarised below; further details can be ob-
tained from the ESR review.


Acute toxicity
No deaths occurred amongst rats receiving a single oral gavage dose of up to 15000 mg/kg
MCCP.

There are no dermal or inhalation data specifically in relation to MCCPs. However, a dermal
LD50 of 13000 mg/kg has been cited for SCCPs, and there was no evidence of toxicity in rats
following inhalation exposure to 3300 mg/m3 (SCCP ESR risk assessment report, 2000).
Considering the structural and physicochemical similarities between SCCPs and MCCPs,
these results suggest that MCCPs will also be of low toxicity by these routes. No
classification for acute toxicity is proposed.

Skin irritation
There are no human data. Single exposure studies in rabbits indicated only „slight‟ erythema
and oedema (Kuhnert 1986 c and d, Chater 1978). However, repeated application to the skin
of rats showed more pronounced effects: slight desquamation progressing to cracking and
thickening of the skin (Moses 1980, Chater 1978). These findings justify classification with
R66.
Eye irritation
There are no human data. Instillation of MCCPs to the eyes of rabbits resulted in no reaction,
or slight and transient conjunctivitis. No classification for eye irritation is proposed.

Respiratory tract irritation
There are no human data, and no evidence from animal studies to indicate the potential for
respiratory tract irritation. No classification is proposed.

Skin and respiratory tract sensitisation
There is no human evidence of skin or respiratory tract sensitisation. For skin sensitisation,
the available animal data provided negative results and there are no obvious structural alerts.
No classification is proposed for these endpoints.

Repeated exposure
The only available data relate to a number of oral dosing studies (up to 90 days duration) that
have investigated the repeated dose toxicity of MCCPs (C14-17, 40% or 52% chlorinated paraf-
fins) in rodents. However only two studies emerge as providing helpful dose-response infor-
mation in respect of classification and labelling (IRDC 1984, Poon et al 1995). The others, all
presented in more detail in the ESR RAR, were generally mechanistic studies on the interplay
between liver and thyroid and the relevance of effects on these organs to human health, con-
ducted at relatively high exposure levels.

In rats, the liver, thyroid and kidney are the target organs for repeated dose toxicity of
MCCPs.

For the liver, increases in weight and changes in enzyme activity are seen in rats at exposure
levels of 36 mg.kg-1.day-1 or more (Poon et al 1995), and these are considered part of an adap-
tive response to an increase in metabolic demand. There is also the possibility that perox-
isome proliferation plays a role. We do not consider these findings to justify classification. At
higher exposure levels (around 360 mg.kg-1.day-1), single cell necrosis was observed in rats
(Poon et al 1995), but this is above the cut-off level for classification.

Increased thyroid weight was observed in a 90-day study only at the highest exposure level
tested, 625 mg/kg/day (IRDC 1984). Histopathologically, lesions such as hyperplasia have
been observed down to the lowest exposure levels tested (eg. 0.4 mg/kg/day by Poon et al
1995) with an exposure-related increase in severity. However, the severity only ranged from
“mild” to “moderate” even across an increase in exposure of 3 orders of magnitude. The thy-
roid changes (increased weight and follicular hypertrophy and hyperplasia) are considered to
occur as a result of repeated stimulation of this organ caused by the well-characterised nega-
tive feedback control effect arising from plasma T4 depletion. This in turn is related to an in-
crease in the activity of hepatic UDPG-transferase. Humans, unlike rodents, possess a T4
binding protein that greatly reduces susceptibility to plasma T4 depletion and thyroid stimula-
tion. The thyroid effects observed in rats are therefore considered of insufficient concern for
classification.

