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Key value for chemical safety assessment

Effects on fertility

Description of key information

In accordance with Section 1.2 of REACH Annex XI, testing does not appear to be scientifically necessary as the weight of evidence indicates no concern for reproductive (fertility and sexual function) effects from Kerosenes. This is based on the lack of activity observed in OECD 421 studies and human data as well as in similar substances.

A GLP 90-day repeat dose oral toxicity study combined with a reproductive study on a JP 8 jet fuel at up to 3000 mg/kg/day in males and 1500 mg/kg/day in females has been reported in IUCLID (Mattie 2000). Males were dosed for at least 70 days prior to mating with untreated females ; there were no treatment-related effects on reproduction or sperm parameters in males, even at the high dose of 3000 mg/kg/day. TheLOAEL for adult males rats was 750 mg/kg/day due to changes in clinical pathology, body weight and organ weights; clearly demonstrating systemic exposure.There were no effects on reproduction, gestation, or litter size in females who were dosed for 90-days prior to mating, and throughout mating, gestation and lactation; females were mated with untreated males. In females there was an increase in liver weight at over 750 mg/klg/day, again demonstrating systemic exposure. Accordingly, the reproduction and fertility NOAEL was 3000 and 1500 mg/kg/day in males and females, respectively.

 

Deodorised kerosene was assessed using a similar design to OECD (Organisation for Economic Cooperation and Development) Guideline 421 for reprotoxic or developmental effects in rats and has been reported in IUCLID (Schreiner 1997). The evaluation involved dermal exposure to up to 494 mg/kg/day for up to 8 weeks. No pathological effects were observed on reproductive organs and no anomalies were found in the first generation of pups. The authors concluded that the NOAEL for deodorised kerosene was >494 mg/kg/day.

 

An inhalation study exposed male Sprague-Dawley rats for 6 hours/day for 91 consecutive days to JP-8 Jet Fuel vapour at concentrations of 0, 250, 500 and 1000 mg/m3 (Witzmann et al., 2003). After exposure the rats were sacrificed and testis were dissected, solubilised, separated and analyzed for expression of testis proteins. The results of the protein analysis show that in exposed rats several testis proteins were increased and several testis proteins were decreased significantly as compared to the controls. The expression levels of the following proteins showed a dose-related increase: HsP86, nicotinic acetylcholine receptor alpha subunit, serum albumin and T-complex protein 1. However, it is unknown if the increased expression of these proteins is related to reproductive malfunctioning. The NOAEC based on these effects is greater than or equal to 1000 mg/m3.  

 

Some human data is available, in a study on exposure during aircraft maintenance (Lemasters at al. 1999) no effects on spermatogenic changes were observed. All mean Industrial Hygiene measures were below 6 ppm, which is less than 10% of the Occupational Safety and Health Administration standard for all chemicals except benzene. Sheet metal workers had the highest mean breath levels for both total solvents (24 ppb) and fuels (28.3 ppb). For most sperm measures, mean values remained in the normal range throughout the 30 weeks of exposure. When jobs were analyzed by exposure groups, some adverse changes were observed. The paint shop group had a significant decline in motility of 19.5% at 30 weeks. Internal dose measures, however, did not show a significant association with spermatogenic changes.

 

There are also two robust 2-generation reproductive studies (OECD 416) conducted with gas-to liquid products, a gas oil and a base oil (Boogaard et al, 2017). In both studies the test material was administered by oral gavage and in both studies, there was no effect on reproductive performance or gestation length and parturition of both the F0 and F1 parental generations. The reproductive toxicity NOEL for the gas oil was 750 mg/kg/day and for the base oil 1000 mg/kg/day; in both substances this was the highest dose tested. The gas oil contains branched and linear C8-C25 distillates and the base oil C18-C50 branched cyclic and linear distillates; these results indicate that the long chain hydrocarbons also present in Kerosenes are not associated with reproductive toxicity as there were no effects on fertility or reproductive function.

 

Hydrocarbon solvents, 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. (Sasol 1995).

Hydrocarbon solvents, 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. (ExxonMobil 1980).

