The decision on actual implementation depends on the results of a further consequence analysis.

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Probit function technical support document Date: July 0 Document id: 00-Decalin-INTERIM Status: interim Author: L. Geraets (RIVM) E-mail response to: safeti-nl@rivm.

1 Probit function technical support document Date: July 0 Document id: 00-Decalin-INTERIM Status: interim Author: L. Geraets (RIVM) response to: safeti-nl@rivm.nl substance name CAS number Decalin -- This document describes the derivation of a probit function for application in a quantitative risk analysis (QRA). The probit function has been derived according to the methodology described in RIVM report This document has been checked for completeness by the Netherlands National Institute of Public Health and the Environment (RIVM). The contents of this document, including the probit function, has been approved by the Dutch Expert Panel on Probit Functions on scientific grounds. External parties have had the opportunity to comment on the derivation of the proposed probit function. The status of this document has now been raised to interim, pending a decision on its formal implementation. The decision on actual implementation depends on the results of a further consequence analysis. Detailed information on the procedures for the derivation, evaluation and formalization of probit functions is available at

Technical support document Decalin 0 0 0 0 0. Substance identification CAS-number: -- (cis/trans isomer mixture) IUPAC name: decahydronaphthalene Synonyms: decahydronaphthalate, bicyclo(.

2 Technical support document Decalin Substance identification CAS-number: -- (cis/trans isomer mixture) IUPAC name: decahydronaphthalene Synonyms: decahydronaphthalate, bicyclo(..0)decane Molecular formula: C 0 H Molecular weight:. g/mol Physical state: liquid (at 0 C and 0. kpa) Boiling point: 0 C (at 0. kpa) Vapour pressure: 0. kpa (at 0 C) Saturated vapor conc: 00 ppm = mg/m (at 0 C) Conversion factor: mg/m = 0. ppm (at 0 C and 0. kpa) ppm =. mg/m (at 0 C and 0. kpa) Labelling: No harmonized human H-sentences. Mechanism of action and toxicological effects following acute exposure Acute effects: Decalin is an irritant to the eyes, skin, and mucous membranes. CNS effects such as tremors, spasms, prostration and CNS depression might occur upon inhalation exposure. Long-term effects: No information is available on long-term toxicity following acute exposure.. Human toxicity data No informative reports on human toxicity following acute inhalation exposure were identified in which details about both health effects and the exposure have been documented in sufficient detail. The lowest concentration to have an effect in humans exposed by inhalation was reported to be 00 ppm ( mg/m ), however no details are available on the type or extent of the effects (Sandmeyer ; BUA ).. Animal acute toxicity data During the literature search the following technical support documents and databases were consulted:. No AEGL TSD, ERPG document and EU RAR was available for decalin.. A full literature search covering publications from 00 onwards was performed in HSDB, MEDline/PubMed, Toxcenter, IUCLID, ECHA, RTECS, IRIS and ToxNet with the following search terms: Substance name and synonyms CAS number lethal* mortal* fatal* LC 0, LC probit. Unpublished data were sought through networks of toxicological scientists. NTP 00; HSDB/TOXNET Page of

3 0 Animal lethal toxicity data focused on acute exposure are described in Appendix. A total of studies were identified -with datasets for species- with data on lethality following acute inhalation exposure. None of the datasets were assigned status A, one of the datasets was assigned status B for deriving the human probit function, and four datasets were assessed to be unfit (status C) for human probit function derivation. Sensory irritation No studies were identified in which sensory irritation was studied.. Probit functions from individual studies All available acute lethality data on decalin are displayed in Figure Vernot - rat 0% Concentration (mg/m, log scale) 000 Vernot - rat 0%-0% Vernot - rat %-% Vernot - rat 00% C. Kinkead/MacEwen and Vernot - mouse %-% C. Kinkead/MacEwen and Vernot - mouse 0%-0% other C-studies 0% other C-studies %- % other C-studies %- % Time (min, log scale) 0 Figure All available acute lethality data for decalin The data that were selected for initial analysis of the animal probit function are presented in Table and Figure. It was possible to derive a probit function for decalin based on the only available study with B quality. However, this B study did not enable to produce a concentration-time-lethality relationship. Probit functions have been calculated and reported in Appendix for this B study. The results of the calculations are presented in Table. Page of

