Lauric acid, monoester with propane-1,2-diol

Endpoint summary

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

sub-chronic toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Study period:

08 July 2015 to 28 January 2016

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Study performed in an accredited GLP compliant laboratory according to current OECD test Guidelines

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH
[Please provide information for all of the points below. Indicate if further information is included as attachment to the same record, or elsewhere in the dataset (insert links in 'Cross-reference' table)]

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
A read-across approach has been suggested based on the metabolism of the common structure of propylene glycol fatty acid esters. Read-across is implemented from already existing data from testing on Dapro FX511, on metabolism products (fatty acid and propylene glycol) and on propylene glycol monolaurate.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)

Source chemical:

Dapro FX 511
EC Number: 285-503-5
CAS Number: 85114-00-7

Target chemical:

RM1004755:
Einecs No. 248-315-4
CAS No. 27194-74-7

See read-across justification report in section 13

3. ANALOGUE APPROACH JUSTIFICATION
A matrix of data has been created using the Dapro FX511 REACH dossier, read-across document for aquatic tox from Dapro FX510 (source) to Dapro FX511 (target), a HPV test plan for the glycol esters of the aliphatic esters chemicals (including Propylene glycol, monostearate (CAS 1323-39-3)) and a Petition to include propylene glycol monolaurate into 7 CFR 205 (constituent of RM1004755).
See read-across justification report in section 13

4. DATA MATRIX
Data matrix is given in read-across justification report in section 13

- Name of test material (as cited in study report): SER-AD FX 511
- Physical state: liquid (colourless, slightly viscous)
- Analytical purity: no data; the purity of the test material was the responsibility of the sponsor
- Storage condition of test material: room temperature

Reason / purpose for cross-reference:

read-across source

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

slight effect of treatement at 1000 mg/kg/day

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

no effects observed

Description (incidence and severity):

There were no ophthalmic findings that were considered to be related to treatment

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

not examined

Behaviour (functional findings):

no effects observed

Description (incidence and severity):

Sensory reactivity responses, grip strength and motor activity were unaffected by treatment

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

An increase in absolute and body weight adjusted liver and kidney weights in males and females
given 500 or 1000 mg/kg/day, attaining statistical significance in the majority of the body weight
adjusted groups.

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Changes in the kidneys of male rats only considered test-item related

Histopathological findings: neoplastic:

no effects observed

Details on results:

