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Administrative data

Key value for chemical safety assessment

Effects on fertility

Additional information

Alchisor TAL 123 can be characterised according to three constituents: Hydrocarbons C11-C14, n-alkanes, isoalkanes, cyclics, aromatics (2-25%), undecan-1-ol and dodecan-1-ol. As defined in the Read-across Justification Document in section 13, data provided for these constituents when considered together is representative of Alchisor TAL 123 and suitable for assessment purposes. Study data for each constituent has been evaluated. In a protective approach the most sensitive study result from across the three constituents has been identified and used to address the hazard endpoint in question.

A number of constituent-specific studies and read across entries are provided in support of this toxicity to reproduction assessment for Alchisor TAL 123. A single reproductive screening test alongside 3 read across entries is provided in support of the toxicity to reproduction of Hydrocarbons C11-C14, n-alkanes, isoalkanes, cyclics, aromatics (2-25%). A combined repeat dose and reproductive/developmental toxicity screening test on dodecan-1-ol is provided as the key study for dodecan-1-ol (Hansen 1992). In addition this study is presented as read across data and key information in support of the toxicity of reproduction of undecan-1-ol. Further supporting information is provided in support of undecan-1-ol.

Hydrocarbons C11-C14, n-alkanes, isoalkanes, cyclics, aromatics (2-25%)

The Hydrocarbons C11-C14, n-alkanes, isoalkanes, cyclics, aromatics (2-25%) components of Alchisor TAL 123 were examined for reproductive toxicity in a reproduction / developmental toxicity screening test (OECD TG 421). Hydrocarbons C11-14, n-alkanes, isoalkanes, cyclics, aromatics (2-25%) hydrocarbon fluids were administered by inhalation at a dose of 0,100, and 300 ppm to groups of rats. It was concluded that Hydrocarbons C11-14, n-alkanes, isoalkanes, cyclics, aromatics (2-25%) hydrocarbon fluids did not induce reproductive toxicity in the offspring or in the parental animals. Therefore, the NOAEL was determined to be >=300 ppm.

As read across evidence, reproductive toxicity studies are available for undecane and C9 aromatics hydrocarbon fluids. Undecane was examined for reproductive toxicity in a reproduction / developmental toxicity screening test (OECD TG 421). Undecane was administered by oral gavage to rats at doses of 0,100,300 and 1000mg/kg/day. It was concluded that C9-14 Aliphatics (<2% Aromatics) hydrocarbon fluids did not induce reproductive toxicity in the offspring or in the parental animals. Therefore, the NOAEL was determined to be >=1000 mg/kg/day (MHW 1996).

C9 Aromatics hydrocarbon fluids were examined for reproductive toxicity in a two-generation reproductive study. The C9 Aromatics hydrocarbon fluids represent the aromatic constituency of the C9-14 aliphatics (2-25% aromatic) hydrocarbon fluids. C9 Aromatics hydrocarbon fluids were administered to mice by inhalation at test atmospheres of 0,100, 500 and 1500ppm. It was concluded that C9-14 Aliphatics (<2% Aromatics) hydrocarbon fluids did not induce reproductive toxicity in the offspring or in the parental animals. Therefore, the NOAEC (inhalation) for reproductive toxicity for the P, F1, and F2 generation was >=1500 ppm (McKee 1990). Based on this study and the lack of systemic toxicity and read-across data, C9-C14 aliphatic, 2-25% aromatic hydrocarbon fluids, are not expected to be reproductive toxicants.

Also, the standard reproductive toxicity requirements for Hydrocarbons C11-C14, n-alkanes, isoalkanes, cyclics, aromatics (2-25%) have been assessed with a combination of alternative tests (i.e. 1-generation reproductive toxicity test/OECD TG 415 + repeat-dose toxicity tests that incorporate reproductive tissue evaluations such as sperm morphology, spermatogenesis and estrous cycle in females). Weight of evidence analysis of the overall reproductive toxicity testing strategy for category 3 and 8 (consisting of Hydrocarbons, C9-C14, aliphatics, <2% aromatics) solvents is attached in section 13 of IUCLID.