4 Table Data selected for initial analysis of the animal probit function of decalin. Study ID Species Probit (C in mg/m, t in min) LC 0 at tested exposure duration (mg/m ) % C.I. Rat 0-min LC 0 0 (0-0) N/A The data of study with rats are presented graphically below n-value % C.I. Vernot - rat 0% Vernot - rat 0%-0% Concentration (mg/m, log scale) 000 Vernot - rat %-% Vernot - rat 00% Time (min, log scale) 0 Figure Data selected for the initial analysis for the derivation of the animal probit function of decalin. Based on criteria outlined in the guideline the data from rat study (Kinkead et al., /MacEwen and Vernot ) were selected for the final dataset for the derivation of the animal probit function and are presented in Table and Figure. The final data eligible for calculating the animal probit function contains one dataset from one study and includes data from one animal species. Table Study ID Data selected for the derivation of the animal probit function of decalin (identical to table ). Species Probit (C in mg/m, t in min) LC 0 at tested exposure duration (mg/m ) % C.I. Rat 0-min LC 0 0 (0-0) N/A n-value % C.I. Page of

5 0000 Vernot - rat 0% Vernot - rat 0%-0% Concentration (mg/m, log scale) 000 Vernot - rat %-% Vernot - rat 00% Time (min, log scale) 0 Figure Final data selected for derivation of the animal probit function of Decalin (identical to figure ).. Derivation of the human probit function To derive the human probit function the results from study (Kinkead et al., /MacEwen and Vernot, ) have been used to derive a point of departure as outlined above. The Point of Departure for the human probit function is a 0-minute animal LC 0 value of 0 mg/m and a default n-value of. The human equivalent LC 0 was calculated by applying the following assessment factors: Table Rationale for the applied assessment factors. Assessment factor for: Factor Rationale Animal to human extrapolation: default Nominal concentration B-study with analytically determined concentrations Page of

6 0 0 Adequacy of database: Only one B-dataset was found. The study was performed using only one exposure duration well outside the exposure duration target range of 0-0 min. This creates a relative large uncertainty because of extrapolation over a large range of exposure duration. The estimated human equivalent 0-minute LC 0 value is 0 / = mg/m. No reliable experimentally determined n-value was available, so the default n-value of was used. Assuming a regression coefficient (b n) of for the slope of the curve, the b-value can be calculated as / n =. The human probit function is then calculated on the human equivalent 0 min LC 0 using the above parameters to solve the following equation to obtain the a-value (the intercept): = a + ln( 0) resulting in the a-value of -.. Pr = -. + ln(c t) with C in mg/m and t in min. The derived human probit function has a scientifically acceptable basis. The probit function is based on one study in the rat with B quality, including animals, an exposure duration of 0 min and response rates between 0 and 00%. The calculated human 0-min LC 0. (Pr =.) calculated with this probit equation is mg/m and the calculated human 0-min LC (Pr =.) is mg/m. Table LC-values calculated with the derived probit function compared with existing acute inhalation exposure guidelines. Estimated level 0 min (mg/m ) 0 min (mg/m ) 0.% lethality, this probit 0 % lethality, this probit AEGL- - - ERPG- - - LBW - - A comparison with equivalent (inter)national guideline levels cannot be made. Page of

