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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
1987-10-28
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: This study is classified as reliable without restriction because it was performed in compliance with OECD guideline 414.
Justification for type of 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 Foots oils. This is based on the lack of activity observed in several similar substances.

Foots oils 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. Foots oils destined for widespread/consumer use are highly refined substances, they originate from a stream of Lubricating Base Oils that act as feedstocks for most of the operations that produce finished Foots oils. Only lubricating base oils that have been sufficiently refined i.e. they pass IP346 content ≤ 3 wt% are used to produce Foots oils. Foots oils have high paraffinic content and most of the PAHs (including 3 – 7 ring) are removed.

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 Foots oils are unlikely to exhibit adverse effects in reproductive toxicity (fertility and developmental) endpoints.
Foots oils predominantly have a typical carbon range of C12 to C50, we can gain information from the component carbon pools of Foots oils from the following sources:
• 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.
• Highly Refined Base Oils (which contain no PAHs and re predominantly C12 to C50)
• Lubricating base oils – these are used as feedstocks for the processes that make Foots oils but are less refined and it can be assumed they would have a worse toxicity profile. They have a typical carbon range number of C12 to C120.

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

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1987
Report Date:
1987

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Remarks:
Insufficient number of dams per group
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Test material form:
liquid: viscous
Details on test material:
Read Across to Other Lubricant Base Oils
This substance is similar to the feed to most of current dewaxing operations.

- Name of test material (as cited in study report): 100 SUS solvent refined base oil
- Substance type: lubricant base oil (IP 346 <3%)
- Lot/batch No.: CRU #84120
- Radiochemical purity (if radiolabelling): [1-14C]Octacosane
- Specific activity (if radiolabelling): 6.15 mCi/mmol
- Other: Density = 0.86 g/mL

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories (Kingston, NY)
- Age at study initiation: 10 and 8 weeks old
- Fasting period before study: No
- Housing: Dams were individually housed after mating.
- Diet (e.g. ad libitum): Ad libitum
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: December 17, 1985 to January 2, 1986

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 to 22
- Humidity (%): 40 to 60%
- Photoperiod (hrs dark / hrs light): 12 hours dark/12 hours light

Administration / exposure

Route of administration:
dermal
Vehicle:
unchanged (no vehicle)
Details on exposure:
TEST SITE
- Area of exposure: Intact dorsal surface
- Type of wrap if used: No wrap was used
- Time intervals for shavings or clippings: Animals were clipped on gestation day 0 and once weekly thereafter

REMOVAL OF TEST SUBSTANCE
- Washing (if done): No washing was performed
- Time after start of exposure: Test material was not removed after exposure.

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 1 cc of 125, 500, or 2000 mg/kg/day

USE OF RESTRAINERS FOR PREVENTING INGESTION: Yes, Elizabethan-style collars
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
No data reported.
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1:1
- Length of cohabitation: Cohabitation period lasted until 55 presumed pregnant rats were obtained.
- Verification of same strain and source of both sexes: No
- Proof of pregnancy: Females were examined every morning during mating for vaginal sperm plugs. The drop-pans under the animals cages also were checked for expelled vaginal plugs daily. Vaginal lavage fluid was examined for the presence of spermatozoa in those dams that exhibited a vaginal plug either in situ or in the drop-pan. Females with the presence of spermatozoa and a vaginal plug were considered to be at day 0 gestation and placed in individual housing units.
Duration of treatment / exposure:
The test material was applied on dose groups 2 through 4 on gestation days 0 through 19; a fifth dose group was used, in which dams were applied the base oil on gestation day 0-17. A base oil fortified with [1-14C]octacosane was administered on gestation day 18.
Frequency of treatment:
Daily
Duration of test:
The acclimation period started on 17 December, 1985. Visceral evaluations ended on August 27, 1987.
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 125, 500, and 2000 mg/kg/day
Basis:
other: dermal exposure
No. of animals per sex per dose:
Control group (0 mg/kg/day): 15 animals
Group 2 (125 mg/kg/day): 10 animals
Group 3 (500 mg/kg/day): 10 animals
Group 4 (2000 mg/kg/day): 15 animals
Group 5 (2000 mg/kg/day plus [1-14C]octacosene: 5 animals
Control animals:
yes, sham-exposed
Details on study design:
Groups 2 through 4 were administered 125, 500, 2000 mg/kg/day using a 1 cc syringe (calibrated in 0.01 cc). Dams were clipped on the dorsal surface, and the test material was dispensed evenly over the test site. Animals were fitted with Elizabethan-style collars. The control group was clipped and collared in a similar fashion. The dorsal skin of each rat was stroked with the tip of a 1 cc syringe, but no test material was applied. A fifth dose group was used, in which dams were applied the base oil on gestation day 0-17 at a dose level of 2000 mg/kg/day. A base oil fortified with [1-14C]octacosane was administered on gestation day 18.

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: At least once daily
- Cage side observations included pathosis, abortion, premature delivery, and/or death.