READ ACROSS DATA: JP-8 Fuel (C9-C16 Aliphatics, 25% Aromatics; Read-across from cat 003)

There were several studies located for the structurally analogous test material, JP-8 fuel. JP-8 fuel was examined for reproductive toxicity in a 70 day male (plus an additional 20 -day mating period) and in a 90 day female one-generation reproductive toxicity study (OECD TG 415). For the male reproductive toxicity study, the reproductive NOAEL >= 3000 mg/kg/day for male rats, which was the highest dose tested. For the female reproductive toxicity study, the reproductive NOAEL >= 1500 mg/kg/day for female rats, which was the highest dose tested. The F1 (fetus) NOAEL = 750 mg/kg/day based on a decrease in body weight that correlated to a decrease in maternal body weight.

READ ACROSS DATA: Stoddard Solvent IIC (C9-C14 Aliphatics, 25% Aromatics; Read-across from cat 003)

A 90 -day inhalation repeat-dose study (OECD TG 413) was located for this test substance. The study evaluated sperm parameters such as number of spermatid heads/testis, per gram testis, per cauda and per gram cauda and epididymal spermatozoal motility. Cauda, epididymis and testes were weighed also. Estrous cycle in females were evaluated. No adverse effects were noted for the assessed parameters. NOAEC for fertility in males and females was >= 2200 mg/m3 which was the highest dose tested

READ ACROSS DATA: Decalin (C10 cyclics)

A 90 -day inhalation repeat-dose study (OECD TG 413) was located for this test substance. The study evaluated sperm parameters such as number of spermatid heads/testis, per gram testis, per cauda and per gram cauda and epididymal spermatozoal motility. Cauda, epididymis and testes were weighed also. Estrous cycle in females were evaluated. No adverse effects were noted for the assessed parameters. NOAEC for fertility in males and females was >= 400 ppm which was the highest dose tested.

SUPPORTING INFORMATION: C9-14 aliphatics (<2% aromatic)

C9-14 aliphatics (2-25% aromatic) hydrocarbon fluids were examined for reproductive toxicity in a reproduction / developmental toxicity screening test (OECD TG 421). C9-14 aliphatics (2-25% aromatic) hydrocarbon fluids were administered by inhalation at a dose of 0,100, and 300 ppm to groups of rats. It was concluded that C9-14 aliphatics (2-25% aromatic) hydrocarbon fluids did not induce reproductive toxicity in the offspring or in the parental animals. Therefore, the NOAEL was determined to be >=300 ppm (1720 mg/m3).

C9-C14 aliphatic, < 2% aromatic hydrocarbon fluids were examined for reproductive toxicity in a 28 day combined repeated dose toxicity study with the reproduction / developmental toxicity screening test (OECD TG 422). C9-C14 aliphatic, < 2% aromatic hydrocarbon fluids were administered oral gavage at a dose of 0, 25, 150, or 1000 mg/kg/day to groups of Sprague-Dawley rats. It was concluded that C9-C14 aliphatic, < 2% aromatic hydrocarbon fluids did not induce reproductive toxicity in the parental animals and no effects on the endocrine system were observed. Therefore, the NOAEL was determined to be >=1000 mg/kg bw/day.

C9-C14 aliphatic, < 2% aromatic hydrocarbon fluids were examined in a reproduction / developmental toxicity screening test (OECD TG 421). C9-C14 aliphatic, < 2% aromatic hydrocarbon fluids were administered by oral gavage at a dose of 0 (vehicle), 100, 300, 1000 mg/kg/day to groups of Sprague-Dawley rats. It was concluded that C9-C14 aliphatic, < 2% aromatic hydrocarbon fluids did not induce reproductive toxicity in the parental animals and no effects on the endocrine system were observed. Therefore, the NOAEL was determined to be >=1000 mg/kg bw/day.

Based on this study and the lack of systemic toxicity, C9-C14 aliphatic, < 2% aromatic hydrocarbon fluids, are not expected to be reproductive toxicants.

Dodecan-1-ol

A combined repeat dose and reproductive/developmental toxicity screening study reported a lack of effects on the reproductive organs of male and female rats receiving dodecan-1-ol (NOAEL > 2000 mg/kg/bw) (Hansen 1992, rel; 2). A read across feeding study reported a lack of effects on the reproductive organs of rats receiving 1 -hexanol (NOAEL 1127 mg/kg) (Scientific Associates Inc., 1966, rel; 2). No adverse effects were noted at any of the dose levels administered during the study.