 

Taken together it is considered that the above provides sufficient evidence to conclude that Kerosenes are unlikely to alter reproductive fertility or sexual function.

 

References

Peter J. Boogaard, Juan-Carlos Carrillo, Linda G. Roberts & Graham F. Whale (2017) Toxicological and ecotoxicological properties of gas-to-liquid (GTL) products. 1. Mammalian toxicology, Critical Reviews in Toxicology, 47:2, 121-144, DOI: 10.1080/10408444.2016.1214676 

 

Tsitou P, Heneweer M, Boogaard PJ. Toxicogenomics in vitro as an alternative tool for safety evaluation of petroleum substances and PAHs with regard to prenatal developmental toxicity.Toxicol in vitro 2015;29:299-307

 

Kamelia L, De Haan L, Ketelslegers HB, Rietjens IMCM, Boogaard PJ.In vitro prenatal developmental toxicity induced by some petroleum substances is mediated by their 3- to 7-ring PAH constituent via activation of the aryl hydrocarbon (Ah) receptor. Toxicol Lett 2019;315:64-76

Grace Lemasters, Donna Olsen, James Yiin, James Lockey, Rakesh Shukla, Sherry Selevan, Steve Schrader, Greg Toth, Donald Evenson, Gabor Huszar(1999). Male reproductive effects of solvent and fuel exposure during aircraft maintenance. Reproductive Toxicology Volume 13, Issue 3, May–June 1999, Pages 155-166.

Sasol 1995: A Combined Repeated Dose Toxicity Study With The Reproduction/Developmental Toxicity Screening Test In Sprague Dawley Rats By The Oral Route (study report), Testing laboratory: Instituto di Ricerche Biomediche, Rome, Italy, Report no: 1995. Owner company; SASOL ITALY, Report date: Jan 1, 1995

ExxonMobil 1980: A Dominant-Lethal Inhalation Study with MRD-78-25 and MRD-78-26 in Rats (study report), HSPA0225. Testing laboratory: Biodynamics Inc., East Millstone, NJ, Report no: 78-7150. Owner company; ExxonMobil Corp, Study number: 80MRL12, Report date: Jan 23, 1980

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Justification for read-across:

Kerosenes are considered to be UVCB substances, and are part of the continuum of petroleum substances originating from crude oil. The substances are categorised according to their chemical specification and refining history. When considering the information available for a particular petroleum category it is appropriate to consider if other categories can provide an insight into expected toxicity.  

Concawe hypothesises that higher tier toxicological effects such as genotoxicity, repeated dose systemic toxicity, reprotoxicity (developmental and fertility) and carcinogenicity are associated with the level and types of polycyclic aromatic hydrocarbons (PAHs). 

Polycyclic aromatic hydrocarbons (PAH) have a conjugated hydrocarbon ring structure and when they include other groups such as alkyl, nitro and amino groups and other elements such as nitrogen, sulphur or oxygen are known as poly cyclic aromatic compounds (PAC’s). PAH are of particular concern as historically certain PAH are considered to be associated with a number of health and environmental toxicities of which benzo[a]pyrene is the best-known example. PAH and PAC are essentially referring to the same molecules, although PAC is a more inclusive term as these contain hetero atoms (atoms other than carbon or hydrogen). However, heterocyclics are sufficiently low in petroleum products so that the two terms can be used inter-changeably. Toxicity is hypothesised to be attributed to interaction with the Aryl Hydrocarbon (Ah) receptor; further details on this hypothesis are available in Tsitou (2015), Kamelia (2019).

 

It is therefore predicted that Kerosenes are unlikely to exhibit adverse effects in reproductive toxicity (fertility and developmental) endpoints.

Kerosenes predominantly have a typical carbon range of C6 to C17, we can gain information from the component carbon pools of Kerosenes from the following sources:

·        Data on kerosenes themselves

·        Gas-to-Liquid products (GTL) which are synthetic hydrocarbons produced from natural gas using a Fisher-Tropsch process. The synthetic crude is refined to a range of products similar to those from natural crude oil but they are essentially free of unsaturated or aromatic constituents (ie PAHs) and also no sulphur-, oxygen- or nitrogen-containing constituents are present. 