No adverse renal effects were seen in males and female rats at 0.4 mg.kg-1.day-1 in a 90-day
study (Poon et al, 1995). Inner medullary tubular dilatation was seen at 4 mg.kg-1.day-1 in the
kidneys of females only. These lesions were slight, with changes increasing only marginally
in severity and incidence at levels higher than this (up to 420 mg.kg-1.day-1 for females). An
exposure-related increase in the incidence and severity of a mixed population of interstitial in-
flammatory cells, tubular regeneration and minimal degenerative changes in the tubular epi-
thelium was seen in treated males and females at 10 mg.kg-1.day-1 or more. At
10 mg.kg-1.day-1 the severity of these changes was graded as „trace‟, and even at the highest
exposure level, 625 mg.kg-1.day-1 was only „mild‟. As the effects observed in the region of the
cut-off level for R48 do not seem to be severe no classification is proposed for repeated-
exposure effects.

Mechanistic studies conducted using short-chain chlorinated paraffins (C10-13, SCCPs) indi-
cate deposition of 2u globulin in proximal convoluted tubules and this may be the primary
mechanism for renal toxicity in male rats.

Mutagenicity
Negative results have been obtained in bacterial mutation asays. There were no in vitro cyto-
genetic or gene mutation assays for MCCPs, although a negative result was obtained in a gene
mutation assay with SCCPs. An in vivo mouse bone marrow chromosomal aberration test and
two bone marrow micronucleus tests were negative using oral doses of up to 5000 mg/kg.
There are no obvious structural alerts. No classification is proposed for this endpoint.

Carcinogenicity
There are no studies on the carcinogenicity of MCCPs. However, given the similarities be-
tween MCCPs and SCCPs in physicochemical properties and in the results obtained in rela-
tion to repeated-dose toxicity, it seems reasonable to presume that the carcinogenic potential
of MCCPs will be similar, at least in qualitative terms, to that of SCCPs.

SCCPs have been found to induce liver and thyroid adenomas and carcinomas, and kidney
tubular cell adenomas in laboratory studies. On mechanistic considerations, in line with pre-
vious discussions by the EC Specialised Experts, the liver and thyroid tumours are considered
not to justify classification. The Specialised Experts felt that the underlying mechanism for
the kidney tumours was unclear and proposed classification of SCCPs as category 3 carcino-
gens. In recent years there have been more mechanistic studies conducted to try to further
clarify the mechanism underlying rodent kidney tumour formation with SCCPs (see the asso-
ciated UK proposal for C&L of SCCPs). Although some uncertainty remains, there is now
more evidence to show that 2u-binding is the primary mechanism for renal toxicity and tu-
mour formation induced by SCCPs in rats. This strongly suggests that the rat kidney effects
are not of concern for human health.

We propose that the carcinogenicity classification of SCCPs should be reconsidered and that
MCCPs should be classified in the same way as SCCPs; our proposal is that MCCPs and
SCCPs should not be classified for carcinogenicity.

Reproductive toxicity – fertility
No human data are available. A limited two-generation rat study (conducted as a range-
finding study for a multi-generation study that was ultimately never performed) in which the
animals received up to 400 mg/kg/day MCCP in the diet revealed no adverse effects on fertil-
ity (IRDC, 1985).

Developmental toxicity
In a conventional study, there were no adverse effects in rats during gestation at maternal
doses of 0, 500, 2000 or 5000 mg/kg/day (IRDC 1984). The only signs of toxicity noted in
pregnant animals were poor grooming and the production of soft faeces amongst rats receiv-
ing 2000 or 5000 mg/kg/day. In a similar study, there were no adverse effects in rabbits re-
ceiving 0, 10, 30 or 100 mg/kg/day (IRDC 1983). There were no signs of maternal toxicity
reported.

In a limited two-generation study (also noted under „Fertility‟) dietary exposure of pregnant
rats to MCCPs (a C14-17 52% chlorinated paraffin) at approximately 400 mg/kg/day produced
internal haemorrhaging and deaths in the pups (IRDC 1985). The deaths occurred only whilst
the young were still suckling, not in utero or immediately post-partum.