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: Yes
- Time schedule for examinations: Gestation days 0, 3, 6, 10, 13, 16, and 20

FOOD CONSUMPTION: Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes; gestation days 0-3, 3-6, 6-10, 10-13, 13-16, and 16-20
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs examined: Thoracic and abdominal cavities of animals in groups 1 through 4 were exposed and all organs were grossly examined.

OTHER: Clinical chemistry endpoints were also evaluated. Blood samples were collected at the time of sacrifice from the aorta of each rat. Clinical chemistry endpoints measured are presented in Table 1 below.

Dose group 5 was sacrificed by over-exposure to ether on gestation day 20. Blood placentae, and foetuses were collected. Placental and foetal samples were homogenized prior to combustion, while blood samples were combusted directly. 14C Radioactivity was determined in combusted samples via a liquid scintillation counter.
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Other: Live and dead foetuses
Fetal examinations:
- External examinations (anomalies, malformations, and variations): Yes: all per litter
- Soft tissue examinations (anomalies, malformations, and variations): Yes: half per litter
- Skeletal examinations (anomalies, malformations, and variations): Yes: half per litter
- Head examinations: No data
Statistics:
An ANOVA followed by Fisher's Exact or Dunnett's test was used to evaluated maternal biophase and caesarean section data. Foetal skeletal and visceral data were evaluated using Fisher's Exact test. Residue data was evaluated through a Student's t-test. Clinical chemistry data was evaluated using the F-test, which was employed to do an ANOVA on the serum data. The Student-Newman-Keul's multiple comparison test was then used. Differences between the control and treated animals were considered statistically significant if the probability of the differences being due to chance was less than 5%.
Indices:
Female mortality; viable female foetuses; viable male foetuses; and preimplantation loss
Historical control data:
No data reported.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
Dermal application of the lubricant base oil to pregnant rats during gestation produced slight dermal irritation at all dose levels. At these dosages, the lubricant base oil produced erythema and flaking of the skin at the site of application in a dose-dependent manner. One animal in the 500 mg/kg/day dose group had dermal oedema. However, no other signs of test material-related toxicity were observed.

Effect levels (maternal animals)

Dose descriptor:
LOAEL
Remarks:
Inferred LOAEL
Effect level:
125 mg/kg bw/day
Basis for effect level:
other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
There was no evidence of teratogenicity. There were no treatment-related changes observed during external, skeletal, or visceral evaluations.

Effect levels (fetuses)

Dose descriptor:
NOAEL
Remarks:
Inferred NOAEL
Effect level:
>= 2 000 mg/kg bw/day
Basis for effect level:
other: teratogenicity

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

Skin Irritation (number affected/number examined)

Observation

Dose Groups (mg/kg/day)

 

0

125

500

2000

Erythema

0/15

1/10

4/10

9/15

Flaking of Skin

0/15

2/10

2/10

4/15

Oedema

0/15

0/15

1/15

0/15

Applicant's summary and conclusion

Conclusions:
Dermal administration of the base oil did not adversely affect maternal reproductive performance, nor did it affect offspring survival or development.
Executive summary:

Justification for Read Across

This substance is similar to the feedstocks for most of current dewaxing operations that produce the finished paraffin and microcrystalline waxes. These lubricant base oil data may serve as the basis for a worst case assessment of the reproductive potential of paraffin and microcrystalline waxes and are summarised in this section.

In a developmental toxicity study, 100 SUS solvent refined base oil was administered to female Sprague Dawley rats dermally. There were five dose group. Groups 2 through 4 (10 dams/group in Groups 2 and 3; 15 dams/group in Group 4) were administered 125, 500, 2000 mg/kg/day using a 1 cc syringe (calibrated in 0.01 cc). Dams were clipped on the dorsal surface, and the test material was dispensed evenly over the test site. Animals were fitted with Elizabethan-style collars. The control group (Group 1; 15 dams/group) was clipped and collared in a similar fashion. For the control group, the dorsal skin of each rat was stroked with the tip of a 1 cc syringe, but no test material was applied. A fifth dose group (5 dams/group) was used, in which dams were applied the base oil on gestation day 0-17 at a dose level of 2000 mg/kg/day. A base oil fortified with [1-14C]octacosane was administered on gestation day 18.

Dermal application of the lubricant base oil to pregnant rats during gestation produced slight dermal irritation at all dose levels. At these dosages, the lubricant base oil produced erythema and flaking of the skin at the site of application in a dose-dependent manner. One animal in the 500 mg/kg/day dose group had dermal oedema.

There were no other signs of maternal toxicity. Serum components were not adversely affected by the test material. According to the Group 5 results, the test material metabolites were able to pass across the placenta, but did not bioacculmulate in the foetuses. A maternal LOAEL was not reported but can be inferred to be 125 mg/kg/day based on skin irritation.

There was no evidence of teratogenicity. There were no treatment-related changes observed during the external, skeletal, or visceral evaluations. Mean foetal weight and crown-rump lengths were comparable across all dose groups. A developmental/teratogenic NOAEL was not reported; however, it can be inferred that this value is 2000 mg/kg/day.

 

This study received a Klimisch score of 1 and is classified as reliable without restriction because this study is compliant with OECD Guideline 414.