·        Hydrocarbon solvents – representative of aliphatic content of kerosenes (predominantly C9 to C14).

 

References

Tsitou P, Heneweer M, Boogaard PJ.Toxicogenomics in vitro as an alternative tool for safety evaluation of petroleum substances and PAHs with regard to prenatal developmental toxicity.Toxicol in vitro 2015;29:299-307

 

Kamelia L, De Haan L, Ketelslegers HB, Rietjens IMCM, Boogaard PJ.In vitro prenatal developmental toxicity induced by some petroleum substances is mediated by their 3- to 7-ring PAH constituent via activation of the aryl hydrocarbon (Ah) receptor. Toxicol Lett 2019;315:64-76

Effects on developmental toxicity

Description of key information

In accordance with Section 1.2 of REACH Annex XI, testing does not appear to be scientifically necessary as the weight of evidence indicates no concern for developmental toxicity effects from Kerosenes. This is based on the lack of activity observed in several similar substances.

 

We have the following information available which can help address concerns about developmental toxicity;

In a reproductive/developmental toxicity screening study reported in IUCLID (Schreiner, et al., 1997), 10 Sprague Dawley rats/sex/group were treated dermally with hydrodesulfurised kerosine for a minimum of 6 hours,7 days/week beginning 14 days premating, during the 14-day mating period and through 20 days of gestation. Dosage equivalents were 0, 165, 330 and 494 mg/kg/day. There is no offspring LOAEL, based on the lack of any effects noted in the offspring. The offspring NOAEL is greater than or equal to 494 mg/kg/day. This was the highest dose tested in the study.

 

In a developmental toxicity study (Cooper and Mattie, 1996), undiluted JP-8 jet fuel was administered to 30 Sprague-Dawley (Crl:CD) rats/dose by gavage at 0, 500, 1000, 1500, or 2000 mg/kg bw/day from days 6 through 15 of gestation. There was a significant decrease in foetal weight in both male and female foetuses with 1500 and 2000 mg/kg/day; maternal weight was also decreased at these dose levels. The test compound did not significantly increase the incidence of malformations or variations compared to the control nor was the sex ratio altered; foetal evaluation included soft tissue and skeletal examinations. The developmental LOAEL is 1500 mg/kg/day, based on reduced foetal weight. The developmental NOAEL is 1000 mg/kg/day.

 

In a pre-natal developmental study (API, 1979b), 20 female presumed-pregnant rats per group were exposed to 106 or 364 ppm kerosine vapour for 6 hours each day on days 6 through 15 of gestation. The animals were sacrificed on day 20 of gestation; foetal evaluation included soft tissue, head and skeletal examinations. There were no effects noted on either the dams or the foetuses. The NOAEC is greater than or equal to 364 ppm, based on the lack of effects and no LOAEC can be determined.

 

Other studies also confirm the lack of developmental toxicity in similar petroleum streams;

Hydrocarbon solvents, 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. (Sasol 1995).

Hydrocarbon solvents, 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. (ExxonMobil 1980).

 

In addition, there are two Gas-to Oil oral prenatal development toxicity study, which can be used to inform us about the non-PAH components of Kerosenes, a gas oil and a base oil (Boogaard et al 2017). In both studies the test material was administered by oral gavage and in both studies there was no effect on foetal development.  The developmental toxicity NOEL for the gas oil was 750 mg/kg/day and for the base oil 1000 mg/kg/day; in both substances this was the highest dose tested. The gas oil contains branched and linear C8-C25 distillates and the base oil C18-C50 branched cyclic and linear distillates; these results indicate that the long chain hydrocarbons also present in Kerosenes are not associated with developmental toxicity.

 

These studies demonstrate that analytically similar substances in the carbon range of C9-16, plus GTL products with no PAH’s, have no effect on foetal development following systemic exposure. In the absence of any triggers with this substance, and similar (even less refined) substances further testing on vertebrate animals for this substance can be omitted.

 

Taken together it is considered that the above provides sufficient evidence to conclude that Kerosenes are unlikely to alter foetal development.