Chronic and sub-chronic toxicity studies have shown that long chain alcohols (LCA) are of low toxicity. Furthermore, combined repeated-dose studies with developmental endpoints, as well as reproductive and developmental studies showed no effects at the highest dose tested.

Undecan-1-ol

A read across combined repeat dose and reproductive/developmental toxicity screening study reported a lack of effects on the reproductive organs of rats receiving 1 -dodecanol (NOAEL 2000 mg/kg/bw) (Hansen 1992, rel; 2). This study also reported a NOAEL for developmental effects to be 2000 mg/kg/bw.

Members of the aliphatic alcohol category (C6-C22 as defined in the Long Chain Alcohols SID Initial Assessment Report (SIAM 2006)) are not expected to impair fertility. This conclusion is based on a weight of evidence approach using data from reproductive screening studies (C12 (dodecan-1-ol), C18 (octadecanol)), a fertility study (C22 (docosanol), together with a lack of effect on the reproductive organs in sub-chromic repeat dose studies over the range of linear and essentially linear alcohols. Based on this it is concluded that both dodecan-1-ol and undecan-1-ol is not expected to impair fertility.

The most sensitive study identified across the 3 constituents of Alchisor TAL 123 for reproductive toxicity has been reported in a study with Hydrocarbons C11-C14, n-alkanes, isoalkanes, cyclics, aromatics (2-25%) with an inhalation NOAEC >300ppm (equivalent to 1720mg/m3). This reliable (Klimisch score 1) OECD 421 comparable study reported pregnancy rates, implantation rate, and implantation efficiency as comparable between exposure groups and negative controls. Studies evaluated for bothundecan-1-oland dodecan-1-ol have reported endpoints that are less sensitive. As a consequence of this study information Alchsior TAL 123 is determined to have a NOAEC for reproductive screening >300ppm.


Short description of key information:
The most sensitive endpoint for reproduction toxicity has been determined in an inhalation administration reproduction/developmental toxicity screening test (OECD 421) with Hydrocarbons C11-C14, n-alkanes, isoalkanes, cyclics, aromatics (2-25%) hydrocarbons fluids. In a reliable study (Klimisch score 1) a NOAEC for reproductive toxicity was reported as >300ppm (1720mg/m3). It should be noted that the test item did not induce reproductive or developmental toxicity in the offspring or the parental animals.
Further, regarding the constituent substance, Hydrocarbons, C11-14, n-alkanes, isoalkanes, cyclics, aromatics (2-25%), a weight of evidence justification covering reproductive toxicity data gaps for category 3 solvents (C9-C14 aliphatics, <2% aromatics) is provided and relies on the following study data:

KEY STUDIES
READ ACROSS DATA:

Repeat-dose study with evaluation of estrous cycle and sperm morphology (OECD TG 413) of Stoddard Solvent IIC - NOAEC for fertility in males/females >= 2200 mg/m3 (highest dose tested)

Repeat-dose study with evaluation of estrous cycle and sperm morphology (OECD TG 413) –of Decalin - NOAEC for fertility in males/females >= 400 ppm (highest dose tested)

JP-8 Fuel
(C9-C16 Aliphatics, 25% aromatics) - One-Generation Reproduction Toxicity Study (OECD TG 415) - Male Fertility Test – Oral Administration - 90d prior to mating, the NOAEL >=3000 mg/kg/day
(C9-C16 Aliphatics, 25% aromatics)
One-Generation Reproduction Toxicity Study (OECD TG 415) - Female Fertility Test – Oral Administration - the NOAEL >=1500 mg/kg/day