7 0 Appendix Study ID: Animal experimental research Author, year: MacEwen and Vernot (); Kinkead et al. () Substance: Decalin Species, strain, sex: Rat, Sprague-Dawley, male Number/sex/conc. group: Age and weight: no information Observation period: days Evaluation of study quality* Criteria Comment Study carried out according to GLP GLP did not exist at the time Study carried out according to OECD OECD guideline 0 did not exist at the 0 guideline(s) time Stability of test compound in test No information atmosphere Use of vehicle (other than air) N/A Whole body / nose-only (incl. Whole body head/nose-only) exposure Type of restrainer N/A Pressure distribution No information Homogeneity of test atmosphere in No information breathing zone of animals Number of air changes per hour Number of air changes not specified; liter inhalation chamber Equilibration time (t) Insufficient information to calculate t Start of exposure relative to No information equilibration Actual concentration measurement Chamber concentrations were analysed using a hydrocarbon analyser Particle size distribution measurement N/A in breathing zone of the animals in case of aerosol exposure Assessment of Reliability B Study seems to meet the standards, though limited to one exposure duration. * Limited information concerning the study characteristics of this acute inhalation study is available. This acute inhalation study was used for concentration-ranging purposes for a 0-day repeated inhalation study and was presented together with the results of this 0-day repeated inhalation study in a different report. No specific details on study characteristics were presented in this report (MacEwen and Vernot ). Results Species Concentration (mg/m ) Exposure duration (min) Lethality Measured Adjusted Male Dead/tested Rat N/A 0 0/ Rat N/A 0 / Rat N/A 0 / Rat N/A 0 / Rat N/A 0 / Page of

8 0 0 Prior to exposing animals to known concentrations to determine the LC 0, rats were exposed to essentially saturated vapours for various time periods. From vapour pressure data, MacEwen and Vernot () considered that these exposures should result in calculated concentrations of approximately 0 ppm ( mg/m ). Exposure of groups of five rats to saturated vapours for, and hour periods, resulted in deaths of, and rats, respectively. The rats were hyperactive early in the exposure but by 0 minutes were exhibiting tonic convulsions, tremors, and prostration. Rats that survived two or more hours of exposure were paralyzed in the posterior half of the body. Even though some of these rats survived as long as days postexposure, they never regained use of this portion of the body. None of the paralyzed rats survived the -day postexposure observation period. Probit function The probit function and associated LC-values have been calculated using the DoseResp program (Wil ten Berge, 0) as Pr = a + b lnc with C for concentration in mg/m. Probit function Species a b n-value Duration (min.) Rat -.0. N/A LC 0 (mg/m ) %-C.I. Male 0 0 (0-0) MacEwen and Vernot () calculated a -hour LC 0 of 0 ppm (0 mg/m ) (% CI: - ppm (- mg/m )). No C t probit function could be calculated from these data alone. Page of

9 0 0 Study ID: C. Author, year: MacEwen and Vernot (); Kinkead et al. () Substance: Decalin Species, strain, sex: Mouse, CF-, female Number/sex/conc. group: 0 Age and weight: no information Observation period: days Evaluation of study quality* Criteria Comment Study carried out according to GLP GLP did not exist at the time Study carried out according to OECD OECD guideline 0 did not exist at the 0 guideline(s) time Stability of test compound in test No information atmosphere Use of vehicle (other than air) N/A Whole body / nose-only (incl. Whole body head/nose-only) exposure Type of restrainer N/A Pressure distribution No information Homogeneity of test atmosphere in No information breathing zone of animals Number of air changes per hour Number of air changes not specified; liter inhalation chamber Equilibration time (t) Insufficient information to calculate t Start of exposure relative to No information equilibration Actual concentration measurement Chamber concentrations were analysed using a hydrocarbon analyser Particle size distribution measurement N/A in breathing zone of the animals in case of aerosol exposure Assessment of Reliability C Study limited to one exposure duration, and more importantly, study includes only two test-concentrations. * Limited information concerning the study characteristics of this acute inhalation study is available. Although this acute inhalation study was used for concentration-ranging purposes for a 0-day repeated inhalation study, and was presented together with the results of this 0-day repeated inhalation study in a different report, also no specific details on study characteristics were presented in this report (MacEwen and Vernot ). Results Species Concentration (mg/m ) Exposure duration (min) Lethality Measured Adjusted Female Dead/tested Mouse 0 N/A 0 /0 Mouse N/A 0 /0 Prior to exposing animals to known concentrations to determine the LC 0, mice were exposed to essentially saturated vapours for various time periods. From vapour Page of