A cross-fostering study has been conducted to help elucidate the mechanism underlying the
mortality seen in rat pups during the lactation phase in the IRDC studies (Hart et al 1985).
Five groups were established:

   1) Females receiving control diet nursed their own pups.
   2) Females on a diet containing MCCPs nursed the pups from previously untreated
      animals.
   3) Females receiving control diet nursed the pups from MCCP-treated animals.
   4) MCCP-treated females nursed their own pups.
   5) Females received MCCP to day 10 of pregnancy only, then received control diet and
      subsequently nursed their own pups.

During lactation, blood samples were taken from pups for analysis of clotting Factor VIII,
Factor X, clotting times and platelet counts. A limited number of breast milk samples were
taken for analysis of MCCP; measurable levels were found in animals from Groups 2 and 4
only.

There were no signs of parental toxicity reported. In Groups 2 and 4 there was a marked in-
crease in pup mortality. These deaths were associated with a decrease in the levels of Factor
X in pups. Other groups were not adversely affected. The absence of toxicity in Group 5 is of
note, and could relate to an absence of MCCP in breast milk or MCCP levels being at a level
below a threshold for this effect.

A full explanation is lacking for the internal haemorraging seen in young pups that received
milk from MCCP-feeding mothers. However, this does not seem to have been a consequence
of impaired physical development. It has been suggested that an adverse maternal effect may
have led to breast milk that was deficient in essential nutrients (eg. vitamin K) leading to
reduced clotting Factor X in the pups. Alternatively, there may have been a more direct
toxicity of MCCP carried to the pups in the breast milk.

We propose classification with R64 given the findings in the mechanistic study showing
problems in rat pups associated with mother‟s milk known to contain MCCPs. As ther edoes
not appear to have been an adverse effect on “normal development” after birth, rather a severe
form of toxicity, the criteria for developmental toxicity classification have not been met and
we propose no classification for this endpoint.

References
Chater B (1978). Acute oral toxicity, skin and eye irritation and skin sensitisation. Report
No. CTL/T/1168. ICI Central Toxicology Laboratory, Alderley Park, Cheshire, UK.

Hart D, Wickramaratne G, De S, Banham P, Chart I, Gaskell B (1985). Chlorinated paraffin
(52% chlorination of intermediate chain length n-paraffins): Investigation into the possible
mechanism of haemorrhage in offspring rats. Report Number CTL/P/1293. ICI Central
Toxicology Laboratory, Alderley Park, Cheshire, UK.

IRDC (1983). Chlorinated paraffin: Teratology study in rabbits. IRDC Report No. 438/032.
International Research and Development Corporation, Mattawan, Michigan, USA 49071.

IRDC (1984). Chlorinated paraffin: Teratology study in rats. IRDC Report No. 438/017. In-
ternational Research and Development Corporation, Mattawan, Michigan, USA 49071.

IRDC (1985). Chlorinated paraffin: Reproduction range-finding study in rats. IRDC Report
No. 438/049. International Research and Development Corporation, Mattawan, Michigan,
USA 49071.

Kuhnert R (1986c). Testing of the acute skin irritating effect of Chloroparaffin 40G (with 1%
stabiliser B74) on rabbits. Huls AG Report Number 0569. Huls AG, Marl, Germany.

Kuhnert R (1986d). Testing for acute dermal irritation in rabbits caused by Chloroparaffin
52G (with 1% stabiliser B74). Huls AG Report Number 0572. Huls AG, Marl, Germany.

Moses S (1980). Cloparin 1049 and „Meflex‟ DC029: a comparison of skin irritation poten-
tial. Report CTL/T/1431. ICI Central Toxicology Laboratory, Alderley Park, Cheshire, UK.

Poon R, Lecavalier P, Chan P, Viau C, Hakansson H, Chu I, Valli V (1995). Subchronic
toxicity of a medium-chain chlorinated paraffin in the rat. J. Appl. Toxicol. 15: 455-463.


HSE Industrial Chemicals Unit
Bootle
Merseyside
UK

16 April 2002

				
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