Effects on developmental toxicity

Description of key information
The most sensitive endpoint for developmental toxicity has been determined in an inhalation administration reproduction/developmental toxicity screening test (OECD 421) with Hydrocarbons C11-C14, n-alkanes, isoalkanes, cyclics, aromatics (2-25%) hydrocarbons fluids. In reliable study (Klimisch score 1) a NOAEC for developmental toxicity was >300ppm (1720mg/m3).
Further, regarding the constituent substance Hydrocarbons, C11-14, n-alkanes, isoalkanes, cyclics, aromatics (2-25%), a weight of evidence justification covering 2-generation reproductive toxicity data gaps for category 3 solvents (C9-C14 aliphatics, <2% aromatics) is provided and relies on the following study data:
OECD Guideline 414 (Prenatal Developmental Toxicity Study) - C9-C12 normal, iso-, cyclics; 2-25% Aromatics. No treatment-related adverse effects to maternal and fetal development. NOAEC for maternal and developmental toxicity was > 300 ppm (highest dose tested).
OECD Guideline 414 (Prenatal Developmental Toxicity Study) - C9-C11 Isoalkanes, cyclics; < 2% Aromatics. - There was no evidence of maternal or fetal toxicity at either exposure level of Hydrocarbons, C9-C11, normal, isoalkanes, cyclics, < 2% aromatics. Based on these results, both the maternal and developmental NOAECs were greater than or equal to 900 ppm (highest dose tested)
OECD Guideline 414 (Prenatal Developmental Toxicity Study) - JP-8 fuel - Fetal weights were reduced at the highest dose tested which was secondary to maternal toxicity. Overall NOAEL was 1000 mg/kg/day
OECD Guideline 414 (Prenatal Developmental Toxicity Study) - C10-C12 iso-alkanes; < 2% Aromatics - There was no evidence of maternal or fetal toxicity at either exposure level tested. Based on these results, both the maternal and developmental NOAELs were greater than or equal to 900 ppm (>= 5220 mg/m^3).
Additional information

Alchisor TAL 123 can be characterised according to three constituents: Hydrocarbons C11-C14, n-alkanes, isoalkanes, cyclics, aromatics (2-25%), undecan-1-ol and dodecan-1-ol. As defined in the ‘Approach Justification Document’ section 13, data provided for these constituents when considered together is representative of Alchisor TAL 123 and suitable for assessment purposes. Data in support of each constituent has been evaluated. In a protective approach the most sensitive study result from across the three constituents has been identified and used to address the hazard endpoint in question.

A reliable (Klimisch 1) developmental study is provided in support of the developmental toxicity evaluation of the Hydrocarbons C11-C14, n-alkanes, isoalkanes, cyclics, aromatics (2 -25%). The key study for both undecan-1-ol and dodecan-1-ol is a combined repeat dose and reproductive/developmental toxicity screening test on dodecan-1-ol in rats (Hansen 1992). In the case of undecan-1-ol this is further supported by guideline comparable supporting studies. Adequate reliable data is available for each constituent. Therefore using a protective approach the dataset is a reliable adequate basis for Alchisor TAL 123 assessment purposes.

Hydrocarbons C11-C14, n-alkanes, isoalkanes, cyclics, aromatics (2-25%)

Hydrocarbons C11-14, n-alkanes, isoalkanes, cyclics, aromatics (2-25%) hydrocarbon fluids are not developmental toxicants. In a developmental study, pregnant dams were exposed by inhalation to 0, 100, or 300ppm test atmospheres of Hydrocarbons C11-14, n-alkanes, isoalkanes, cyclics, aromatics (2 -25%) fluids during gestational days 6 through 15. No adverse maternal or fetal effects were noted at any dose level. Thus, Hydrocarbons C11-14, n-alkanes, isoalkanes, cyclics, aromatics (2-25%) hydrocarbon fluids did not produce any maternal or fetal toxicity or any developmental effects in rats. Based on the study results, the maternal and developmental toxicity NOAEL is >= 300 ppm. Based on this study and the lack of systemic toxicity, Hydrocarbons C11-14, n-alkanes, isoalkanes, cyclics, aromatics (2-25%) hydrocarbon fluids, are not expected to be developmental toxicants.

Also, the following data is used in a weight of evidence approach for Category 3 hydrocarbon solvents to address developmental toxicity data requirements for Hydrocarbons C11-14, n-alkanes, isoalkanes, cyclics, aromatics (2-25%).

READ ACROSS DATA: Hydrocarbons, C9-C12, n-, iso-, cyclics; 2-25% Aromatics

A segment II inhalation teratology study was conducted in Sprague-Dawley rats with a C8-C13 mixed aliphatic/aromatic solvent containing 19% aromatics (CAS RN 64742-82-1) (EBSI, 1979c). In this study, pregnant female rats (20/dose group) were exposed to 0, 100, and 300 ppm of test material for 6 hours per day on days 6 through 15 of gestation. This study included a chamber-exposed negative control and an acetylsalicyclic acid positive control (400 mg/kg/day by gastric intubation from days 6 to 15). Parameters evaluated included the following: maternal mortality, pregnancy rate, body weight gain, physical observations and necropsy observations; corpora lutea and uterine implantation data; fetal size, sex ratios and ossification variation data; and fetal external, soft tissue and skeletal malformation data.