Test item-related effects on the cortex of the kidney consisted of minimal to moderate hyaline droplets, as intracytoplasmic droplets and eosinophilic inclusion round bodies surrounded by a clear halo on males receiving 250 mg/kg/day or above, although one control male was also observed with this change. Many xenobiotics bind to alpha-2u-globulin and decrease effectiveness of lysosomal degradation in male rats. These findings are likely to be alpha-2u-globulin nephropathy, which is a sex and species specific entity. In addition, minimal to slight tubular basophilia with interstitial fibrosis was recorded in males given 250, 500 and 1000 mg/kg/day, which was predominantly characterized by multifocal clusters of basophilic tubules, nuclear crowding, tubular dilatation, interstitial inflammator y cell infiltrates and thickening of the basal membranes (demonstrated by the PAS stain), which in one male progressed to tubular necrosis. These findings correlated with increased kidney weights and increased levels of urea in males given 500 or 1000 mg/kg/day after 13 weeks of treatment. The test item changes observed in the kidneys were considered adverse in males given 500 or 1000 mg/kg/day as the findings reflected dose-dependent changes that correlated with elevated urea and increased
kidney weights.
In the liver, minimal centrilobular eosinophilia/hypertrophy was observed in males and females given 1000 mg/kg/day and females given 500 mg/kg/day. This finding correlated with increased liver weights in both males and females after 13 weeks of treatment and was expected for this compound class. The test item, RD 15134 (2-Ethylhexanoic acid, monoester with propane 1,2–diol) is related to ethyl hexanoic acid, which is considered a peroxisome proliferator that typically produces hypertrophy of the centrilobular hepatocytes due to the increase of the volume of peroxisomes, accompanied by lipid reduction and increased liver weights (Sundberg et al., 1994; Keith et al., 1992). There are considerable species differences in sensitivity to peroxisomal proliferation and humans appear to be less susceptible to many peroxisomal proliferators (Chevalier et al., 1998). The test-item related changes in the liver were not considered adverse as these changes represented an adaptive response.
The changes in the thyroid are considered secondary to the induction of liver metabolism enzymes. There was an increased incidence of minimal follicular cell hypertrophy observed in all treated groups, with a higher incidence in the males. The incidence in the males given 500 mg/kg/day was slightly higher than 1000 mg/kg/day, which reflects a degree of biological variation between treated males. Some studies have shown that peroxisome proliferators lead to enzymatic induction in the liver, which can induce increased breakdown of thyroid hormones and also displace thyroid hormones from serum carrier proteins. This will consequently lead to lower circulating levels of thyroid hormones, resulting in a release from negative feedback inhibition and compensatory increased secretion of TSH from the pituitary gland, resulting in follicular cell hypertrophy in the thyroid (Richardson and Klaasen, 2010, Miller et al., 2001). Again, there are considerable species differences in thyroid hormone synthesis, transport and metabolism between rodents and humans. The thyroid changes are not considered adverse as the follicular cell hypertrophy
reflects a rodent specific adaptive response.
In the absence of histopathological correlate the following changes were not considered to be of toxicologically significance; the decrease in haematocrit, haemoglobin concentration and red blood cells counts in males receiving 250, 500 or 1000 mg/kg/day, a decrease in haematocrit and h
aemoglobin concentration in females at 1000 mg/kg/day. In addition, there was no correlate for low mean cell haemoglobin and mean cell volume in females receiving 500 or 1000 mg/kg/day and changes were seen in neutrophils, lymphocytes, and basophils, with an associated reduction in
overall low white blood cell count or the low large unstained stain cell counts or shorter activated partial thromboplastin time in females receiving 1000 mg/kg/day. Similarly, total protein and albumin concentration were low in treated males, with an associated high A/G ratio in high dose males were not considered to be toxicologically significant.

Dose descriptor:

NOAEL

Effect level:

250 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: Based primarily on the changes seen in the kidney

Remarks on result:

other: Based primarily on the changes seen in the kidneys

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

female

Basis for effect level:

other: No test substance effects seen at 1000 mg/kg bw/day the highest dose level tested

Remarks on result:

not determinable due to absence of adverse toxic effects

Critical effects observed:

yes

Lowest effective dose / conc.:

500 mg/kg bw/day (actual dose received)

System:

urinary

Organ:

kidney

Treatment related:

yes

Dose response relationship:

yes

Relevant for humans:

not specified

Conclusions:

It is concluded that oral administration of RD 15134, a coalescing agent, to Sprague-Dawley Crl:CD(SD) rats at 250, 500 or 1000 mg/kg/day for 13 weeks was relatively well-tolerated at doses in males at 250 mg/kg/day and in females up to 1000 mg/kg/day. In males, a dose of 500 mg/kg/day or above resulted in hyaline droplets and tubular basophilia with interstitial fibrosis in the kidney, with an associated increase in kidney weight and urea concentration.
It is therefore considered that the no-observed-adverse- effect-level (NOAEL) was 250 mg/kg/day in males, based primarily on the changes seen in the kidneys, and 1000 mg/kg/day in females.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

250 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test) conducted in 2015 with no deficiencies and assigned Klimisch 1

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

It is concluded that oral administration of RD 15134 (the read-across analogue for RM1004755), also a coalescing agent, to Sprague-Dawley Crl:CD(SD) rats at 250, 500 or 1000 mg/kg/day for 13 weeks was relatively well-tolerated at doses in males at 250 mg/kg/day and in females up to 1000 mg/kg/day. In males, a dose of 500 mg/kg/day or above resulted in hyaline droplets and tubular basophilia with interstitial fibrosis in the kidney, with an associated increase in kidney weight and urea concentration. It is therefore considered that the no-observed-adverse-effect-level (NOAEL) was 250 mg/kg/day in males based primarily on the changes seen in the kidneys and 1000 mg/kg/day in females.

Justification for classification or non-classification

RM1004755 is not classified for specific organ toxicity, repeated exposure, as the NOAEL of the read-across analogue (RD 15134) in male rats is 250 mg/kg/day, according to CLP classification.