References

Peter J. Boogaard, Juan-Carlos Carrillo, Linda G. Roberts & Graham F. Whale (2017) Toxicological and ecotoxicological properties of gas-to-liquid (GTL) products. 1. Mammalian toxicology, Critical Reviews in Toxicology, 47:2, 121-144, DOI: 10.1080/10408444.2016.1214676

Sasol 1995: A Combined Repeated Dose Toxicity Study With The Reproduction/Developmental Toxicity Screening Test In Sprague Dawley Rats By The Oral Route (study report), Testing laboratory: Instituto di Ricerche Biomediche, Rome, Italy, Report no: 1995. Owner company; SASOL ITALY, Report date: Jan 1, 1995

ExxonMobil 1980: A Dominant-Lethal Inhalation Study with MRD-78-25 and MRD-78-26 in Rats (study report), HSPA0225. Testing laboratory: Biodynamics Inc., East Millstone, NJ, Report no: 78-7150. Owner company; ExxonMobil Corp, Study number: 80MRL12, Report date: Jan 23, 1980

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no adverse effect observed
Study duration:
subchronic
Species:
rat
Additional information

Justification for read-across:

Kerosenes are considered to be UVCB substances, and are part of the continuum of petroleum substances originating from crude oil. The substances are categorised according to their chemical specification and refining history. When considering the information available for a particular petroleum category it is appropriate to consider if other categories can provide an insight into expected toxicity. 

 

Concawe hypothesises that higher tier toxicological effects such as genotoxicity, repeated dose systemic toxicity, reprotoxicity (developmental and fertility) and carcinogenicity are associated with the level and types of polycyclic aromatic hydrocarbons (PAHs). 

Polycyclic aromatic hydrocarbons (PAH) have a conjugated hydrocarbon ring structure and when they include other groups such as alkyl, nitro and amino groups and other elements such as nitrogen, sulphur or oxygen are known as poly cyclic aromatic compounds (PAC’s). PAH are of particular concern as historically certain PAH are considered to be associated with a number of health and environmental toxicities of which benzo[a]pyrene is the best-known example. PAH and PAC are essentially referring to the same molecules, although PAC is a more inclusive term as these contain hetero atoms (atoms other than carbon or hydrogen). However, heterocyclics are sufficiently low in petroleum products so that the two terms can be used inter-changeably. Toxicity is hypothesised to be attributed to interaction with the Aryl Hydrocarbon (Ah) receptor; further details on this hypothesis are available in Tsitou (2015), Kamelia (2019).

 

It is therefore predicted that Kerosenes are unlikely to exhibit adverse effects in reproductive toxicity (fertility and developmental) endpoints.

Kerosenes predominantly have a typical carbon range of C6 to C17, we can gain information from the component carbon pools of Kerosenes from the following sources:

·        Data on kerosenes themselves

·        Gas-to-Liquid products (GTL) which are synthetic hydrocarbons produced from natural gas using a Fisher-Tropsch process. The synthetic crude is refined to a range of products similar to those from natural crude oil but they are essentially free of unsaturated or aromatic constituents (ie PAHs) and also no sulphur-, oxygen- or nitrogen-containing constituents are present. 

·        Hydrocarbon solvents – representative of aliphatic content of kerosenes (predominantly C9 to C14).

 

References

Tsitou P, Heneweer M, Boogaard PJ.Toxicogenomics in vitro as an alternative tool for safety evaluation of petroleum substances and PAHs with regard to prenatal developmental toxicity.Toxicol in vitro 2015;29:299-307

 

Kamelia L, De Haan L, Ketelslegers HB, Rietjens IMCM, Boogaard PJ.In vitro prenatal developmental toxicity induced by some petroleum substances is mediated by their 3- to 7-ring PAH constituent via activation of the aryl hydrocarbon (Ah) receptor. Toxicol Lett 2019;315:64-76

Justification for classification or non-classification

Based on a weight of evidence and category read-across approach, there is insufficient data to classify kerosenes as toxic for reproduction under Annex VI of EU CLP Regulation (EC No. 1272/2008).