No mortality occurred during the study. No treatment-related physical observations were observed. Treated females gained more weight than chamber-exposed controls during the post-dosing interval. Pregnancy rates were comparable to chamber-exposed controls. The mean number of corpora lutea was significantly decreased in the 300 ppm dose group but was not considered to be a treatment-related effect since ovulation occurred prior to initiation of treatment. An increase in implantation efficiency was observed in treated groups but is not considered indicative of an adverse effect. The number of live fetuses, resorption sites and the incidence of dams with one or more resorption sites were comparable with controls. A few gross lesions were observed at necropsy but no treatment-related effects were indicated.

Mean crown-rump distances (both sexes) were considered comparable between the chamber-exposed and treated groups. Although some statistically significant differences were observed in crown-rump distances between these same groups, the differences were slight with no apparent dose-response pattern and were not considered to be treatment-related. Sex ratio was unremarkable. The incidence of fetuses with ossification variations was comparable to chamber-exposed controls. No treatment-related effects were observed for external, soft tissue and skeletal evaluations of fetuses recovered from treated females.

In summary, under the conditions of this test, the C8-C13 mixed aliphatic/aromatic solvent containing 19% aromatics was neither embryotoxic nor teratogenic in the rats. The NOAEC for maternal and developmental toxicity was 300 ppm.

READ ACROSS DATA: Hydrocarbons, C9-C11, n-, iso-, cyclics; < 2% Aromatics

A Prenatal Developmental Toxicity Study equivalent or similar to OECD Guideline 414 with Hydrocarbons, C9-C11, normal, isoalkanes, cyclics, < 2% aromatics (CAS RN 64742-48-9). The test material was administered to pregnant female Sprague-Dawley rats by inhalation exposure to vapor concentrations of 0, 300 or 900 ppm, 6 hours/day during gestation days 6 to 15 to assess developmental toxicity following guidelines similar to OECD 414. Included in this study was a negative control (chamber exposed) group and a positive control group that was treated via gastric intubation on gestational days 6-15 with 400mg/kg/day of acetylsalicylic acid. All surviving females were sacrificed on Day 21 of gestation and fetuses examined for external, soft tissue and skeletal malformations.

All fetal survival, size and sex data for groups treated with test material were considered comparable to negative control data. Slight delays or variation in the normal ossification process were observed in treated animals. However, such variations are common as the time of normal ossification can vary and the frequencies of the variations were comparable to those of the variations observed in the control animals. The incidence of fetuses with external malformations and incidences of litters containing malformed fetuses in the groups treated with test material were considered comparable to the control data. No significant difference in the incidence of visceral malformations was observed in the treated groups. The incidence of fetuses with soft tissue malformations in groups treated with test material was comparable to the negative control.

In the positive control group, the percentage of live fetuses and mean fetal weights were significantly lower than the negative control and the percentage of resorbed fetuses was significantly higher than control. The incidence of fetuses with ossification variations was significantly higher than the control value. The incidence of fetuses with soft tissue malformations was significantly higher in the positive control treated group than the negative control.

Pregnancy rate, mortality, body weight gain and gross postmortem observations were unaffected by treatment. Hydrocarbons, C9-C11, normal, isoalkanes, cyclics, < 2% aromatics had no effect on reproductive endpoints, fetal size, sex distribution, ossification variations, or fetal examination endpoints. Thus, there was no evidence of maternal or fetal toxicity at either exposure level of Hydrocarbons, C9-C11, normal, isoalkanes, cyclics, < 2% aromatics. Based on these results, both the maternal and developmental NOAECs were greater than or equal to 900 ppm (5220 mg/m3).