10 pressure data, MacEwen and Vernot () considered that these exposures should result in calculated concentrations of approximately 0 ppm ( mg/m ). Five of mice died after hours exposure to saturated vapours while none of 0 died after hour. Symptoms were similar to the rats with tonic convulsions and tremors. However, none of the survivors showed any paralysis as was seen in the rats. Probit function A probit function could not be derived. Page 0 of

11 0 0 Study ID: other C studies Gage (0) exposed male and female Alderley Park rats to decalin. Exposures were performed in inhalation chambers under dynamic atmosphere conditions. The test atmosphere was prepared by injecting a liquid at a known rate into a metered stream of air by means of a controlled fluid-feed atomizer. A single hour exposure to 000 ppm ( mg/m ) decalin resulted in mortality preceded by tremors and convulsions in animals (out of total animals (m+f)). Congestion of the lungs was reported as finding upon autopsy. Repeated (0x) hour exposures to 00 ppm (0 mg/m ) resulted in no adverse effects. MacEwan and Vernot () exposed five guinea pigs (strain and sex not specified) to ppm ( mg/m ) decalin for four hours. The guinea pigs were asymptomatic during the -hour exposure period and during the -day postexposure observation period. Smyth et al. () exposed male rats (strain not specified) for hours to 00 ppm ( mg/m ). Four out of six animals died. In a preliminary test the maximum time for inhalation of saturated vapours (not further specified) by rats without the occurrence of deaths was h. Page of

12 Appendix Reference list BUA (). Decahydronaphthalene. BUA-report, december. GDCh- Advisory Committee on Existing Chemicals (BUA) Chemiekaarten, e editie, Den Haag. TNO/SDU uitgevers 0 Gage J.C. The subacute inhalation toxicity of 0 industrial chemicals (0). Brit. J. Indus. Med, -. Gaworski C.L., Haun C.C., MacEwen J.D., Vernot C.H., Bruner R.H., Amster R.L., and Cowan M.J., Jr. (). A 0-day vapor inhalation toxicity study of decalin. Fundam. Appl. Toxicol., -. Kinkead E.R., Wolfe R.E., Buunger S.K., Doyle R.L. (). Acute inhalation toxicity of decalin in rodents. Acute Toxic Data (s),. MacEwen J.D. and Vernot E.H. (). Toxic hazards Research Unit Annual Technical Report: AMRL-TR-- Aerospace Medical Research Laboratory. Wright Patterson Air Force Base, Ohio. MacEwen J.D. and Vernot E.H. (). Toxic hazards Research Unit Annual Technical Report: AMRL-TR-- Aerospace Medical Research Laboratory. Wright Patterson Air Force Base, Ohio. NTP (00). NTP Technical Report on the Toxicology and Carcinogenesis studies of decalin (CAS No. --) in F/N rats and BCF mice and a toxicology study of decalin in male NBR rats (INHALATION STUDIES). January 00, National Toxicology Program, NTP TR, NIH Publication No. 0-. Sandmeyer, E.E. (). Alicyclic hydrocarbons. In Patty s Industrial Hygiene and Toxicology (G.D. Clayton and F.E. Clayton, Eds.), rd revised ed., Vol. B, pp. -. John Wiley and Sons, New York. RIVM. Interventiewaarden gevaarlijke stoffen. Ruijten M.W.M.M., J.H.E. Arts, P.J. Boogaard, P.M.J. Bos, H. Muijser, A. Wijbenga. Methods for the derivation of probit functions to predict acute lethality following inhalation of toxic substances. RIVM report Bilthoven, RIVM, 0. Smyth H.F., Carpenter C.P., Weil C.S (). Range-finding toxicity data: list IV. AMA Arch. Hyg. Occup. Med., -. Page of

The decision on actual implementation depends on the results of a further consequence analysis.

The decision on actual implementation depends on the results of a further consequence analysis. 00- allylamine interim TSD Probit function technical support document Date: February 0 Document id: 00-allylamine-interim Status: interim Author: drs. W. ter Burg, RIVM substance name CAS number Allylamine