READ ACROSS DATA: JP-8 Fuel (C9-C16 Aliphatics, 25% Aromatics) JP-8, a less refined C8-C16 hydrocarbon stream with an approximate aromatic content of 22-25% can be used as a read across for mixed C9-C14 aliphatic solvents produced to narrower specifications. This substance was tested in a classical developmental toxicity test in Sprague-Dawley rats under a study design similar to OECD 414. Timed pregnant rats were given daily doses from days 6-15 of gestation at treatment levels of 0, 500, 1000, 1500 or 2000 mg/kg/day. The rats were sacrificed on gestational day 20 and the uterine contents were examined. The principal effects were maternal; 9/30 dams died in the high dose group and body weight gains were reduced in the 1000 and 1500 mg/kg/day groups. The maternal no effect level was 500 mg/kg/day. In the fetal examinations, there were no effects on fetal survival but fetal weights were reduced in the 1500 and 2000 mg/kg/day groups; secondary to maternal toxicity. There were no differences in rates of malformation or variations between groups. The overall developmental no effect level was 1000 mg/kg/day.

READ ACROSS DATA: C10-C12 Isoalkanes; < 2% Aromatics

A C10 -C12 isoalkane (< 2% aromatics) was administered to pregnant female rats by inhalation exposure to vapor concentrations of 300 or 900 ppm, 6 hours/day during gestation days 6 to 15 to assess developmental toxicity. Included in this study was a negative control (chamber exposed) group and a positive control group that was treated via gastric intubation on gestational days 6-15 with 400mg/kg/day of acetylsalicylic acid. All surviving females were sacrificed on Day 21 of testation and fetuses examined for external, soft tissue and skeletal malformations. Pregnancy rate, mortality, body weight gain and gross postmortem observations were unaffected by treatment. Treatment at either dose level had no effect on reproductive endpoints, fetal size, sex distribution, ossification variation, or fetal examination endpoints. Thus, there was no evidence of maternal or fetal toxicity at either exposure level tested. Based on these results, both the maternal and developmental NOAELs were greater than or equal to 900 ppm (>= 5220 mg/m^3).

Dodecan-1-ol

A combined repeat dose and reproductive/developmental toxicity screening study reported a lack of effects on the reproductive organs of male and female rats receiving dodecan-1-ol (NOAEL > 2000 mg/kg/bw) (Hansen 1992, rel; 2). This study also reported a NOAEL for developmental effects to be 2000 mg/kg/bw. A read across feeding study reported a lack of effects on the reproductive organs of rats receiving 1 -hexanol (NOAEL 1127 mg/kg) (Scientific Associates Inc., 1966, rel; 2). No adverse effects were noted at any of the dose levels administered during the study. Based on the weight of evidence from other alcohols across the category and this reliable screening study it is concluded that dodecan-1-ol is unlikely to be a developmental toxicant in the absence of maternal toxicity.

Undecan-1ol

On the basis of a read across provided in the form of the combined repeat dose and reproductive/developmental toxicity screening study with dodecan-1-ol presented above, the NOAEL for developmental effects following exposure to undecan-1-ol is determined to be 2000mg/kg.Representative data are available for the subcategory of linear alcohols, covering the low (C6, C8, C9), intermediate (C10, C12) and high (C18, C22 and higher) carbon chain lengths of this class. For the essentially linear alcohols, the key data are derived from the supporting substances isoamyl alcohol and C7-11 alcohol [CAS 85566-14 9], consisting of C7, C9 and C11 alcohol (65% linear). The available test data indicate that for both linear and essentially linear alcohols there is no evidence of foetotoxicity in the absence of maternal toxicity and supports the conclusion that undecyl alcohols are not expected to be developmental toxicants in the absence of maternal toxicity.

The most sensitive study identified across the 3 constituents of Alchisor TAL 123 for developmental toxicity has been reported in a study with Hydrocarbons C11-C14, n-alkanes, isoalkanes, cyclics, aromatics (2-25%) with an inhalation NOAEC >300ppm (equivalent to 1720mg/m3). This reliable (Klimisch score 1) OECD 421 comparable study reported no adverse effects due to exposure to the test substance in either dams or foetuses. No treatment related malformation effects were noted in the foetuses. Studies evaluated for both undecan-1-ol and dodecan-1-ol have reported endpoints that are less sensitive. As a consequence of this study information Alchisor TAL 123 is determined to have a NOAEC for developmental screening >300ppm.

Justification for classification or non-classification

These findings do not warrant classification of Alchisor TAL 123 as a reproductive or developmental toxin under the new Regulation (EC) 1272/2008 on classification, labelling and packaging of substances and mixtures (CLP) or under the Directive 67/518/EEC for dangerous substances and Directive 1999/45/EC for preparations.